Research Article
May Growth Hormone be Useful for Regenerative Therapies With Stem Cells?
Jesús Devesa* and Pablo Devesa
Corresponding Author: Jesus Devesa, Medical Center Foltra, Travesia de Montouto 24, 15886-Teo, Spain
Received: November 8, 2017; Accepted: November 30, 2017; Published: November 26, 2018;
Citation: Devesa J & Devesa P. (2018) May Growth Hormone be Useful for Regenerative Therapies With Stem Cells? Stem Cell Res Th, 3(1): 98-112.
Copyrights: ©2018 Devesa J & Devesa J. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
 

This study was designed for analyzing the current concepts about GH and stem cells treatments in some acquired neurological injuries (cerebral palsy, stroke, traumatic brain injury) and myocardial infarction. From this analysis we can conclude that while it seems that GH plays an important therapeutic role, it is also clear that stem cells are a promising therapeutic alternative; althoughthere is still a need to clarify what is the optimal window of time for their administration after each one of these damages, as well as the best route of administration in each case and the most appropriate number of stem cells that should be administered. Since the largest number of implanted stem cells do not integrate into the damaged tissue, but rather exert their actions by releasing a number of trophic factors, most of them physiologically induced by GH, and die within a few days after being administered, studies must be done to try to genetically modify these stem cells in GMP facilities so that they can replace and repair the damaged tissues. Here we also provide evidences indicating that GH administration may be of utility for increasing the number of endogenous, and exogenously administered, stem cells allowing their survival, differentiation and migration to the damaged area. In adition, we suggest that each individual may have their stem cells stored in a cell bank, so that he could receive them early after any of these injuries.  

 

Keywords: Growth hormone, Stem cells, Cerebral palsy, Stroke, Traumatic brain injury, Cardiac infarction

 

Abbreviations: GH: Growth Hormone; IPSCs: Induced Pluripotent Stem Cells; HSCs: Hematopoietic Stem Cells; MSCs: Mesenchymal Stem Cells; NSCs: Neural Stem Cells; GMP: Good Manufacturing Practice; TBI: Traumatic Brain Injury; CSCs: Cardiac Stem Cells; EPCs: Endothelial Progenitor Cells

 

INTRODUCTION

In this review we will analyze whether the administration of Growth hormone, concomitantly with the implants of stem cells and/or subsequently to these, could improve the results of stem cells therapies in four pathologies (cerebral palsy, stroke, traumatic brain injury and myocardial infarction), that due to their high prevalence, morbidity and mortality require the use of new therapeutic strategies.

We first analyze the therapeutic effects of GH, given alone, and then the current knowledge about stem cells therapies. Lastly we will consider whether GH might be useful for being administered conjointly with stem cells for improving the effects of these therapies.

Growth Hormone (GH)

Classically GH has been considered a metabolic hormone, produced by the pituitary gland, responsible for the longitudinal growth of the organism until the end of puberty. However, this quite simple concept has been changed in the last years because of a number of findings indicating that the hormone plays in the human body quite more and different important effects far beyond than those previously established [1]. Moreover, apart of its well known pituitary production and release for playing an endocrine role, we know since years ago, that both the hormone and its receptor (GHR) are expressed in practically all tissues, if not in all of them, in which the hormone plays an auto/paracrine role [2-5]. GH and brain

Particularly important is the expression of GH, and its receptor, in neural stem cells where it seems to play a key role in the proliferation, differentiation, migration and survival of these neural precursors [6,7], therefore suggesting that GH might be an important factor for brain repair after an injury, a hypothesis already proposed many years ago [8]. Apart of the crucial role that the GH/IGF-I system plays during the brain development in embryos [9,10], the expression of GH in neurogenic regions of the postnatal brain, as Figure 1 shows, has been demonstrated in a number of already ancient studies [11,12]. These and many other studies led to the possibility that GH administration could be of utility, in humans and some laboratory animals, in the repair of brain after an injury (cerebral palsy, stroke or traumatic brain injury), a possibility already demonstrated by a number of studies from ours and other groups [13-34]. In fact, in rats, the expression of GH and its receptor is markedly upregulated after brain injury, suggesting that the hormone may enhance neuroregeneration after brain injury [35]. However, the positive effects of GH administration on brain repair, inducing the proliferation on stem cells existing in neurogenic niches of the brain (Figure 2), could only be observed in laboratory animals in which brain injury had previously been induced [26,35,36] or in studies in vitro [28,37,38].

GH and cardiovascular system

GH plays also very important effects on the cardiovascular system. It has been shown that an endothelial dysfunction exists in GH-deficient (GHD) patients leading to a lesser edothelium-dependent vasodilation [39]. This is most likely produced by a lesser nitric oxide (NO) production by the endothelium [40]. The administration of GH restores the affected endothelial function and increases the production of NO [39-41], and decreases the oxidative stress associated to the endothelial damage [39]. Moreover, GH administration is able to reverse the intima-media thickness [5,39]. From this and other data it is likely that GH can play a very important role as an inductor of the mechanisms physiologically involved in recovery after a cardiovascular injury. Recent pre-clinical studies support such a possibility. For instance, it has been proven, in rats, that treatment with GH after myocardial infarction enhanced angiogenesis and myofibroblast activation and improves post-infarction remodeling [42]. This was also observed in another study in which GH was delivered from an alginate scaffold injected around the ischemic area of myocardium after coronary ligation, leading to a clear amelioration of ventricular function and exhibiting long-term antiarrhytmic potential [43].

Stem cells

Since the late 70's, stem cells therapies have been a promising strategy for the treatment of many diseases, including cancer, AIDS, heart infarctions, stroke, traumatic brain injuries, lung affectations, cerebral palsy, and a number of neurodegenerative and eye diseases, blood diseases, liver failure, diabetes, colitis, cartilage degenerations, among many others.

Stem cell therapies had their origin in older therapies, such as blood transfusion, bone marrow and organ transplantation and in vitro fertilization. Improvement of these therapies soon started to require ex vivo processing before their use as a pharmaceutical product, moving from "transplantation" to "stem cell therapy".

There are many potential forms of stem cells therapies depending on the finalaim of the therapeutic strategy. In general we can envisage three main different aims when a stem cell therapy strategy is designed:

1.       To restore the cell population that has been lost or damaged. These include regeneration of blood vessels, brain, heart, liver, cartilage and bone.

2.       To modify immune responses to either enhance (anti-tumor) or to lower (autoimmune diseases) T and B cell responses.

3.       To restore normal functions of tissues or cells through paracrine secretions of soluble factors.

To date, according to the information provided by the U.S. National Library of Medicine (http://www.clinicaltrials.gov, November 2017), there are 4565 studies for stem cells therapies in a really high number of different diseases, including a rare form of Parkinsonism as it is the Progressive Supranuclear Palsy.

The different cell types used in the treatments currently carried out can come from the same patient (autologous) or can be derived from a donor (allogeneic). Depending on the country and its specific health laws, the origin of the cells used may be quite different; for instance, pluripotent stem cells (human embryonic stem cells or induced pluripotent stem cells (IPSCs) [44] and even stem cells obtained from parthenogenetically activated human oocytes [45]) are not allowed for its use in stem cells therapies in Europe but in other ountries, such as China and USA. However, due to ethical reasons and/or technical difficulties together with the possibility of inducing important adverse side effects (i.e., tumorigenicity in the case of human embryonic stem cells, and perhaps IPSCs too), during the last years the field of stem cells therapies is progressing towards the clinical use of multipotent adult stem cells obtained from many different sources. These adult stem cells are found in all adult tissues and they physiologically participate in the regeneration of the tissues where they belong. This is the case, for example, of hematopoietic stem cells (HSCs), mesenchymal stem cells (MSCs) and neural stem cells (NSCs).

HSCs

HSCs are able to migrate to the bone marrow and give rise to all hematopoietic cell types when injected intravenously; therefore they are useful for treating primary immunodeficiencies and hemoglobinopaties, but also for treating cancer, neurodegenerative and cardiac disorders. Of course these treatments would be ideally performed by using autologous cells, but HSCs (originally characterised in humans as CD34+, Lin- cells) from healthy HLA-compatible donors orgene-modified allogeneic HSCs could also be used. This would impede the appearance of graft versus host disease.

CD34 is a cell surface antigen, first discovered in a cell surface glycoprotein [46,47] that is early expressed in hematopoietic and vascular-associated tissue [48]. It is an adhesion molecule, but also facilitates cell migration [48], including chemokine-dependent migration of eosinophils, hence facilitatingthe development of allergic asthma [49]. Moreover, HSCS don't express mature blood cells markers, such as Lin (lineage-positive cells). Therefore, HSCs can be easily identified and isolated by flow cytometry from other blood cells in the sample, by staining them with specific markers for CD34 and Lin.

MSCS

MSCs are very attractive stem cells for use in clinic because: 1) they are able to give rise to different tissue types and therefore could, at least theoretically, be used for tissue repair; 2) they are able to modulate the immune system and can therefore be used as a way to decrease immune responses; 3) MSCs are quite easy to be isolated and expanded.

MSCs can be obtained from many different tissues, such as: bone marrow, adipose tissue, dental pulp, synovial membranes, Wharton's jelly, umbilical cord blood, liver tissue, etc. They have to be positive for CD105, CD90 and CD73, negative for MHC-II, CD11b, CD14, CD31, CD34 and CD45 and also express low levels of MHC-I.

MSCs have shown important therapeutic benefits in several pathologies including graft versus host disease, diabetes, cardiovascular diseases, bone and cartilage diseases, neurological diseases, liver and lung diseases, Crohn disease [50] and recently they have been proved to be useful in spinal cord injuries [51]. In addition, the ability of MSCs to differentiate into epitelia-like cells have suggested that they could be useful to contribute to wound repair when administered locally [52-55]. Moreover, a special type of MSCs, the Muse cells (Multilineage-differentiating stress-enduring) can be obtained from cultured bone marrow-mesenchymal stem cells showing important repair effects after being transplanted into mice with neurological diseases because they differentiate into neurons and connect with host intact neurons [56].

NSCs

NSCs transplantation has been studied in animal models as an attempt to repair brain and spinal cord injuries. However, of all the possible neural sources of NSCs only the olfactory ensheathing cells, obtained from the olfactory mucosa, are readily accessible and capable of lifelong regeneration. They have been used in laboratory animals with spinal cord injuries, but it is still not clear that these cells will produce significant positive effects in humans with similar spinal cord injuries. However, a recent work in rats demonstrated that NSCs expanded from the postnatal subventricular zone engrafted into the hippocampus of young and aged animals leading to the production of newly born neurons and even to the appearance of new neurogenic niches in non-neurogenic regions, generating new neurons for a high period of time after grafting [57,58]. This opens new perspectives for treating a number of brain pathologies, including neurodegenerative diseases, but specially for recovering the lost recent memory and abnormal neurogenesis after hippocampal injury.

Recently, it has been reported that primitive NSCs (pNSCS) can be easily obtained from human induced pluripotent stem cells (hPSCS) [59]. These NSCs express neural stem cells markers (Pax6, Sox2 and Nestin and are negative for Oct4). They present the advantage that can be expanded for multiple passages, and can be differentiated into neurons, astrocytes and oligodendrocytes, which allow them to be useful for treating different neural diseases. Moreover, and depending on the brain area they can give origin to different neuronal subtypes, including dopaminergic, GABAergic and motor neurons. This, together with the fact that only 7 days are needed for inducing hPSCS into pNSCs opens new therapeutic perspectives which still have to be explored in clinical trials. 

After this brief review about the sources and types of stem cells able to be infused in human patients, we will focus on four situations that, due to their high prevalence in the population and their extreme severity, require rapid action in terms of stem cell treatments.

Cerebral palsy (CP): Cerebral palsy is a non-progressive disease occurring in 2-2.5/1.000 live births, and is mainly characterized by motor disorders, although many of the children also suffer cognitive affectations, speech impairments or absence of language, hearing and visual affectations (these range from squint to absolute blindness), seizures, drooling, etc. CP is usually produced by damage to the developing brain, because of many causes, including maternal infections (such as those frequently produced by cytomegalovirus) or toxic habits, but also is produced by asphyxia before birth, hypoxia/ischemia at birth, brain trauma during labor and delivery or prematurity leading to a brain white matter affectation known as Periventricular Leukomalacia and parenchymal venous infarction complicating germinal matrix/intraventricular hemorrhage. Other causes are related to post-natal infections (i.e., meningitis) or traumas. In any case, given the age at which it occurs, CP represents a a great public health problem and tremendous economic costs for the patient's family and the state. According to a study carried out in Denmark, the cost of CP throughout the life of one of these patients is around $1.2 million of US dollars for men and about $1.1 million of US dollars for women [60].

Due to the magnitude of this problem in terms of both personal and familiar affectations, and social costs, the need exists for urgently finding a therapeutic solution for children with CP. 

Stroke: In Spain, as in many other developed countries, cerebrovascular diseases are the second main cause of mortality in the population, and the first in women [61]. In 2011, the Hospital Morbidity Survey of the National Statistics Institute reported 116.017 strokes and 14.933 transient ischemic episodes; this implies an incidence of 252 strokes and 32 ischemic episodes per 100.000 people. These data presumably will increase in the coming years due to the habits of life and the aging of population.

There are two types of stroke, ischemic and hemorrhagic. Ischemic strokes represent about 86% of strokes [62] and are the consequence of blocked or narrowed arteries because the progression of a thrombus or the existence of atherosclerosis which leads to increased stiffness and endothelial dysfunction. In turn, hemorrhagic strokes occur because of blood leaking into the brain, usually produced by increased blood pressure and the rupture of an existing aneurysm (usually leading to a subarachnoidal hemorrhage, which presents a very high morbidity and mortality) or a congenital arteriovenous malformation. As is logical, the severity of the stroke, independently of its origin, requires an inmediate intervention, different depending on whether the stroke is ischemic or hemorrhagic, but after the acute period remnant sequels exist. These depend on the brain area affected, but the most severe and difficult to be corrected are: hand paralysis, aphasia and loss of recent memory.

Traumatic brain injury (TBI): In the case of TBI, the annual incidence of new cases in Spain was estimated at 200 per 100.000 inhabitants, 40% of them being due to traffic accidents (data from 2006).

It is clear that, as it occurs in stroke, the high social and sanitary impact that TBI produces requires urgent measures in terms of prevention but also of recovery of the neural injuries suffered once the critical episode has been resolved in the hospital.

TBI is quite different from stroke, since the brain injuries produced after TBI usually are diffuse and progressive, while in stroke they are generally restricted to the area affected; the main problem associated with TBI is the development of a diffuse axonal injury, an event that can lead to instant death, or progress during days or weeks due to axonal shearing, and subsequent progressive brain inflammation, leading the patient to a vegetative coma or permanent disabilities. This is a main reason for treating to develop new therapeutic strategies in order to prevent these terrific consequences.

Myocardial infarction: This occurs when the blood supply to a part of the heart decreases or is fully interrupted because of the blockade of a coronary artery produced by the rupture of an atherosclerotic plaque. The result is heart damage that can lead to the sudden death of the patient. Urgent treatmet is therefore needed, with anticoagulants, such as aspirin, or percutaneous coronary intervention for trying to push open the affected coronary or perform a thrombolysis. Later, a stent can be placed in the location in which the coronary artery had been occluded, or a coronary bypass surgery can be carried out. However, none of these have been reported to recover the damaged muscle heart, rather they try to prevent the appearance of a new episode. Hypertension, smoking, obesity, increased LDL/HDL cholesterol ratio, sedentary life and excessive alcohol intake are risk factorsfor developing a myocardial infarction along the life.

 

 

 

 

DISCUSSION

After a brief description of the effects of GH at the neural and cardiovascular levels, as well as the main types of stem cells used in a series of treatments, and a schematic description of what four important pathologies mean, we will now analyze whether it would be feasible to combine the administration of GH, given its own effects and those exerted by the high number of trophic factors whose expression is induced by this hormone, with stem cell treatments in these pathologies, to try to achieve better results.

Cerebral palsy

While many recent studies analyzing the effects of stem cells treatments describe positive, although rather modest, results in cerebral palsy [63-68], most of them use cord blood stem cells, a treatment that is impossible to be carried out in Spain, because national health laws do not allow to store the umbilical cord of any newborn for its own use. Rather, these umbilical cords are stored for public use in any patient who could need it in a future; for example for cancer treatments once the HLA compatibility has been checked. This does not exclude that if the delivery has taken place in a private hospital, the family can request the collection of the cord to be stored in a private stem cells bank located in another country.

Some of the aforementioned studies utilized BMCs, but there were no clear differences in terms of the results obtained [69], perhaps because only some symptoms of the disease were improved after the therapies with stem cells. Moreover, it is unclear what should be the optimal route of administration or when it should take place or the minimum number of cells that should be administered. In any case, independently of their origin, stem cells need to be isolated and expanded in a GMP facility until reaching the needed amount for an adequate infusion and effectivity. This is not a major problem in the case of children under two years of age, more or less, a period of time during which the brain is still developing and has a great plasticity. However, it seems logical that an early intervention (after prematurity or perinatal hypoxia/ischemia) will reduce the brain damage and the recovery of it will be easier.In fact, we have been able to fully recover the brain of children with CP due to prematurity or perinatal hypoxia/ischemia,by treating him with GH as early as 16 days of age, after a cardiac arrest in utero of 20 min due to massive bleeding produced by Vasa previa (Figure 3) or in some other CP children who began to be treated during the first two years of life. In turn, older CP children in whom spasticity and motor disorders are well established experience lesser improvements when receiving GH and neurorehabilitation [70]. Therefore, it would be useful to study whether a combination of GH and stem cells therapies would produce more benefits to these older CP children, especially if we take into account that data from our group indicate that at least 70% of children with CP lack normal GH secretion [71].

Stroke

During the last years many studies analyzed the efficiency of the application of human adult stem cells from different sources (bone marrow, umbilical cord, adipose tissue, even menstrual blood, among others) for the recovery of the disturbed neuronal circuitry and disruption of the blood-brain-barrier after stroke [72-83]. These are only a small but representative sample of the high number of published articles about stem cells therapies for the treatment of stroke. The results have been controversial regarding the efficacy of this type of therapy. Most likely the finding of significant improvements or, on the contrary, the lack of beneficial effects depends on multiple factors, such as: the time elapsed between stroke and treatment, the via of administration of stem cells (intravenous, intra-arterial, intrathecal) and, perhaps, the age of the patients at which they are treated, because the reparative properties of the brain decrease while aging.

Regarding the time elapsed after the stroke occurred and the treatment with stem cells starts, a clinical trial administering intravenous MSCs in the acute phase of stroke has being carried out in UK and USA [79], without sigificant improvements observed at 90 days in neurological outcomes, and another one is commencing in many european countries including different Spanish hospitals. However, a recent clinical trial performed in Hong Kong in patients who had suffered cerebral haemorrhage one year before being treated with intravenous injections of autologous MSCs showed improvements of motor disabilities and cognitive impairments over a year after being treated [84].

While along the Introduction we have described many positive effects regarding the use of different types of stem cells for treating very complicated pathologies, a main problem, such as the integration and differentiation of these cells for repairing the damaged brain remains unsolved, at least in human patients. In fact, after a stroke, only a few number of exogenously administered stem cells integrated into the neural networks of recipients, while the majority of implanted cells die few time after being administered [85]. Even more, a minor fraction of surviving cells after being implanted is differentiated into astrocytes, but not into neurons [85]. Despite this, significant neurological recoveries have been reported, suggesting that they had to be due to the fact that the implanted stem cells release several neurotrophic growth factors [86], cytokines and immuno-modulators which would enhance the neurogenesis, that quickly is stimulated after a brain damage, and the generation of new blood vessels, reducing the neuroinflammation, and promoting the formation of new synaptic connections. This means that the main action of stem cells therapies for neurovascular regeneration after a stroke is based on its trophic support to the ischemic brain [87], mainly activating the neurons surrounding the damaged area (penumbra area), or, as recently described, inducing endogenous NSCs towards neuronal differentiation [88]. However, once again we have to remind that GH not only induces adult neurogenesis, but also induces the exppression of many neurotrophic factors, such as IGF-I, Erythropoietin (EPO), EGF, bFGF, BDNF, VEGF, and the release of a number of cytokines; in addition, the hormone promotes an increased turnover of important neurotransmitters [1], therefore mimicking the action of transplanted stem cells, while increasing their survival via Pi3K/Akt. On these bases, it is reasonable to assume that a combination of a treatment with GH and stem cells would produce better results at the time of treating a stroke with stem cells transplants (Figure 4)Traumatic brain injury

Due to its nature, TBI is lesser able to be treated with a local application of stem cells during the acute phase of the injury [89]. However, a number of preclinical studies indicate that administration of MSCs seem to be effective for brain repair after TBI in rats [90-104]. Despite these data, few studies have been done, until now, in human patients. In fact, when seeking for these studies on the website Clinicaltrials.gov, only five can be found. Three of them have been completed (one in children) and two are still recruiting patients (adult TBI Phase 2b).

In 2013, Tian et al. [105] reported the results of autologous bone marrow MSCs administration by lumbar puncture in 97 patients in the subacute stage of TBI. Interestingly, 24 of these patients were in persistent vegetative state and 11 of them showed significant improvements in consciousness after the treatment, while 27 of 73 patients with severe motor disorders also showed improvements in motor functions. They concluded that this kind of therapy is safe and effective, and also, as it seems to be logic, that young patients improved better than older ones. Another very important and also logical conclusion was that this therapy has to be applied early in the subacute stage of TBI for obtaining better results. More recently, an intravenous autologous bone marrow MSCs was shown to decrease the needs of intense treatment for decreasing intracranial pressure, the severity of brain injury and duration of neurointensive cares in children early receiving these stem cells after TBI [106]. These positive results have been postulated to be due to the effect of stem cells on the neuroinflammation that TBI produces. Another recent study in three patients suffering neurological sequelae after difusse axonal injury, showed that the intrathecal administration of autologous MSCs resulted in improvements of their neurological situation and a diffuse and progressive increase in the cerebral metabolism of glucose, as reflected by positron emission tomography (PET) [107]. Given that glucose is the main nutrient for neurons, this result clearly indicates that brain activity improved after the intrathecal administration of MSCs.

But, again, similar results occur when treating TBI with GH. We were the first to use this hormone (December 2002) at a very early stage of a TBI that produced diffusse axonal injury, traumatic subarachnoidal hemorrhage, multiple fronto-temporal and intraventricular bleeding and brainstem damage; fortunately, the patient had a very good recovery and eight months after his TBI produced by a car accident, he went back to his University studies and he reached the degree of European PhD and lives a fully normal life. We published it 11 years later (25, Case 1). Hence, GH might also be useful for treating TBI with stem cells transplants, helping these stem cells to survive, differentiate and release neurotrophic factors. Moreover, GHD is a common finding in TBI patients.

Myocardial infarction

In 1999 it was published, in rats, that autologous bone marrow cells transplanted into ventricular tissue damaged by an induced myocardial injury, produced 3 weeks before the stem cells transplant, induced angiogenesis and formed cardiac-like muscle cells improving myocardial function [108]. Since this pioneering study, many publications reported conflicting data about the potential of stem cells on regenerating contractile myocardial tissue after a myocardial infarction. However, in 2003 it was reported that in the human adult heart exists a subpopulation of replicating myocytes (CSCs) able to act in normal hearts and pathological cardiac situations [109]. That is, as it occurs in the brain, the adult heart contains multipotent stem cells able to self-renewing, producing myocytes, smooth muscle, and endothelial cells. This opened a new therapeutic strategy for reduce the mortality of ischemic cardiomyopathy (Figure 5).

However, three years later, the same group communicated that in response to different forms of stress, these CSCs acquire a senescent phenotype, thus losing their functional properties as reparative agents [110]. In order to avoid this problem, these authors proposed the search of mechanisms able to produce the activation of CSCs in situ and to clarify the mechanisms responsibles for the senescence to prevent or reverse its presentation [110].

CSCs have been successfully isolated from biopsies of human myocardium and expanded ex vivo without any lost of its potential for differentiating into cardiomyocytes and vascular cells [111], therefore allowing the autologous transplantation back into the heart mediating, together with the resident CSCs, myocardial regeneration to a significant degree.

These studies may explain the fact that intramyocardial injection of MSCs overexpressing the survival factor Akt may significantly repair infarcted myocardium in rats and improve cardiac function, as early as 3 days after the injection, despite that only a small number of MSCs differentiated into cardiomyocytes [112]. It seems to be clear that in addition of the survival role that Akt plays [113], cytokines and growth factors released by the impanted MSCs contribute to the results obtained in that study [112]. In addition, timing of intracoronary transplantation in acute myocardial infarction is another key factor for positive outcomes, as a recent meta-analysis of 34 randomized controlled trials shows [114]. Curiously, the ideal window of time for this therapy ranges from 3 to 7 days, rather than within 24 h after the acute myocardial infarction, as one would think. Another key factor for positive outcomes is the number of MSCs administered, no lesser than 108-109 [115].

Despite these promising previous studies, the current situation is still far from being clear. A number of preclinical and clinical studies have analyzed the potential of endothelial progenitor cells (EPCs) and CSCs for repairing cardiovascular diseases, but while some of these studies show improvements in left ventricular ejection fraction in patients with acute myocardial infarction, other results have been poor or no significant clinical benefit has been observed in many cases [116].

Another source of stem cells, possibly useful for being used after a cardiac infarction, is the adipose tissue surrounding the heart. From this tissue MSCs can be isolated, and when injected intramyocardially in postinfarcted mice and rats enhance myocardial vascularization, reduce the infarct size and express cardiac and endothelial markers [117]. However, these stem cells have not yet been tested in clinical studies [118].

GH plays a direct function on myocardial growth and heart functionality during the fetal development [119] and induces the expression of specific contractile proteins. The hormone also regulates cardiac metabolism, by increasing amino acid uptake, protein synthesis, the size of cardiomyocytes and the expression of specific genes, as well as reduces apoptosis of cardiomyocytes [120-126]. Due to the positive effects that GH exerts on heart, it may be hypothesized that GH treatment might be of utility in patients with heart failure, mainly in those GHDs. Moreover, the hormone increases VEGF expression and angiogenesis in the myocardium of rats after infarction [127,128]. Therefore, as in the other pathologies here analyzed, GH administration could be useful for enhancing the reparative strategies postulated to be used in transplanting stem cells in the heart to improve cardiac function after myocardial infarction [129]. These positive effects of the hormone on heart are not observed, just the contrary, in acromegalic patients, but in them, the hormone is released in high and sustained concentrations during years, a situation very different from the one we are suggesing.

In order to improve the survival and integration of administered stem cells in the damaged brain or heart, a number of ex vivo modifications of these cells (including gene therapies for enhancing the therapeutic effects of these cells or its specific delivery to a particular tissue) or implantable devices containing them, have been proposed [77,130-138].

As stated above, a number of references indicate that the administration of growth hormone (GH) might be of great utility when commencing a therapy with stem cells in any of the pathologies we analyzed.

The rationale of the use of GH together with stem cells administration comes not only for the already described actions of the hormone (for instance cells survival, and stem cells proliferation, differentiation and migration), but also from the fact that GH induces the expression of a number of factors with known neurotrophic and cardiac activity. For example, IGF-I, EGF, FGF, VEGF, BDNF, EPO, etc. [1]. In addition, it would not be necessary a long time GH administration, therefore avoiding the apparition of possible undesirable side-effects. Even more, GH could be administered early after the brain or cardiac injuries, before stem cells could be implanted.

With regard to stem cells administration, although it is not well established what would be the optimal window of time or the number of cells needed for that administration, it seems clear that the sooner they were administered and the higher the number the better the results would be. In this sense, we believe it would interesting to create a bank of adult stem cells in which, from a certain age, a certain person could store cryopreserved their own stem cells, so that if he/she later suffer a neurological or cardiac emergency their own cells would be available for a prompt administration, without needing to wait until these cells were harvested and proliferated. Harvesting would be not a problem, but reaching the needed amount of stem cells needed for the implant could represent a life-threatening time. This is schematized in Figure 6.  Lastly, the best way for administration of stem cells seems to be intrathecally, for neurological injuries, whenever they do not increase brain inflammation and the immune response associated with stroke and TBI, although new neurosurgical techniques utilizing stereotaxy for intracerebral implants are very promising. On the other hand, intra-arterial administration seems to be more effective than intravenous, since avoids microemboli formation and the loss of a large number of cells in lungs.

CONCLUSION

Stem cells implants from many different sources are a potential solution for several acquired neural and cardiac injuries. However, the time window for these implants achieve maximum restorative effectiveness is still under debate and dependent on the type and severity of existing damage, as it happens with the number of cells which need to be administered and the route of administration. The administration of GH, regardless of whether the patient is GH-deficient or not, can be an effective tool to make treatments with stem cells more efficient in these diseases.

ACKNOWLEDGEMENT

This study has been funded by Foundation Foltra (Teo, Spain).

CONFLICT OF INTERESTS

The authors declare that no conflict of interests exists.

 

1.       Devesa J, Almenglo C, Devesa P (2016) Multiple effects of growth hormone in the body: Is it really the hormone for growth? Clin Med Insights: Endocrinol Diabetes 9: 1-25.

2.       Devesa J, Diaz MJ, Odriozola A, Arce V, Lima L (1991) Neurorregulacion de la expresion de la secrecion de hormona de crecimiento (GH) y expresion del gen de esta hormona en pro-y eucariotas. Endocrinologia 38: 33-41. 

3.       Devesa J, Devesa P, Reimunde P (2010) Growth hormone revisited. Med Clin (Barc) 135: 665-670.

4.       Arce VM, Devesa P, Devesa J (2013) Role of Growth Hormone in the treatment of neural diseases: From neuroprotection to neural repair. Neurosci Res 76: 179-186.

5.       Caicedo D, Devesa P, Arce VM, Requena J, Devesa J (2017) Critical lower limb ischemia could benefit from growth hormone therapy for wound healing and limb salvage. Ther Adv Cardiovasc Dis.

6.       Pathipati P, Gorba T, Scheepens A, Goffin V, Sun Y, et al. (2011) Growth hormone and prolactin regulate human neural stem cell regenerative activity. Neuroscience 190: 409-427. 

7.       Devesa P, Agasse F, Xapelli, Almenglo C, Devesa J, et al. (2014) Growth hormone pathways signaling for cell proliferation and survival in hippocampal neural precursors from postnatal mice. BMC Neurosci 15: 100.

8.       Scheepens A, Williams CE, Breier BH, Guan J, Gluckman PD (2000) A role for the somatotropic axis in neural development, injury and disease. J Pediatr Endocrinol Metab 13: 1483-1491.

9.       Garcia-Aragon J, Lobie PE, Muscat GE, Gobius KS, Norstedt G, et al. (1992) Prenatal expression of the growth hormone (GH) receptor/binding protein in the rat: A role for GH in embryonic and fetal development? Development 114: 869-876.

10.    Turnley AM, Faux CH, Rietze RL, Coonan JR, Bartlett PF (2002) Suppressor of cytokine signaling 2 regulates neuronal differentiation by inhibiting growth hormone signaling. Nat Neurosci 5: 1155-1162.

11.    Lobie PE, Garcia-Aragon J, Lincoln DT, Barnard R, Wilcox JN, et al. (1993) Localization and ontogeny of growth hormone receptor gene expression in the central nervous system. Brain Res Dev Brain Res 74: 225-233.

12.    Donahue CP, Jensen RV, Ochiishi T, Eisenstein I, Zhao M, et al. (2002) Transcriptional profiling reveals regulated genes in the hippocampus during memory formation. Hippocampus 12: 821-833.

13.    Parent JM (2003) Injury-induced neurogenesis in the adult mammalian brain. Neuroscientist 9: 261-272.

14.    Sun LY, Evans MS, Hsieh J, Panici J, Bartke A (2005) Increased neurogenesis in dentate gyrus of long-lived Ames dwarf mice. Endocrinology 146: 1138-1144.

15.    Sun LY, Al-Regaiey K, Masternak MM, Wang J, Bartke A (2005) Local expression of GH and IGF-1 in the hippocampus of GH-deficient long-lived mice. Neurobiol Aging 26: 929-937.

16.    Scheepens A, Sirimanne ES, Breier BH, Clark RG, Gluckman PD, et al. (2001) Growth hormone as a neuronal rescue factor during recovery from CNS injury. Neuroscience 104: 677-687.

17.    Devesa J, Reimunde P, Devesa A, Souto S, Lopez-Amado M, et al. (2009) Recovery from neurological sequelae secondary to oncological brain surgery in an adult growth hormone-deficient patient after growth hormone treatment. J Rehabil Med 41: 775-777.

18.    Maric NP, Doknic M, Pavlovic D, Pekic S, Stojanovic M, et al. (2010) Psychiatric and neuropsychological changes in growth hormone-deficient patients after traumatic brain injury in response to growth hormone therapy. J Endocrinol Invest 33: 770-775.

19.    High WM Jr, Briones-Galang M, Clark JA, Gilkison C, Mossberg KA, et al. (2010) Effect of growth hormone replacement therapy on cognition after traumatic brain injury. J Neurotrauma 27: 1565-1575.

20.    Reimunde P, Rodicio C, Lopez N, Alonso A, Devesa P, et al. (2010) Effects of recombinant growth hormone replacement and physical rehabilitation in recovery of gross motor function in children with cerebral palsy. Ther Clin Risk Manag 6: 585-592.

21.    Reimunde P, Quintana A, Castanon B, Casteleiro N, Vilarnovo Z, et al. (2011) Effects of growth hormone (GH) replacement and cognitive rehabilitation in patients with cognitive disorders after traumatic brain injury. Brain Inj 25: 65-73.

22.    Devesa J, Alonso B, Casteleiro N, Couto P, Castanon B, et al. (2011) Effects of recombinant growth hormone (GH) replacement and psychomotor and cognitive stimulation in the neurodevelopment of GH-deficient (GHD) children with cerebral palsy: A pilot study. Ther Clin Risk Manag 7: 199-206.

23.    Li RC, Guo SZ, Raccurt M, Moudilou E, Morel G, et al. (2011) Exogenous growth hormone attenuates cognitive deficits induced by intermittent hypoxia in rats. Neurosci 196: 237-250.

24.    Song J, Park K, Lee H, Kim M (2012) The effect of recombinant human growth hormone therapy in patients with completed stroke: A pilot trial. Ann Rehabil Med 36: 447-457.

25.    Devesa J, Reimunde P, Devesa P, Barbera M, Arce V (2013) Growth hormone (GH) and brain trauma. Horm Behav 63: 331-344.

26.    Heredia M, Fuente A, Criado J, Yajeya J, Devesa J, et al. (2013) Early growth hormone (GH) treatment promotes relevant motor functional improvement after severe frontal cortex lesion in adult rats. Behav Brain Res 247: 48-58.

27.    Moreau OK, Cortet-Rudelli C, Yollin E, Merlen E, Daveluy W, et al. (2013) Growth hormone replacement therapy in patients with traumatic brain injury. J Neurotrauma 30: 998-1006.

28.    Alba-Betancourt C, Luna-Acosta JL, Ramirez-Martinez CE, Avila-Gonzalez D, Granados-Avalos E, et al. (2013) Neuro-protective effects of growth hormone (GH) after hypoxia-ischemia injury in embryonic chicken cerebellum. Gen Comp Endocrinol 183: 17-31.

29.    Nyberg F, Hallberg M (2013) Growth hormone and cognitive function. Nat Rev Endocrinol 9: 357-365.

30.    Rhodin A, von Ehren M, Skottheim B, Gronbladh A, Ortiz-Nieto F, et al. (2014) Recombinant human growth hormone improves cognitive capacity in a pain patient exposed to chronic opioids. Acta Anaesthesiol Scand 58: 759-765.

31.    Zhang H, Han M, Zhang X, Sun X, Ling F (2014) The effect and mechanism of growth hormone replacement on cognitive function in rats with traumatic brain injury. PLoS One 9: e108518.

32.    Devesa J, Diaz-Getino G, Rey P, Garcia-Cancela J, Loures I, et al. (2015) Brain recovery after a plane crash: Treatment with growth hormone (GH) and neurorehabilitation: A case report. Int J Mol Sci 16: 30470-30482.

33.    Gardner CJ, Mattsson AF, Daousi C, Korbonits M, Koltowska-Haggstrom M, et al. (2015) GH deficiency after traumatic brain injury: Improvement in quality of life with GH therapy: Analysis of the KIMS database. Eur J Endocrinol 172: 371-381. 

34.    Devesa J, Lema H, Zas E, Munin B, Taboada P, et al. (2016) Learning and memory recoveries in a young girl treated with growth hormone and neurorehabilitation. J Clin Med 5.

35.    Christophidis LJ, Gorba T, Gustavsson M, Williams CE, Werther GA, et al. (2009) Growth hormone receptor immunoreactivity is increased in the subventricular zone of juvenile rat brain after focal ischemia: A potential role for growth hormone in injury-induced neurogenesis. Growth Horm IGF Res 19: 497-506.

36.    Devesa P, Reimunde P, Gallego R, Devesa J, Arce VM (2011) Growth hormone (GH) treatment may cooperate with locally-produced GH in increasing the proliferative response of hippocampal progenitors to kainate-induced injury. Brain Inj 25: 503-510.

37.    Almenglo C, Devesa P, Devesa J, Arce VM (2017) GPE promotes the proliferation and migration of mouse embryonic neural stem cells and their progeny in vitro. Int J Mol Sci 18.

38.    Martinez-Moreno CG, Fleming T, Carranza M, Avila-Mendoza J, Luna M, et al. (2017) Growth hormone protects against kainate excitotoxicity and induces BDNF and NT3 expression in chicken neuroretinal cells. Exp Eye Res 166: 1-12.

39.    Evans LM, Davies JS, Anderson RA, Ellis GR, Jackson SK, et al. (2000) The effect of GH replacement therapy on endothelial function and oxidative stress in adult growth hormone deficiency. Eur J Endocrinol 142: 254-262.

40.    Boger RH (1999) Nitric oxide and the mediation of the hemodynamic effects of growth hormone in humans. J Endocrinol Invest 22: 7581.

41.    Napoli R, Guardasole V, Angelini V, D'Amico F, Zarra E, et al. (2003) Acute effects of growth hormone on vascular function in human subjects. J Clin Endocrinol Metab 88: 2817-2820.

42.    Daskalopoulos EP, Vilaeti AD, Barka E, Mantzouratou P, Kouroupis D, et al. (2015) Attenuation of post-infarction remodeling in rats by sustained myocardial growth hormone administration. Growth Factors 12: 1-9.

43.    Kontonika M, Barka E, Roumpi M, La Rocca V, Lekkas P, et al. (2017) Prolonged intra-myocardial growth hormone administration ameliorates post-infarction electrophysiologic remodeling in rats. Growth Factors 35: 1-11.

44.    Takahasi K, Yamanaka S (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126: 663-676.

45.    Mai Q, Yu Y, Li T, Wang L, Chen MJ, et al. (2007) Derivation of human embryonic stem cell lines from parthenogenetic blastocysts. Cell Res 17: 1008-1019.

46.    Civin CI, Strauss LC, Brovall C, Fackler MJ, Schwartz JF, et al. (1984) Antigenic analysis of hematopoiesis. III. A hematopoietic progenitor cell surface antigen defined by a monoclonal antibody raised against KG-1a cells. J Immunol 133: 157-165.

47.    Tindle RW, Katz F, Martin H, Watt D, Catovsky D, et al. (1987) BI-3C5 (CD34) defines multipotential and lineage restricted progenitor cells and their leukaemic counterparts: Leucocyte typing 111: White cell differentiation antigens. Oxford University Press.

48.    Nielsen JS, McNagny KM (2008) Novel functions of the CD34 family. J Cell Sci 121: 3683-3692.

49.    Blanchet MR, Maltby S, Haddon DJ, Merkens H, Zbytnuik L, et al. (2007) CD34 facilitates the development of allergic asthma. Blood 110: 2005-2012.

50.    Squillaro T, Peluso G, Galderisi U (2016) Clinical trials with mesenchymal stem cells: An update. Cell Transplant 25: 829-848.

51.    Vaquero J, Zurita M, Rico MA, Bonilla C, Aguayo C, et al. (2016) An approach to personalized cell therapy in chronic complete paraplegia: The Puerta de Hierro phase I/II clinical trial. Cytotherapy 18: 1025-1036.

52.    Sasaki M, Abe R, Fujita Y, Ando S, Inokuma D, et al. (2008) Mesenchymal stem cells are recruited into wounded skin and contribute to wound repair by transdifferentiation into multiple skin cell type. J Immunol 180: 2581-2587.

53.    Li M, Ikehara S (2013) Bone-marrow-derived mesenchymal stem cells for organ repair. Stem Cells Int 2013: 132642.

54.    Sanz-Baro R, Garcia-Arranz M, Guadalajara H, de la Quintana P, Herreros MD, et al. (2015) First-in-human case study: Pregnancy in women with Crohn's perianal fistula treated with adipose-derived stem cells: A safety study. Stem Cells Transl Med 4: 598-602.

55.    Garcia-Olmo D, Schwartz DA (2015) Cumulative evidence that mesenchymal stem cells promote healing of perianal fistulas of patients with Crohn's disease. Gastroenterology 149: 853-857.

56.    Uchida H, Niizuma K, Kushida Y, Wakao S, Tominaga T, et al. (2017) Human muse cells reconstruct neuronal circuitry in subacute lacunar stroke model. Stroke 48: 428-435.

57.    Hattiangady B, Shetty AK (2012) Neural stem cell grafting counteracts hippocampal injury-mediated impairments in mood, memory and neurogenesis. Stem Cells Transl Med 1: 696-708.

58.    Shetty AK, Hattiangady B (2016) Grafted subventricular zone neural stem cells display robust engraftment and similar differentiation properties and form new neurogenic niches in the young and aged hippocampus. Stem Cells Transl Med 5: 1204-1215.

59.    Yan Y, Shin S, Jha BS, Liu Q, Sheng J, Li F, et al. (2013) Efficient and rapid derivation of primitive neural stem cells and generation of brain subtype neurons from human pluripotent stem cells. Stem Cells Transl Med 2: 862-870.

60.    Kruse M, Michelsen SI, Flachs EM, Bronnum-Hansen H, Madsen M, et al. (2009) Lifetime costs of cerebral palsy. Dev Med Child Neurol 51: 622-628.

61.    Brea A, Laclaustra M, Martorell E, Pedragosa A (2013) Epidemiology of cerebrovascular disease in Spain. Clin Invest Arterioscl 25: 211-217.

62.    Koh SH, Park HH (2017) Neurogenesis in stroke recovery. Transl Stroke Res 8: 3-13.

63.    Abi Chahine NH, Wehbe TW, Hilal RA, Zoghbi VV, Melki AE, et al. (2016) Treatment of cerebral palsy with stem cells: A report of 17 cases. Int J Stem Cells 9: 90-95.

64.    Park KI, Lee YH, Rah WJ, Jo SH, Park SB, et al. (2017) Effect of intravenous infusion of G-CSF-mobilized peripheral blood mononuclear cells on upper extremity function in cerebral palsy children. Ann Rehab Med 41: 113-120.

65.    Liu X, Fu X, Dai G, Wang X, Zhang Z, et al. (2017) Comparative analysis of curative effect of bone marrow mesenchymal stem cell and bone marrow mononuclear cell transplantation for spastic cerebral palsy. J Transl Med 15: 48.

66.    Nguyen LT, Nguyen AT, Vu CD, Ngo DV, Bui AV (2017) Outcomes of autologous bone marrow mononuclear cells for cerebral palsy: An open label uncontrolled clinical trial. BMC Pediatr 17: 104.

67.    McDonald CA, Fahey MC, Jenkin G, Miller SL (2017) Umbilical cord blood cells for treatment of cerebral palsy; timing and treatment options. Pediatr Res Sep 22.

68.    Sun JM, Song AW, Case LE, Mikati MA, Gustafson KE, et al. (2017) Effect of autologous cord blood infusion on motor function and brain connectivity in young children with cerebral palsy: a randomized, placebo-controlled trial. Stem Cells Transl Med 6: 2071-2078.

69.    Kulak-Bejda A, Kulak P, Bejda G, Krajewska-Kulak E, et al. (2016) Stem cells therapy in cerebral palsy: A systematic review. Brain Dev 38: 699-705.

70.    Devesa J, Devesa P, Reimunde P, Arce V (2012) Growth hormone and kynesitherapy for bain injury recovery. In: Brain Injury. Pathogenesis, monitoring, recovery and management. InTech, Rijeka, Croatia.

71.    Devesa J, Casteleiro N, Rodicio C, López N, Reimunde P (2010) Growth hormone deficiency and cerebral palsy. Ther Clin Risk Manag 6: 413-418.

72.    Barcena-Orbe A, Rodríguez-Arias CA, Rivero-Martin B, Canizal-Garcia JM, Mestre-Moreiro C, et al. (2006) Overview of head injury. Neurocirugia (Astur) 17: 495-518.

73.    Ding DC, Shyu WC, Lin SZ, Li H (2006) Current concepts in adult stem cell therapy for stroke. Curr Med Chem 13: 3565-3574.

74.    Prasad K, Sharma A, Garg A, Mohanty S, Bhatnagar S, et al. (2014) Intravenous autologous bone marrow mononuclear stem cell therapy for ischemic stroke: A multicentric, randomized trial. Stroke 45: 3618-3624.

75.    Moniche F, Escudero I, Zapata-Arriaza E, Usero-Ruiz M, Prieto-León M, et al. (2015) Intra-arterial bone marrow mononuclear cells (BM-MNCs) transplantation in acute ischemic stroke (IBIS trial): Protocol of a phase II, randomized, dose-finding, controlled multicenter trial. Int J Stroke 10: 1149-1152.

76.    Azad TD, Veeravagu A, Steinberg GK (2016) Neurorestoration after stroke. Neurosurg Focus 40: E2.

77.    Steinberg GK, Kondziolka D, Wechsler LR, Lunsford LD, Coburn ML, et al. (2016) Clinical outcomes of transplanted modified bone marrow-derived mesenchymal stem cells in stroke: A phase 1/2a study. Stroke 47: 1817-1824.

78.    Kumar A, Prasad M, Jali VP, Pandit AK, Misra S, et al. (2017) Bone marrow mononuclear cell therapy in ischaemic stroke: A systematic review. Acta Neurol Scand 135: 496-506.

79.    Hess DC, Wechsler LR, Clark WM, Savitz SI, Ford GA, et al. (2017) Safety and efficacy of multipotent adult progenitor cells in acute ischaemic stroke (MASTERS): A randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Neurol 16: 360-368.

80.    Kenmuir CL, Wechsler LR (2017) Update on cell therapy for stroke. Stroke Vasc Neurol 2: 59-64.

81.    Detante O, Moisan A, Hommel M, Jaillard A (2017) Controlled clinical trials of cell therapy in stroke: Meta-analysis at six months after treatment. Int J Stroke 12: 748-751.

82.    Huang H, Lin F, Jiang J, Chen Y, Mei A, et al. (2017) Effects of intra-arterial transplantation of adipose-derived stem cells on the expression of netrin-1 and its receptor DCC in the peri-infarct cortex after experimental stroke. Stem Cell Res Ther 8: 223.

83.    Reis C, Wilkinson M, Reis H, Akyol O, Gospodarev V, et al. (2017) A look into stem cell therapy: Exploring the options for treatment of ischemic stroke. Stem Cells Int.

84.    Tsang KS, Ng CPS, Zhu XL, Wong GKC, Lu G, et al. (2017) Phase I/II randomized controlled trial of autologous bone marrow-derived mesenchymal stem cell therapy for chronic stroke. World J Stem Cells 9: 133-143.

85.    Duan X, Lu L, Wang Y, Zhang F, Mao J, et al. (2017) The long-term fate of mesenchymal stem cells labeled with magnetic resonance imaging-visible polymersomes in cerebral ischemia. Int J Nanomed 12: 6705-6719.

86.    Seo HG, Yi Y, Oh BM, Paik NJ (2017) Neuroprotective effect of secreted factors from human adipose stem cells in a rat stroke model. Neurol Res 39: 1114-1124.

87.    Wei L, Wei ZZ, Jiang MQ, Mohamad O, Yu SP (2017) Stem cell transplantation therapy for multifaceted therapeutic benefits after stroke. Prog Neurobiol 157: 49-78.

88.    Chen L, Qiu R, Li L, He D, Lv H, et al. (2014) The role of exogenous neural stem cells transplantation in cerebral ischemic stroke. J Biomed Nanotechnol 10: 3219-3230.

89.    Cox CS (2017) Cellular therapy for traumatic neurological injury. Pediatr Res.

90.    Longhi L, Zanier ER, Royo N, Stochetti N, McIntosh TK (2005) Stem cell transplantation as a therapeutic strategy for traumatic brain injury. Transpl Immunol 15: 143-148.

91.    Chen Q, Long Y, Yuan X, Zou L, Sun J, et al. (2005) Protective effects of bone marrow stromal cell transplantation in injured rodent brain: Synthesis of neurotrophic factors. J Neurosci Res 80: 611-619.

92.    Xue S, Zhang HT, Zhang P, Luo J, Chen ZZ, et al. (2010) Functional endothelial progenitor cells derived from adipose tissue show beneficial effect on cell therapy of traumatic brain injury. Neurosci Lett 473: 186-191.

93.    Walker PA, Harting MT, Jimenez F, Shah SK, Pati S, et al. (2010) Direct intrathecal implantation of mesenchymal stromal cells leads to enhanced neuroprotection via an NFkappaB-mediated increase in interleukin-6 production. Stem Cells Dev 19: 867-876.

94.    Galindo LT, Filippo TR, Semedo P, Ariza CB, Moreira CM, et al. (2011) Mesenchymal stem cell therapy modulates the inflammatory response in experimental traumatic brain injury. Neurol Res Int 2011: 564089.

95.    Grigorian AS, Gilerovich EG, Pavlichenko NN, Kruglyakov PV, Sokolova IB, et al. (2011) Effect of transplantation of mesenchymal stem cells on neuronal survival and formation of a glial scar in the brain of rats with severe traumatic brain injury. Bull Exp Biol Med 150: 551-555.

96.    Lundberg J, Sodersten E, Sundstrom E, Le Blanc K, Andersson T, et al. (2012) Targeted intra-arterial transplantation of stem cells to the injured CNS is more effective than intravenous administration: Engraftment is dependent on cell type and adhesion molecule expression. Cell Transplant 21: 333-343.

97.    Jiang J, Bu X, Liu M, Cheng P (2012) Transplantation of autologous bone marrow-derived mesenchymal stem cells for traumatic brain injury. Neural Regen Res 5: 46-53.

98.    Zhang R, Liu Y, Yan K, Chen L, Chen XR, et al. (2013) Anti-inflammatory and immunomodulatory mechanisms of mesenchymal stem cell transplantation in experimental traumatic brain injury. J Neuroinflammation 10: 106.

99.    Anbari F, Khalili MA, Bahrami AR, Khoradmehr A, Sadeghian F, et al. (2014) Intravenous transplantation of bone marrow mesenchymal stem cells promotes neural regeneration after traumatic brain injury. Neural Regen Res 9: 919-923.

100.Peng W, Sun J, Sheng C, Wang Z, Wang Y, et al. (2015) Systematic review and meta-analysis of efficacy of mesenchymal stem cells on locomotor recovery in animal models of traumatic brain injury. Stem Cell Res Ther 6: 47.

101.Turtzo LC, Budde MD, Dean DD, Gold EM, Lewis BK, et al. (2015) Failure of intravenous or intracardiac delivery of mesenchymal stromal cells to improve outcomes after focal traumatic brain injury in the female rat. PLoS One 10: e0126551.

102.Mishra SK, Rana P, Khushu S, Gangenahalli G (2017) Therapeutic prospective of infused allogenic cultured mesenchymal stem cells in traumatic brain injury mice: A longitudinal proton magnetic resonance spectroscopy assessment. Stem Cells Transl Med 6: 316-329.

103.Dori I, Petrakis S, Giannakopoulou A, Bekiari C, Grivas I, et al. (2017) Seven days post-injury fate and effects of genetically labelled adipose-derived mesenchymal cells on a rat traumatic brain injury experimental model. Histol Histopathol 32: 1041-1055.

104.Hasan A, Deeb G, Rahal R, Atwi K, Mondello S, et al. (2017) Mesenchymal stem cells in the treatment of traumatic brain injury. Front Neurol 8: 28.

105.Tian C, Wang X, Wang X, Wang L, Wang X, et al. (2013) Autologous bone marrow mesenchymal stem cell therapy in the subacute stage of traumatic brain injury by lumbar puncture. Exp Clin Transplant 11: 176-181.

106.Liao GP, Harting MT, Hetz RA, Walker PA, Shah SK, et al. (2015) Autologous bone marrow mononuclear cells reduce therapeutic intensity for severe traumatic brain injury in children. Pediatr Crit Care Med 16: 245-255.

107.Vaquero J, Zurita M, Bonilla C, Fernández C, Rubio JJ, et al. (2017) Progressive increase in brain glucose metabolism after intrathecal administration of autologous mesenchymal stromal cells in patients with diffuse axonal injury. Cytotherapy 19: 88-94.

108.Tomita S, Li RK, Weisel RD, Mickle DA, Kim EJ, et al. (1999) Autologous transplantation of bone marrow cells improves damaged heart function. Circulation 100: II247-256.

109.Beltrami AP, Barlucchi L, Torella D, Baker M, Limana F, et al. (2003) Adult cardiac stem cells are multipotent and support myocardial regeneration. Cell 114: 763-776.

110.Torella D, Ellison GM, Méndez-Ferrer S, Ibañez B, Nadal-Ginard B (2006) Resident human cardiac stem cells: Role in cardiac cellular homeostasis and potential for myocardial regeneration. Nat Clin Pract Cardiovasc Med Suppl 1: S8-13.

111.Barile L, Messina E, Giacomello A, Marbán E (2007) Endogenous cardiac stem cells. Prog Cardiovasc Dis 50: 31-48.

112.Noiseux N, Gnecchi M, Lopez-Ilasaca M, Zhang L, Solomon SD, et al. (2006) Mesenchymal stem cells overexpressing Akt dramatically repair infarcted myocardium and improve cardiac function despite infrequent cellular fusion or differentiation. Mol Ther 14: 640-650.

113.Costoya JA, Finidori J, Moutoussamy S, Senarís R, Devesa J, et al. (1999) Activation of growth hormone receptor delivers an antiapoptotic signal: Evidence for a role of Akt in this pathway. Endocrinology 140: 5937-5943.

114.Xu JY, Liu D, Zhong Y, Huang RC (2017) Effects of timing on intracoronary autologous bone marrow-derived cell transplantation in acute myocardial infarction: A meta-analysis of randomized controlled trials. Stem Cell Res Ther 8: 231.

115.Xu JY, Cai WY, Tian M, Liu D, Huang RC (2016) Stem cell transplantation dose in patients with acute myocardial infarction: A meta-analysis. Chronic Dis Transl Med 2: 92-101.

116.Bianconi V, Sahebkar A, Kovanen P, Bagaglia F, Ricciuti B, et al. (2017) Endothelial and cardiac progenitor cells for cardiovascular repair: A controversial paradigm in cell therapy. Pharmacol Ther pii: S0163-7258(17)30214-0.

117.Bayes-Genis A, Soler-Botija C, Farré J, Sepúlveda P, Raya A, et al. (2010) Human progenitor cells derived from cardiac adipose tissue ameliorate myocardial infarction in rodents. J Mol Cell Cardio l49: 771-780.

118.Roura S, Gálvez-Montón C, Mirabel C, Vives J, et al. (2017) Mesenchymal stem cells for cardiac repair: Are the actors ready for the clinical scenario? Stem Cell Res Ther 8: 238.

119.Sacca L, Cittadini A, Fazio S (1994) Growth hormone and the heart. Endocr Rev 15: 555-573.

120.Li Q, Li B, Wang X, Leri A, Jana KP, et al. (1997) Overexpression of insulin-like growth factor-I in mice protects from myocyte death after infarction, attenuating ventricular dilation, wall stress and cardiac hypertrophy. J Clin Invest 100: 1991-1999.

121.Timsit J, Riou B, Bertherat J, Wisnewsky C, Kato NS, et al. (1990) Effects of chronic growth hormone hypersecretion on intrinsic contractility, energetics, isomyosin pattern and myosin adenosinetriphosphatase activity of ratleft ventricle. J Clin Invest 86: 507-515.

122.Cittadini A, Ishiguro Y, Stromer H, Spindler M, Moses AC, et al. (1998) Insulin-like growth factor-1 but not growth hormone augments mammalian myocardial contractility by sensitizing the myofilament to Ca2+ through a wortmannin-sensitive pathway: Studies in rat and ferret isolated muscles. Circ Res 83: 50-59.

123.Mayoux E, Ventura-Clapier R, Timsit J, Behar-Cohen F, Hoffmann C, et al. (1993) Mechanical properties of rat cardiac skinned fibers are altered by chronic growth hormone hypersecretion. Circ Res 72: 57-64.

124.Bruel A, Oxlund H (1995) Biosynthetic growth hormone increase the collagen deposition rate in rat aorta and heart. Eur J Endocrinol 132: 195-199.

125.Buerke M, Murohara T, Skurk C, Nuss C, Tomaselli K, et al. (1995) Cardioprotective effect of insulin-like growth factor I in myocardial ischemia followed by reperfusion. Proc Natl Acad Sci U S A 92: 8031-8035.

126.Ren J (2002) Short-term administration of insulin-like growth factor (IGF-1) does not induce myocardial IGF-1 resistance. Growth Horm IGF Res 12: 162-168.

127.Kusano K, Tsutsumi Y, Dean J, Gavin M, Ma H, et al. (2007) Long-term stable expression of human growth hormone by rAAV promotes myocardial protection post-myocardial infarction. J Mol Cell Cardiol 42: 390-399.

128.Rong SL, Lu YX, Liao YH, Wang XL, Wang YJ, et al. (2008) Effects of transplanted myoblasts transfected with human growth hormone gene on improvement of ventricular function of rats. Chin Med J 121: 347-354.

129.Nakajima K, Fujita J, Matsui M, Tohyama S, Tamura N, et al. (2015) Gelatin hydrogel enhances the engraftment of transplanted cardiomyocytes and angiogenesis to ameliorate cardiac function after myocardial infarction. PLos One 10: e0133308.

130.Helie A, Brinker T (2011) Clinical translation of stem cell therapy in traumatic brain inury: The potential of encapsulated mesenchymal cell biodelivery of glucagon-like peptide-1. Dialogues Clin Neurosci 13: 279-286.

131.Chen KH, Chen CH, Wallace CG, Yuen CM, Kao GS, et al. (2016) Intravenous administration of xenogenic adipose-derived mesenchymal stem cells (ADMSC) and ADMSC-derived exosomes markedly reduced brain infarct volume and preserved neurological function in rat after acute ischemic stroke. Oncotarget 7: 74537-74556.

132.Bang OY, Kim BH, Cha JM, Moon GJ (2016) Adult stem cell therapy for stroke: Challenges and progress. J Stroke 18: 256-266.

133.Chung CY, Lin MH, Lee IN, Lee TH, Lee MH, et al. (2017) Brain-derived neurotrophic factor loaded PS80 PBCA nanocarrier for in vitro neural differentiation of mouse induced pluripotent stem cells. Int J Mol Sci 18: E663.

134.Wang TW, Chang KC, Chen LH, Liao SY, Yeh CW, et al. (2017) Effects of an injectable functionalized self-assembling nanopeptide hydrogel on angiogenesis and neurogenesis for regeneration of the central nervous system. Nanoscale 9: 16281-16292.

135.Shichinohe H, Kawabori M, Iijima H, Teramoto T, Abumiya T, et al. (2017) Research on advanced intervention using novel bone marrow stem cell (RAINBOW): A study protocol for a phase I, open-label, uncontrolled, dose-response trial of autologous bone marrow stromal cell transplantation in patients with acute ischemic stroke. BMC Neurol 17: 179.

136.Tseng KY, Anttila JE, Khodosevich K, Tuominen RK, Lindahl M, et al. (2017) MANF promotes differentiation and migration of neural progenitor cells with potential neural regenerative effects in stroke. Mol Ther.

137.Fisher SA, Doree C, Mathur A, Taggart DP, Martin-Rendon E (2016) Stem cell therapy for chronic ischaemic heart disease and congestive heart failure. Cochrane Database Syst Rev 2: CD007888.

138.Lewis FC, Kumar SD, Ellison-Hughes GM (2017) Non-invasive strategies for stimulating endogenous repair and regenerative mechanisms in the damaged heart. Pharmacol Res.1.       Devesa J, Almenglo C, Devesa P (2016) Multiple effects of growth hormone in the body: Is it really the hormone for growth? Clin Med Insights: Endocrinol Diabetes 9: 1-25.

2.       Devesa J, Diaz MJ, Odriozola A, Arce V, Lima L (1991) Neurorregulacion de la expresion de la secrecion de hormona de crecimiento (GH) y expresion del gen de esta hormona en pro-y eucariotas. Endocrinologia 38: 33-41. 

3.       Devesa J, Devesa P, Reimunde P (2010) Growth hormone revisited. Med Clin (Barc) 135: 665-670.

4.       Arce VM, Devesa P, Devesa J (2013) Role of Growth Hormone in the treatment of neural diseases: From neuroprotection to neural repair. Neurosci Res 76: 179-186.

5.       Caicedo D, Devesa P, Arce VM, Requena J, Devesa J (2017) Critical lower limb ischemia could benefit from growth hormone therapy for wound healing and limb salvage. Ther Adv Cardiovasc Dis.

6.       Pathipati P, Gorba T, Scheepens A, Goffin V, Sun Y, et al. (2011) Growth hormone and prolactin regulate human neural stem cell regenerative activity. Neuroscience 190: 409-427. 

7.       Devesa P, Agasse F, Xapelli, Almenglo C, Devesa J, et al. (2014) Growth hormone pathways signaling for cell proliferation and survival in hippocampal neural precursors from postnatal mice. BMC Neurosci 15: 100.

8.       Scheepens A, Williams CE, Breier BH, Guan J, Gluckman PD (2000) A role for the somatotropic axis in neural development, injury and disease. J Pediatr Endocrinol Metab 13: 1483-1491.

9.       Garcia-Aragon J, Lobie PE, Muscat GE, Gobius KS, Norstedt G, et al. (1992) Prenatal expression of the growth hormone (GH) receptor/binding protein in the rat: A role for GH in embryonic and fetal development? Development 114: 869-876.

10.    Turnley AM, Faux CH, Rietze RL, Coonan JR, Bartlett PF (2002) Suppressor of cytokine signaling 2 regulates neuronal differentiation by inhibiting growth hormone signaling. Nat Neurosci 5: 1155-1162.

11.    Lobie PE, Garcia-Aragon J, Lincoln DT, Barnard R, Wilcox JN, et al. (1993) Localization and ontogeny of growth hormone receptor gene expression in the central nervous system. Brain Res Dev Brain Res 74: 225-233.

12.    Donahue CP, Jensen RV, Ochiishi T, Eisenstein I, Zhao M, et al. (2002) Transcriptional profiling reveals regulated genes in the hippocampus during memory formation. Hippocampus 12: 821-833.

13.    Parent JM (2003) Injury-induced neurogenesis in the adult mammalian brain. Neuroscientist 9: 261-272.

14.    Sun LY, Evans MS, Hsieh J, Panici J, Bartke A (2005) Increased neurogenesis in dentate gyrus of long-lived Ames dwarf mice. Endocrinology 146: 1138-1144.

15.    Sun LY, Al-Regaiey K, Masternak MM, Wang J, Bartke A (2005) Local expression of GH and IGF-1 in the hippocampus of GH-deficient long-lived mice. Neurobiol Aging 26: 929-937.

16.    Scheepens A, Sirimanne ES, Breier BH, Clark RG, Gluckman PD, et al. (2001) Growth hormone as a neuronal rescue factor during recovery from CNS injury. Neuroscience 104: 677-687.

17.    Devesa J, Reimunde P, Devesa A, Souto S, Lopez-Amado M, et al. (2009) Recovery from neurological sequelae secondary to oncological brain surgery in an adult growth hormone-deficient patient after growth hormone treatment. J Rehabil Med 41: 775-777.

18.    Maric NP, Doknic M, Pavlovic D, Pekic S, Stojanovic M, et al. (2010) Psychiatric and neuropsychological changes in growth hormone-deficient patients after traumatic brain injury in response to growth hormone therapy. J Endocrinol Invest 33: 770-775.

19.    High WM Jr, Briones-Galang M, Clark JA, Gilkison C, Mossberg KA, et al. (2010) Effect of growth hormone replacement therapy on cognition after traumatic brain injury. J Neurotrauma 27: 1565-1575.

20.    Reimunde P, Rodicio C, Lopez N, Alonso A, Devesa P, et al. (2010) Effects of recombinant growth hormone replacement and physical rehabilitation in recovery of gross motor function in children with cerebral palsy. Ther Clin Risk Manag 6: 585-592.

21.    Reimunde P, Quintana A, Castanon B, Casteleiro N, Vilarnovo Z, et al. (2011) Effects of growth hormone (GH) replacement and cognitive rehabilitation in patients with cognitive disorders after traumatic brain injury. Brain Inj 25: 65-73.

22.    Devesa J, Alonso B, Casteleiro N, Couto P, Castanon B, et al. (2011) Effects of recombinant growth hormone (GH) replacement and psychomotor and cognitive stimulation in the neurodevelopment of GH-deficient (GHD) children with cerebral palsy: A pilot study. Ther Clin Risk Manag 7: 199-206.

23.    Li RC, Guo SZ, Raccurt M, Moudilou E, Morel G, et al. (2011) Exogenous growth hormone attenuates cognitive deficits induced by intermittent hypoxia in rats. Neurosci 196: 237-250.

24.    Song J, Park K, Lee H, Kim M (2012) The effect of recombinant human growth hormone therapy in patients with completed stroke: A pilot trial. Ann Rehabil Med 36: 447-457.

25.    Devesa J, Reimunde P, Devesa P, Barbera M, Arce V (2013) Growth hormone (GH) and brain trauma. Horm Behav 63: 331-344.

26.    Heredia M, Fuente A, Criado J, Yajeya J, Devesa J, et al. (2013) Early growth hormone (GH) treatment promotes relevant motor functional improvement after severe frontal cortex lesion in adult rats. Behav Brain Res 247: 48-58.

27.    Moreau OK, Cortet-Rudelli C, Yollin E, Merlen E, Daveluy W, et al. (2013) Growth hormone replacement therapy in patients with traumatic brain injury. J Neurotrauma 30: 998-1006.

28.    Alba-Betancourt C, Luna-Acosta JL, Ramirez-Martinez CE, Avila-Gonzalez D, Granados-Avalos E, et al. (2013) Neuro-protective effects of growth hormone (GH) after hypoxia-ischemia injury in embryonic chicken cerebellum. Gen Comp Endocrinol 183: 17-31.

29.    Nyberg F, Hallberg M (2013) Growth hormone and cognitive function. Nat Rev Endocrinol 9: 357-365.

30.    Rhodin A, von Ehren M, Skottheim B, Gronbladh A, Ortiz-Nieto F, et al. (2014) Recombinant human growth hormone improves cognitive capacity in a pain patient exposed to chronic opioids. Acta Anaesthesiol Scand 58: 759-765.

31.    Zhang H, Han M, Zhang X, Sun X, Ling F (2014) The effect and mechanism of growth hormone replacement on cognitive function in rats with traumatic brain injury. PLoS One 9: e108518.

32.    Devesa J, Diaz-Getino G, Rey P, Garcia-Cancela J, Loures I, et al. (2015) Brain recovery after a plane crash: Treatment with growth hormone (GH) and neurorehabilitation: A case report. Int J Mol Sci 16: 30470-30482.

33.    Gardner CJ, Mattsson AF, Daousi C, Korbonits M, Koltowska-Haggstrom M, et al. (2015) GH deficiency after traumatic brain injury: Improvement in quality of life with GH therapy: Analysis of the KIMS database. Eur J Endocrinol 172: 371-381. 

34.    Devesa J, Lema H, Zas E, Munin B, Taboada P, et al. (2016) Learning and memory recoveries in a young girl treated with growth hormone and neurorehabilitation. J Clin Med 5.

35.    Christophidis LJ, Gorba T, Gustavsson M, Williams CE, Werther GA, et al. (2009) Growth hormone receptor immunoreactivity is increased in the subventricular zone of juvenile rat brain after focal ischemia: A potential role for growth hormone in injury-induced neurogenesis. Growth Horm IGF Res 19: 497-506.

36.    Devesa P, Reimunde P, Gallego R, Devesa J, Arce VM (2011) Growth hormone (GH) treatment may cooperate with locally-produced GH in increasing the proliferative response of hippocampal progenitors to kainate-induced injury. Brain Inj 25: 503-510.

37.    Almenglo C, Devesa P, Devesa J, Arce VM (2017) GPE promotes the proliferation and migration of mouse embryonic neural stem cells and their progeny in vitro. Int J Mol Sci 18.

38.    Martinez-Moreno CG, Fleming T, Carranza M, Avila-Mendoza J, Luna M, et al. (2017) Growth hormone protects against kainate excitotoxicity and induces BDNF and NT3 expression in chicken neuroretinal cells. Exp Eye Res 166: 1-12.

39.    Evans LM, Davies JS, Anderson RA, Ellis GR, Jackson SK, et al. (2000) The effect of GH replacement therapy on endothelial function and oxidative stress in adult growth hormone deficiency. Eur J Endocrinol 142: 254-262.

40.    Boger RH (1999) Nitric oxide and the mediation of the hemodynamic effects of growth hormone in humans. J Endocrinol Invest 22: 7581.

41.    Napoli R, Guardasole V, Angelini V, D'Amico F, Zarra E, et al. (2003) Acute effects of growth hormone on vascular function in human subjects. J Clin Endocrinol Metab 88: 2817-2820.

42.    Daskalopoulos EP, Vilaeti AD, Barka E, Mantzouratou P, Kouroupis D, et al. (2015) Attenuation of post-infarction remodeling in rats by sustained myocardial growth hormone administration. Growth Factors 12: 1-9.

43.    Kontonika M, Barka E, Roumpi M, La Rocca V, Lekkas P, et al. (2017) Prolonged intra-myocardial growth hormone administration ameliorates post-infarction electrophysiologic remodeling in rats. Growth Factors 35: 1-11.

44.    Takahasi K, Yamanaka S (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126: 663-676.

45.    Mai Q, Yu Y, Li T, Wang L, Chen MJ, et al. (2007) Derivation of human embryonic stem cell lines from parthenogenetic blastocysts. Cell Res 17: 1008-1019.

46.    Civin CI, Strauss LC, Brovall C, Fackler MJ, Schwartz JF, et al. (1984) Antigenic analysis of hematopoiesis. III. A hematopoietic progenitor cell surface antigen defined by a monoclonal antibody raised against KG-1a cells. J Immunol 133: 157-165.

47.    Tindle RW, Katz F, Martin H, Watt D, Catovsky D, et al. (1987) BI-3C5 (CD34) defines multipotential and lineage restricted progenitor cells and their leukaemic counterparts: Leucocyte typing 111: White cell differentiation antigens. Oxford University Press.

48.    Nielsen JS, McNagny KM (2008) Novel functions of the CD34 family. J Cell Sci 121: 3683-3692.

49.    Blanchet MR, Maltby S, Haddon DJ, Merkens H, Zbytnuik L, et al. (2007) CD34 facilitates the development of allergic asthma. Blood 110: 2005-2012.

50.    Squillaro T, Peluso G, Galderisi U (2016) Clinical trials with mesenchymal stem cells: An update. Cell Transplant 25: 829-848.

51.    Vaquero J, Zurita M, Rico MA, Bonilla C, Aguayo C, et al. (2016) An approach to personalized cell therapy in chronic complete paraplegia: The Puerta de Hierro phase I/II clinical trial. Cytotherapy 18: 1025-1036.

52.    Sasaki M, Abe R, Fujita Y, Ando S, Inokuma D, et al. (2008) Mesenchymal stem cells are recruited into wounded skin and contribute to wound repair by transdifferentiation into multiple skin cell type. J Immunol 180: 2581-2587.

53.    Li M, Ikehara S (2013) Bone-marrow-derived mesenchymal stem cells for organ repair. Stem Cells Int 2013: 132642.

54.    Sanz-Baro R, Garcia-Arranz M, Guadalajara H, de la Quintana P, Herreros MD, et al. (2015) First-in-human case study: Pregnancy in women with Crohn's perianal fistula treated with adipose-derived stem cells: A safety study. Stem Cells Transl Med 4: 598-602.

55.    Garcia-Olmo D, Schwartz DA (2015) Cumulative evidence that mesenchymal stem cells promote healing of perianal fistulas of patients with Crohn's disease. Gastroenterology 149: 853-857.

56.    Uchida H, Niizuma K, Kushida Y, Wakao S, Tominaga T, et al. (2017) Human muse cells reconstruct neuronal circuitry in subacute lacunar stroke model. Stroke 48: 428-435.

57.    Hattiangady B, Shetty AK (2012) Neural stem cell grafting counteracts hippocampal injury-mediated impairments in mood, memory and neurogenesis. Stem Cells Transl Med 1: 696-708.

58.    Shetty AK, Hattiangady B (2016) Grafted subventricular zone neural stem cells display robust engraftment and similar differentiation properties and form new neurogenic niches in the young and aged hippocampus. Stem Cells Transl Med 5: 1204-1215.

59.    Yan Y, Shin S, Jha BS, Liu Q, Sheng J, Li F, et al. (2013) Efficient and rapid derivation of primitive neural stem cells and generation of brain subtype neurons from human pluripotent stem cells. Stem Cells Transl Med 2: 862-870.

60.    Kruse M, Michelsen SI, Flachs EM, Bronnum-Hansen H, Madsen M, et al. (2009) Lifetime costs of cerebral palsy. Dev Med Child Neurol 51: 622-628.

61.    Brea A, Laclaustra M, Martorell E, Pedragosa A (2013) Epidemiology of cerebrovascular disease in Spain. Clin Invest Arterioscl 25: 211-217.

62.    Koh SH, Park HH (2017) Neurogenesis in stroke recovery. Transl Stroke Res 8: 3-13.

63.    Abi Chahine NH, Wehbe TW, Hilal RA, Zoghbi VV, Melki AE, et al. (2016) Treatment of cerebral palsy with stem cells: A report of 17 cases. Int J Stem Cells 9: 90-95.

64.    Park KI, Lee YH, Rah WJ, Jo SH, Park SB, et al. (2017) Effect of intravenous infusion of G-CSF-mobilized peripheral blood mononuclear cells on upper extremity function in cerebral palsy children. Ann Rehab Med 41: 113-120.

65.    Liu X, Fu X, Dai G, Wang X, Zhang Z, et al. (2017) Comparative analysis of curative effect of bone marrow mesenchymal stem cell and bone marrow mononuclear cell transplantation for spastic cerebral palsy. J Transl Med 15: 48.

66.    Nguyen LT, Nguyen AT, Vu CD, Ngo DV, Bui AV (2017) Outcomes of autologous bone marrow mononuclear cells for cerebral palsy: An open label uncontrolled clinical trial. BMC Pediatr 17: 104.

67.    McDonald CA, Fahey MC, Jenkin G, Miller SL (2017) Umbilical cord blood cells for treatment of cerebral palsy; timing and treatment options. Pediatr Res Sep 22.

68.    Sun JM, Song AW, Case LE, Mikati MA, Gustafson KE, et al. (2017) Effect of autologous cord blood infusion on motor function and brain connectivity in young children with cerebral palsy: a randomized, placebo-controlled trial. Stem Cells Transl Med 6: 2071-2078.

69.    Kulak-Bejda A, Kulak P, Bejda G, Krajewska-Kulak E, et al. (2016) Stem cells therapy in cerebral palsy: A systematic review. Brain Dev 38: 699-705.

70.    Devesa J, Devesa P, Reimunde P, Arce V (2012) Growth hormone and kynesitherapy for bain injury recovery. In: Brain Injury. Pathogenesis, monitoring, recovery and management. InTech, Rijeka, Croatia.

71.    Devesa J, Casteleiro N, Rodicio C, López N, Reimunde P (2010) Growth hormone deficiency and cerebral palsy. Ther Clin Risk Manag 6: 413-418.

72.    Barcena-Orbe A, Rodríguez-Arias CA, Rivero-Martin B, Canizal-Garcia JM, Mestre-Moreiro C, et al. (2006) Overview of head injury. Neurocirugia (Astur) 17: 495-518.

73.    Ding DC, Shyu WC, Lin SZ, Li H (2006) Current concepts in adult stem cell therapy for stroke. Curr Med Chem 13: 3565-3574.

74.    Prasad K, Sharma A, Garg A, Mohanty S, Bhatnagar S, et al. (2014) Intravenous autologous bone marrow mononuclear stem cell therapy for ischemic stroke: A multicentric, randomized trial. Stroke 45: 3618-3624.

75.    Moniche F, Escudero I, Zapata-Arriaza E, Usero-Ruiz M, Prieto-León M, et al. (2015) Intra-arterial bone marrow mononuclear cells (BM-MNCs) transplantation in acute ischemic stroke (IBIS trial): Protocol of a phase II, randomized, dose-finding, controlled multicenter trial. Int J Stroke 10: 1149-1152.

76.    Azad TD, Veeravagu A, Steinberg GK (2016) Neurorestoration after stroke. Neurosurg Focus 40: E2.

77.    Steinberg GK, Kondziolka D, Wechsler LR, Lunsford LD, Coburn ML, et al. (2016) Clinical outcomes of transplanted modified bone marrow-derived mesenchymal stem cells in stroke: A phase 1/2a study. Stroke 47: 1817-1824.

78.    Kumar A, Prasad M, Jali VP, Pandit AK, Misra S, et al. (2017) Bone marrow mononuclear cell therapy in ischaemic stroke: A systematic review. Acta Neurol Scand 135: 496-506.

79.    Hess DC, Wechsler LR, Clark WM, Savitz SI, Ford GA, et al. (2017) Safety and efficacy of multipotent adult progenitor cells in acute ischaemic stroke (MASTERS): A randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Neurol 16: 360-368.

80.    Kenmuir CL, Wechsler LR (2017) Update on cell therapy for stroke. Stroke Vasc Neurol 2: 59-64.

81.    Detante O, Moisan A, Hommel M, Jaillard A (2017) Controlled clinical trials of cell therapy in stroke: Meta-analysis at six months after treatment. Int J Stroke 12: 748-751.

82.    Huang H, Lin F, Jiang J, Chen Y, Mei A, et al. (2017) Effects of intra-arterial transplantation of adipose-derived stem cells on the expression of netrin-1 and its receptor DCC in the peri-infarct cortex after experimental stroke. Stem Cell Res Ther 8: 223.

83.    Reis C, Wilkinson M, Reis H, Akyol O, Gospodarev V, et al. (2017) A look into stem cell therapy: Exploring the options for treatment of ischemic stroke. Stem Cells Int.

84.    Tsang KS, Ng CPS, Zhu XL, Wong GKC, Lu G, et al. (2017) Phase I/II randomized controlled trial of autologous bone marrow-derived mesenchymal stem cell therapy for chronic stroke. World J Stem Cells 9: 133-143.

85.    Duan X, Lu L, Wang Y, Zhang F, Mao J, et al. (2017) The long-term fate of mesenchymal stem cells labeled with magnetic resonance imaging-visible polymersomes in cerebral ischemia. Int J Nanomed 12: 6705-6719.

86.    Seo HG, Yi Y, Oh BM, Paik NJ (2017) Neuroprotective effect of secreted factors from human adipose stem cells in a rat stroke model. Neurol Res 39: 1114-1124.

87.    Wei L, Wei ZZ, Jiang MQ, Mohamad O, Yu SP (2017) Stem cell transplantation therapy for multifaceted therapeutic benefits after stroke. Prog Neurobiol 157: 49-78.

88.    Chen L, Qiu R, Li L, He D, Lv H, et al. (2014) The role of exogenous neural stem cells transplantation in cerebral ischemic stroke. J Biomed Nanotechnol 10: 3219-3230.

89.    Cox CS (2017) Cellular therapy for traumatic neurological injury. Pediatr Res.

90.    Longhi L, Zanier ER, Royo N, Stochetti N, McIntosh TK (2005) Stem cell transplantation as a therapeutic strategy for traumatic brain injury. Transpl Immunol 15: 143-148.

91.    Chen Q, Long Y, Yuan X, Zou L, Sun J, et al. (2005) Protective effects of bone marrow stromal cell transplantation in injured rodent brain: Synthesis of neurotrophic factors. J Neurosci Res 80: 611-619.

92.    Xue S, Zhang HT, Zhang P, Luo J, Chen ZZ, et al. (2010) Functional endothelial progenitor cells derived from adipose tissue show beneficial effect on cell therapy of traumatic brain injury. Neurosci Lett 473: 186-191.

93.    Walker PA, Harting MT, Jimenez F, Shah SK, Pati S, et al. (2010) Direct intrathecal implantation of mesenchymal stromal cells leads to enhanced neuroprotection via an NFkappaB-mediated increase in interleukin-6 production. Stem Cells Dev 19: 867-876.

94.    Galindo LT, Filippo TR, Semedo P, Ariza CB, Moreira CM, et al. (2011) Mesenchymal stem cell therapy modulates the inflammatory response in experimental traumatic brain injury. Neurol Res Int 2011: 564089.

95.    Grigorian AS, Gilerovich EG, Pavlichenko NN, Kruglyakov PV, Sokolova IB, et al. (2011) Effect of transplantation of mesenchymal stem cells on neuronal survival and formation of a glial scar in the brain of rats with severe traumatic brain injury. Bull Exp Biol Med 150: 551-555.

96.    Lundberg J, Sodersten E, Sundstrom E, Le Blanc K, Andersson T, et al. (2012) Targeted intra-arterial transplantation of stem cells to the injured CNS is more effective than intravenous administration: Engraftment is dependent on cell type and adhesion molecule expression. Cell Transplant 21: 333-343.

97.    Jiang J, Bu X, Liu M, Cheng P (2012) Transplantation of autologous bone marrow-derived mesenchymal stem cells for traumatic brain injury. Neural Regen Res 5: 46-53.

98.    Zhang R, Liu Y, Yan K, Chen L, Chen XR, et al. (2013) Anti-inflammatory and immunomodulatory mechanisms of mesenchymal stem cell transplantation in experimental traumatic brain injury. J Neuroinflammation 10: 106.

99.    Anbari F, Khalili MA, Bahrami AR, Khoradmehr A, Sadeghian F, et al. (2014) Intravenous transplantation of bone marrow mesenchymal stem cells promotes neural regeneration after traumatic brain injury. Neural Regen Res 9: 919-923.

100.Peng W, Sun J, Sheng C, Wang Z, Wang Y, et al. (2015) Systematic review and meta-analysis of efficacy of mesenchymal stem cells on locomotor recovery in animal models of traumatic brain injury. Stem Cell Res Ther 6: 47.

101.Turtzo LC, Budde MD, Dean DD, Gold EM, Lewis BK, et al. (2015) Failure of intravenous or intracardiac delivery of mesenchymal stromal cells to improve outcomes after focal traumatic brain injury in the female rat. PLoS One 10: e0126551.

102.Mishra SK, Rana P, Khushu S, Gangenahalli G (2017) Therapeutic prospective of infused allogenic cultured mesenchymal stem cells in traumatic brain injury mice: A longitudinal proton magnetic resonance spectroscopy assessment. Stem Cells Transl Med 6: 316-329.

103.Dori I, Petrakis S, Giannakopoulou A, Bekiari C, Grivas I, et al. (2017) Seven days post-injury fate and effects of genetically labelled adipose-derived mesenchymal cells on a rat traumatic brain injury experimental model. Histol Histopathol 32: 1041-1055.

104.Hasan A, Deeb G, Rahal R, Atwi K, Mondello S, et al. (2017) Mesenchymal stem cells in the treatment of traumatic brain injury. Front Neurol 8: 28.

105.Tian C, Wang X, Wang X, Wang L, Wang X, et al. (2013) Autologous bone marrow mesenchymal stem cell therapy in the subacute stage of traumatic brain injury by lumbar puncture. Exp Clin Transplant 11: 176-181.

106.Liao GP, Harting MT, Hetz RA, Walker PA, Shah SK, et al. (2015) Autologous bone marrow mononuclear cells reduce therapeutic intensity for severe traumatic brain injury in children. Pediatr Crit Care Med 16: 245-255.

107.Vaquero J, Zurita M, Bonilla C, Fernández C, Rubio JJ, et al. (2017) Progressive increase in brain glucose metabolism after intrathecal administration of autologous mesenchymal stromal cells in patients with diffuse axonal injury. Cytotherapy 19: 88-94.

108.Tomita S, Li RK, Weisel RD, Mickle DA, Kim EJ, et al. (1999) Autologous transplantation of bone marrow cells improves damaged heart function. Circulation 100: II247-256.

109.Beltrami AP, Barlucchi L, Torella D, Baker M, Limana F, et al. (2003) Adult cardiac stem cells are multipotent and support myocardial regeneration. Cell 114: 763-776.

110.Torella D, Ellison GM, Méndez-Ferrer S, Ibañez B, Nadal-Ginard B (2006) Resident human cardiac stem cells: Role in cardiac cellular homeostasis and potential for myocardial regeneration. Nat Clin Pract Cardiovasc Med Suppl 1: S8-13.

111.Barile L, Messina E, Giacomello A, Marbán E (2007) Endogenous cardiac stem cells. Prog Cardiovasc Dis 50: 31-48.

112.Noiseux N, Gnecchi M, Lopez-Ilasaca M, Zhang L, Solomon SD, et al. (2006) Mesenchymal stem cells overexpressing Akt dramatically repair infarcted myocardium and improve cardiac function despite infrequent cellular fusion or differentiation. Mol Ther 14: 640-650.

113.Costoya JA, Finidori J, Moutoussamy S, Senarís R, Devesa J, et al. (1999) Activation of growth hormone receptor delivers an antiapoptotic signal: Evidence for a role of Akt in this pathway. Endocrinology 140: 5937-5943.

114.Xu JY, Liu D, Zhong Y, Huang RC (2017) Effects of timing on intracoronary autologous bone marrow-derived cell transplantation in acute myocardial infarction: A meta-analysis of randomized controlled trials. Stem Cell Res Ther 8: 231.

115.Xu JY, Cai WY, Tian M, Liu D, Huang RC (2016) Stem cell transplantation dose in patients with acute myocardial infarction: A meta-analysis. Chronic Dis Transl Med 2: 92-101.

116.Bianconi V, Sahebkar A, Kovanen P, Bagaglia F, Ricciuti B, et al. (2017) Endothelial and cardiac progenitor cells for cardiovascular repair: A controversial paradigm in cell therapy. Pharmacol Ther pii: S0163-7258(17)30214-0.

117.Bayes-Genis A, Soler-Botija C, Farré J, Sepúlveda P, Raya A, et al. (2010) Human progenitor cells derived from cardiac adipose tissue ameliorate myocardial infarction in rodents. J Mol Cell Cardio l49: 771-780.

118.Roura S, Gálvez-Montón C, Mirabel C, Vives J, et al. (2017) Mesenchymal stem cells for cardiac repair: Are the actors ready for the clinical scenario? Stem Cell Res Ther 8: 238.

119.Sacca L, Cittadini A, Fazio S (1994) Growth hormone and the heart. Endocr Rev 15: 555-573.

120.Li Q, Li B, Wang X, Leri A, Jana KP, et al. (1997) Overexpression of insulin-like growth factor-I in mice protects from myocyte death after infarction, attenuating ventricular dilation, wall stress and cardiac hypertrophy. J Clin Invest 100: 1991-1999.

121.Timsit J, Riou B, Bertherat J, Wisnewsky C, Kato NS, et al. (1990) Effects of chronic growth hormone hypersecretion on intrinsic contractility, energetics, isomyosin pattern and myosin adenosinetriphosphatase activity of ratleft ventricle. J Clin Invest 86: 507-515.

122.Cittadini A, Ishiguro Y, Stromer H, Spindler M, Moses AC, et al. (1998) Insulin-like growth factor-1 but not growth hormone augments mammalian myocardial contractility by sensitizing the myofilament to Ca2+ through a wortmannin-sensitive pathway: Studies in rat and ferret isolated muscles. Circ Res 83: 50-59.

123.Mayoux E, Ventura-Clapier R, Timsit J, Behar-Cohen F, Hoffmann C, et al. (1993) Mechanical properties of rat cardiac skinned fibers are altered by chronic growth hormone hypersecretion. Circ Res 72: 57-64.

124.Bruel A, Oxlund H (1995) Biosynthetic growth hormone increase the collagen deposition rate in rat aorta and heart. Eur J Endocrinol 132: 195-199.

125.Buerke M, Murohara T, Skurk C, Nuss C, Tomaselli K, et al. (1995) Cardioprotective effect of insulin-like growth factor I in myocardial ischemia followed by reperfusion. Proc Natl Acad Sci U S A 92: 8031-8035.

126.Ren J (2002) Short-term administration of insulin-like growth factor (IGF-1) does not induce myocardial IGF-1 resistance. Growth Horm IGF Res 12: 162-168.

127.Kusano K, Tsutsumi Y, Dean J, Gavin M, Ma H, et al. (2007) Long-term stable expression of human growth hormone by rAAV promotes myocardial protection post-myocardial infarction. J Mol Cell Cardiol 42: 390-399.

128.Rong SL, Lu YX, Liao YH, Wang XL, Wang YJ, et al. (2008) Effects of transplanted myoblasts transfected with human growth hormone gene on improvement of ventricular function of rats. Chin Med J 121: 347-354.

129.Nakajima K, Fujita J, Matsui M, Tohyama S, Tamura N, et al. (2015) Gelatin hydrogel enhances the engraftment of transplanted cardiomyocytes and angiogenesis to ameliorate cardiac function after myocardial infarction. PLos One 10: e0133308.

130.Helie A, Brinker T (2011) Clinical translation of stem cell therapy in traumatic brain inury: The potential of encapsulated mesenchymal cell biodelivery of glucagon-like peptide-1. Dialogues Clin Neurosci 13: 279-286.

131.Chen KH, Chen CH, Wallace CG, Yuen CM, Kao GS, et al. (2016) Intravenous administration of xenogenic adipose-derived mesenchymal stem cells (ADMSC) and ADMSC-derived exosomes markedly reduced brain infarct volume and preserved neurological function in rat after acute ischemic stroke. Oncotarget 7: 74537-74556.

132.Bang OY, Kim BH, Cha JM, Moon GJ (2016) Adult stem cell therapy for stroke: Challenges and progress. J Stroke 18: 256-266.

133.Chung CY, Lin MH, Lee IN, Lee TH, Lee MH, et al. (2017) Brain-derived neurotrophic factor loaded PS80 PBCA nanocarrier for in vitro neural differentiation of mouse induced pluripotent stem cells. Int J Mol Sci 18: E663.

134.Wang TW, Chang KC, Chen LH, Liao SY, Yeh CW, et al. (2017) Effects of an injectable functionalized self-assembling nanopeptide hydrogel on angiogenesis and neurogenesis for regeneration of the central nervous system. Nanoscale 9: 16281-16292.

135.Shichinohe H, Kawabori M, Iijima H, Teramoto T, Abumiya T, et al. (2017) Research on advanced intervention using novel bone marrow stem cell (RAINBOW): A study protocol for a phase I, open-label, uncontrolled, dose-response trial of autologous bone marrow stromal cell transplantation in patients with acute ischemic stroke. BMC Neurol 17: 179.

136.Tseng KY, Anttila JE, Khodosevich K, Tuominen RK, Lindahl M, et al. (2017) MANF promotes differentiation and migration of neural progenitor cells with potential neural regenerative effects in stroke. Mol Ther.

137.Fisher SA, Doree C, Mathur A, Taggart DP, Martin-Rendon E (2016) Stem cell therapy for chronic ischaemic heart disease and congestive heart failure. Cochrane Database Syst Rev 2: CD007888.

138.Lewis FC, Kumar SD, Ellison-Hughes GM (2017) Non-invasive strategies for stimulating endogenous repair and regenerative mechanisms in the damaged heart. Pharmacol Res.