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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].
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.
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.
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].
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
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].
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.
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.
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