University of Groningen
Regulatory role of fibroblast growth factors on hematopoietic stem cells
Yeoh, Joyce Siew Gaik
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CHAPTER 1
Fibroblast growth factors as regulators of stem cell
self renewal and aging
Joyce S. G. Yeoh and Gerald de Haan
Department of Cell Biology, Section Stem Cell Biology, University
Medical Centre Groningen, The Netherlands
Submitted in Mechanisms of Ageing and Development, in press
17
Fibroblast growth factors regulates stem cell self renewal and aging
Abstract
Organ and tissue dysfunction which is readily observable during aging results from a
loss of cellular homeostasis and reduced stem cell self renewal. Over the past 10
years, studies have been aimed at delineating growth factors that will sustain and
promote the self renewal potential of stem cells and support the expansion of
primitive stem cells in vitro and in vivo. Recently, strong evidence is emerging
indicating that fibroblast growth factors (FGFs) play a crucial role in stem cell
maintenance. FGFs belong to a family of polypeptide growth factors that are involved
in multiple functions including cell proliferation, differentiation, survival and motility.
In this review, we discuss the regulatory role of FGFs on hematopoietic stem cells
(HSCs), neural stem cells (NSCs) and embryonic stem (ES) cells in maintaining stem
cell self renewal. These findings are useful and important to further our knowledge in
stem cell biology and for therapeutic approaches.
18
Fibroblast growth factors regulates stem cell self renewal and aging
Introduction
FGFs are a family of polypeptide growth factors that are involved in embryonic
development and adult tissue homeostasis. Twenty-two FGF genes have been
identified in the genome of humans and mice1. During embryogenesis, FGFs (FGF-7,
-8 and -10) govern the development of parenchymal organs, such as the lung and
limb2-4. In adults, FGFs are important in maintaining general tissue homeostasis,
including functions such as tissue repair and regeneration, metabolism and
angiogenesis5;6.
Stem cells are active during embryonic development and in most adult tissues, playing
an important role in normal homeostasis and tissue integrity. In adult tissues, stem
cells have been identified or isolated from an ever increasing array of tissues, such as
bone marrow7;8, skin9-12, intestinal epithelium13, myocardium14;15 and brain16-18.The
unique ability of tissue specific stem cells to self renew, differentiate and proliferate is
critically important to an organism during development and to maintain tissue
homeostasis. Stem cell self renewal ensures that a potentially unlimited supply of
stem cells exists, irrespective of demands put on the system by repetitive cell turnover during aging or stress.
However, unlimited stem cell self renewal may not exist, as stem cells are exposed to
both intrinsic and extrinsic effectors of damage. For example, the skin will age more
rapidly for an individual who has more exposure to ultraviolet rays than one who does
not. The liver of an alcoholic would have aged more rapidly than a teetotaler and
chemotherapeutic drugs used to treat cancer will have deleterious effects on HSCs.
Evidently, exposure to environmental or genetic factors induces differentiation and
apoptosis or inhibits the asymmetrical self renewal division of stem cells. Tissues in
which stem cell self renewal is inhibited would not be able to replenish the
differentiated cells, thereby impending function and integrity. Thus, this suggests that
tissue aging results from stem cell aging which in turn results from a decrease in stem
cell self renewal capacity19-22. Consequently, it has become increasingly important to
study regulators which will enhance stem cell self renewal during aging. Here, we
review recent advances in our understanding of the effects of FGFs on enhanced self
renewal and maintenance of stem cells. Our focus will be on HSC, NSCs and ES cells
as FGFs are crucial growth factors for all three stem cell systems. In addition, these
three stem cell species are by far the best characterized stem cells in in vitro and in
19
Fibroblast growth factors regulates stem cell self renewal and aging
vivo models. Finally, these stem cells appear to be of vital relevance in a variety of
age-related diseases, ranging from hematopoietic disorders, cancer, cardiovascular
disease and neurodegenerative disorders.
Fibroblast Growth Factors
To date, 22 FGFs have been identified. They range in molecular weight from 17 to 34
kDa and share 13-71% amino acid identity in vertebrates (reviewed by Ornitz and
Itoh, 20011). FGFs mediate their biological responses by binding with high affinity to
cell surface tyrosine kinase FGF receptors (FGFR). Four functional FGFR genes
(Fgfr1-Fgfr4) have been identified in vertebrates1. Following receptor binding, FGFs
induce dimerization and phosphorylation of specific cytoplasmic tyrosine residues.
The phosphorylation of FGFRs triggers the activation of downstream cytoplasmic
signal transduction pathways23. Furthermore, FGFs interact with low affinity to
heparan sulfate proteoglycans (HSPGs)24, which acts to stabilize FGFs and prevent
thermal denaturation and proteolysis. In addition HSPGs are required for FGFs to
activate FGFRs effectively (reviewed by Powers et al. 2000; Dailey et al. 2005 6;25).
The expression of all known FGFs in an array of mouse and human tissues and
organs, was analyzed by researchers at the Genomics Institute of the Novartis
Research Foundation (GNF) and is publicly available in the SymAtlas database
(http://symatlas.gnf.org/SymAtlas/)26. Figure 1.1 illustrates a selection of those FGFs
with the most variable expression levels across various tissues and organs. Most FGFs
are ubiquitously expressed. However, some FGFs are selectively expressed in tissues
and organs such as spleen (FGF-2), blastocysts (FGF-4), kidney (FGF-1), lung (FGF1), dorsal root ganglion (FGF-1 and -13), embryo (FGF-5 and -15), salivary gland
(FGF-23), pancreas (FGF-4 and -18) and pituitary (FGF-14). The complex expression
of FGFs suggests that these growth factors play an important role in maintaining
tissue homeostasis in many tissues and organs.
20
Fibroblast growth factors regulates stem cell self renewal and aging
Fgf4 gnf1m27000_at
Fgf5 gnf1m11382_a_at
*130
*225
*9,000
Fgf2 gnf1m01118_at
*150
Fgf1 gnf1m11999_at
Brown fat
Adipose tissue
Adrenal gland
Bone
Bone marrow
Amygdala
Frontal cortex
Preoptic
Trigeminal
Cerebellum
Cerebral cortex
Dorsal root ganglia
Dorsal striatum
Hippocampus
Hypothalamus
Main olfactory epithelium
Olfactory bulb
Spinal cord lower
Spinal cord upper
Substantia nigra
Blastocysts
Embryo day 10.5
Embryo day 6.5
Embryo day 7.5
Embryo day 8.5
Embryo day 9.5
Fertilized egg
Mammary gland (lact)
Ovary
Placenta
Prostate
Testis
Umbilical cord
Uterus
Oocyte
Heart
Large intestine
Small intestine
B220+ B-cells
CD4+ T-cells
CD8+ T-cells
Liver
Lung
Lymph node
Skeletal muscle
Vomeronasal organ
Salivary gland
Tongue
Pancreas
Pituitary
Digits
Epidermis
Snout epidermis
Spleen
Stomach
Thymus
Thyroid
Trachea
Bladder
Kidney
Retina
Relative Expression
Fgf14 gnf1m24788_at
Fgf15 gnf1m01116_a_at
*85
*200
*900
*50,000
Fgf13 gnf1m00725_at
Fgf10 gnf1m12419_at
Brown fat
Adipose tissue
Adrenal gland
Bone
Bone marrow
Amygdala
Frontal cortex
Preoptic
Trigeminal
Cerebellum
Cerebral cortex
Dorsal root ganglia
Dorsal striatum
Hippocampus
Hypothalamus
Main olfactory epithelium
Olfactory bulb
Spinal cord lower
Spinal cord upper
Substantia nigra
Blastocysts
Embryo day 10.5
Embryo day 6.5
Embryo day 7.5
Embryo day 8.5
Embryo day 9.5
Fertilized egg
Mammary gland (lact)
Ovary
Placenta
Prostate
Testis
Umbilical cord
Uterus
Oocyte
Heart
Large intestine
Small intestine
B220+ B-cells
CD4+ T-cells
CD8+ T-cells
Liver
Lung
Lymph node
Skeletal muscle
Vomeronasal organ
Salivary gland
Tongue
Pancreas
Pituitary
Digits
Epidermis
Snout epidermis
Spleen
Stomach
Thymus
Thyroid
Trachea
Bladder
Kidney
Retina
Relative Expression
Fg20 gnf1m27635_at
Relative Expression
*90
*300
Legend
Fgf23 gnf1m30275_at
*450
Fgf18 gnf1m27457_at
Brown fat
Adipose tissue
Adrenal gland
Bone
Bone marrow
Amygdala
Frontal cortex
Preoptic
Trigeminal
Cerebellum
Cerebral cortex
Dorsal root ganglia
Dorsal striatum
Hippocampus
Hypothalamus
Main olfactory epithelium
Olfactory bulb
Spinal cord lower
Spinal cord upper
Substantia nigra
Blastocysts
Embryo day 10.5
Embryo day 6.5
Embryo day 7.5
Embryo day 8.5
Embryo day 9.5
Fertilized egg
Mammary gland (lact)
Ovary
Placenta
Prostate
Testis
Umbilical cord
Uterus
Oocyte
Heart
Large intestine
Small intestine
B220+ B-cells
CD4+ T-cells
CD8+ T-cells
Liver
Lung
Lymph node
Skeletal muscle
Vomeronasal organ
Salivary gland
Tongue
Pancreas
Pituitary
Digits
Epidermis
Snout epidermis
Spleen
Stomach
Thymus
Thyroid
Trachea
Bladder
Kidney
Retina
Brown fat
Adipose tissue
Adrenal gland
Bone
Bone marrow
Amygdala
Frontal cortex
Preoptic
Trigeminal
Cerebellum
Cerebral cortex
Dorsal root ganglia
Dorsal striatum
Hippocampus
Hypothalamus
Main olfactory epithelium
Olfactory bulb
Spinal cord lower
Spinal cord upper
Substantia nigra
Blastocysts
Embryo day 10.5
Embryo day 6.5
Embryo day 7.5
Embryo day 8.5
Embryo day 9.5
Fertilized Egg
Mammary gland (lact)
Ovary
Placenta
Prostate
Testis
Umbilical cord
Uterus
Oocyte
Heart
Large intestine
Small intestine
B220+ B-cells
CD4+ T-cells
CD8+ T-cells
Liver
Lung
Lymph node
Skeletal muscle
Vomeronasal organ
Salivary gland
Tongue
Pancreas
Pituitary
Digits
Epidermis
Snout epidermis
Spleen
Stomach
Thymus
Thyroid
Trachea
Bladder
Kidney
Retina
Figure 1.1: Expression levels of FGFs in an array of tissues and organs obtained from SymAtlas
database. Only FGFs showing significant expression are shown in this figure. Further information
regarding the remaining FGFs can be found at http://symstlas.gnf.org/SymAtlas. Horizontal scales are
linear, ranging from zero to the final marked value.
21
Fibroblast growth factors regulates stem cell self renewal and aging
Effects of FGFs on stem cells
Hematopoietic Stem Cells
HSCs are pluripotent cells, possessing high proliferative and self renewal potential.
They ultimately regenerate and maintain all blood cell types of both the lymphoid and
myeloid lineages, producing billions of new circulating but short-lived cells each day.
In the early 1960s, Till and McCulloch introduced the first quantitative in vivo assay
for stem cells in the bone marrow8. Ever since, researchers have focused on soluble or
cell-bound growth factors that promote HSC self-renewal, maintenance, survival and
proliferation.
Hematopoiesis involves interactions between HSCs and stroma to provide a favorable
microenvironment for the development of progenitors. Stromal cells are an important
source of cytokines that regulate proliferation, differentiation and maturation of
progenitor cells27-29. As hematopoietic regulatory factors, FGFs can potentially exert
their effects at two critical aspects of hematopoiesis: the HSC proper and/or
maintenance of stem cell supporting stromal cells30.
Initial
studies
demonstrated
32;33
megakaryocytopoiesis
that
FGF-1
induced
granulopoiesis31
and
. Recent studies have shown that both FGF-1 and FGF-2
can sustain the proliferation of hematopoietic progenitor cells, maintaining their
primitive phenotype34-36. FGF-1 was shown to be involved in the expansion of multilineage, serially transplantable long-term repopulating HSCs34. Most noticeably, we
reported that the culturing of unfractionated mouse bone marrow in serum-free media
supplemented only with FGF-1 resulted in a significant and sustained expansion of
cells with both lymphoid and myeloid repopulating capacity34. Additionally, we
recently reported that culturing bone marrow stem cells in the combination of FGF-1
and FGF-2 for at least five weeks, maintained long-term repopulation (LTR)35. Using
the FGF culture system as a tool, Crcareva et al. demonstrated that FGF-1 expanded
bone marrow cells could be utilized for gene delivery to promote radioprotection and
increase long-term BM reconstitution36. FGF-1 has also been used in combination
with stem cell factor (SCF), thrombopoietin (TPO) and insulin-like growth factor 2
(IGF2) to culture BM HSCs for 10 days. Competitive repopulation analysis revealed a
~20-fold increase in long-term HSCs37.
FGF-2 has been known to enhance the colony stimulating activity of IL-3,
erythropoietin (Epo) and granulocyte macrophage colony stimulating factor (GM-
22
Fibroblast growth factors regulates stem cell self renewal and aging
CSF) on hematopoietic progenitor cells derived from normal human adult peripheral
blood and murine bone marrow in vitro38;39. In addition, FGF-2 appears to have a
stimulatory role on murine pluripotent hematopoietic cells in a spleen colony-forming
unit (CFU-S) assay. Murine non-adherent bone marrow cells were infused into
lethally irradiated mice to reconstitute hematopoiesis in vivo. Preincubation of the
marrow cells with FGF-2 lead to an increase in the number of day 9 and day 12 CFUS39. Several reports exist demonstrating a role of other FGFs in maintaining
hematopoiesis and HSCs. For example, FGF-4 alters the hematopoietic potential of
human long-term bone marrow cultures by increasing the number of progenitors of
the cultures40.
The stimulation of both early and late hematopoiesis suggests the presence of FGFRs
on both pluripotent and lineage committed progenitors. Fgfr1 and Fgfr2 expression
was detected in murine unfractionated bone marrow cells, and in several purified
mature peripheral cell populations (megakaryocytes and platelets, macrophages,
granulocytes, T and B lymphocytes)32. Previous studies from our group have shown
that Fgfr1, -3 and -4 can be detected on a primitive mouse Lin-Sca-1+c-Kit+ HSC
population34.
Unlike systemically acting growth factors, such as Epo and granulocyte colony
stimulating factor (G-CSF), FGFs probably function locally in a paracrine or
autocrine manner. For example, it is clear that FGF-2 plays a regulatory role in early
and late hematopoiesis possibly by interacting directly with HSCs. However, as FGF2 lacks signal sequences it is a poorly secreted protein suggesting that it must be
produced locally by surrounding cells. Thus it is of importance to know which cells
produce the growth factor in situ as these cells may specify stem cell self renewal.
Hematopoietic stem cells are in intimate contact with the bone microenvironment
(niche) and cell-cell contact appears to be responsible for the proliferative capacity of
HSCs41.Within the niche, the bone marrow extracellular matrix is postulated to serve
as a reservoir of growth factors and hematopoietic cytokines42;43. Since FGF-2 was
found to be present in the bone marrow extracellular matrix, the most obvious source
of FGF-2 is the stromal fibroblasts44, which are able to both produce and respond to
FGF-2. FGF-2 was reported to be a potent mitogen for bone marrow stromal cells in
vitro38;45-48. Non-adherent hematopoietic progenitors can grow and differentiate over a
pre-established stromal cell layer in long-term bone marrow cultures. Under these
conditions, FGF-2 stimulated myelopoiesis by increasing the number of non-adherent
23
Fibroblast growth factors regulates stem cell self renewal and aging
myeloid precursors48. Clearly, FGFs, in particular FGF-2 affects both stroma and
hematopoietic progenitor cells, indicating that it is involved in both hematopoiesis and
maintenance of the microenvironment.
It is therefore highly probable that besides acting on the stem cell itself, FGFs may
interact with stromal niche cells (Figure 1.2)29;49;50. Both mechanisms may induce the
release of other molecules important for the regulation of cell proliferation. Taken
together, these results indicate that in vitro FGFs play a variety of regulatory roles
which prolong homeostatic tissue renewal. The relevance of these in vitro data for in
vivo stem cell behavior remains to be explored. Most notably, it would be highly
relevant to assess how activities of FGFs provide a buffer against age-related cell
stress that may occur.
Figure 1.2: Mechanism of action of FGFs on HSCs. FGFs may interact directly with the HSC
promoting self renewal and/or interact with progenitor cells, releasing autocrine growth factors or other
molecules important for cell proliferation. FGFs may also interact directly with stromal cells within the
stem cell niche, releasing secondary growth factors necessary for the expansion of HSCs. Both methods
are plausible as receptors for FGFs have been found on HSCs and stromal cells. Red diamonds
represent the FGF ligand, green rectangles represent FGFR and question marks indicate that the
existence of FGF/FGFR complex remains speculative.
24
Fibroblast growth factors regulates stem cell self renewal and aging
Neural stem cells
Neurogenesis occurs throughout vertebrate life in the subgranular zone of the
hippocampal dentate gyrus and in the telencephalic subventricular zone (SVZ).
Although neurogenesis persists in the adult, its rate declines with age in rats51, mice52,
monkeys53 and humans54;55. The functional consequence of age-associated reduction
in neurogenesis is not clear. However, restoring neurogenesis may be a strategy for
preventing neural stem cell aging.
Like many other stem cells, neural stem cells (NSCs) possess three cardinal
properties: self renewal, extensive proliferation and the ability to generate functional
end-stage cells such as neurons, glial cells and oligodendrocytes (see review by Gage,
2000; Alvarez-Buylla et al., 2001; Weiss et al., 1996; Seaberg et al., 2003 and Rao,
199956-60). NSCs appear to be present in the SVZ in all vertebrate species tested. They
can be selectively cultured from the central nervous system using only two growth
factors; epidermal growth factor (EGF) and FGF-218;61;62. For example, FGF-2 and
EGF have been used alone and in combination to isolate and maintain stem cells of
the adult SVZ, the spinal cord, adult striatum and hippocampus18;63-69.
In the presence of EGF and/or FGF-2, cultured NSCs in suspension give rise to
clonally expanded aggregates called neurospheres. Cultured neurospheres will
generate neurons and glia when plated without growth factor on adhesive substrates18.
Neurospheres have been derived from adult striatum, hippocampus, mesencephalon,
SVZ and spinal cord18;67;68;70;71. It is important to realize that not all the NSC progeny
in neurospheres are stem cells. Rather, a heterogenous population of cells exists in
which only 10% to 50% of the progeny retain stem cell features and the remaining
cells undergo spontaneous differentiation. Quite similar to the situation in
hematopoiesis, this brings up the concept of a stem cell niche. The cluster of a
heterogeneous population of cells may aid the survival of NSCs in vitro or enable
growth factors such as FGF-2 to act on differentiated/accessory cells, resulting in the
release of additional growth factors which regulate NSC self renewal and
proliferation. Following in vitro culturing differentiating/differentiated cells rapidly
die and only surviving NSCs that retain long-term, self-renewal capacity produce new
neurospheres72. Neurospheres may be cultured for extended periods of time,
representing a renewable source of NSCs that may facilitate neurogenesis. It is
therefore a promising cellular source for biotherapies of neurodegenerative diseases.
25
Fibroblast growth factors regulates stem cell self renewal and aging
There is also ample evidence that FGFs are relevant for in vivo neurogenesis. The
intraventricular delivery of FGF-2 increased cell proliferation within the adult
SVZ73;74, however it no longer promoted the generation of pyramidal neurons in the
cerebral cortex75. Further studies report that subcutaneous injections of FGF-2
enhanced
dentate
neurogenesis
in
both
neonatal
and
adult
brain76;77.
Intracerebroventricular infusion of FGF-2 has been shown to upregulate dentate
neurogenesis in the aged brain78. FGF-2 knock-out mice are viable, fertile and
phenotypically indistinguishable from wild-type. However they do display a reduction
in neuronal density in the motor cortex, neuronal deficiency in the cervical spinal cord
and ectopic neurons in the hippocampal commissure79;80. With these phenotypes, it is
not surprising that FGF-2 plays such a crucial role in neurogenesis and NSCs
regulation. Mice deficient for FGF-481, FGF-882-85, FGF-986 and FGF-1087 are lethal.
Taken together, it is evident that FGF-2 plays a key role in regulating the
proliferation, differentiation and survival of NSCs in vitro and in vivo. Despite a
reduction in basal neurogenesis in dentate gyrus and SVZ the aged mouse retains the
ability to respond to neurogenesis-stimulating effects of growth factors, such as FGF278. These observations suggest that a decrease in levels of stem/progenitor cell
proliferation factors, such as FGF-2, in the microenvironment of the subgranular zone
are one of the potential causes of age-related decreases in neurogenesis. Increasing the
concentration of FGF-2 and perhaps other growth factors may decrease the process of
stem cell aging and enhance neurogenesis.
Embryonic stem cells
Embryonic stem (ES) cells are derived from totipotent cells of the inner cell mass of
the early mammalian embryo and are capable of seemingly unlimited and
undifferentiated proliferation in vitro88;89. For unknown reasons they are refractory to
the senescence program that halts proliferation in adult cells. Potentially, the high
levels of telomerase in ES cells contribute to this characteristic indefinite self renewal
potential. As a result, ES cells have much greater developmental potential than adult
stem cells. ES cell lines have been derived from mouse (mES) cells and human (hES).
The factors and culture condition that regulate and mediate self-renewal of mouse and
hES cells appear to be different, although their isolation conditions are similar.
Similar to mES cells, hES cells were initially isolated by culturing inner cell mass
cells on fibroblast feeder layers in medium containing serum90;91. In contrast to mES
26
Fibroblast growth factors regulates stem cell self renewal and aging
cells92;93, leukemia inhibiting factor (LIF) does not sustain and support hES cells90;94.
It is now widely accepted that the exogenous addition of FGF-2 to hES cells promote
hES cell self-renewal and the capacity to differentiate into a large number of somatic
cell types95;96. The addition of FGF-2 to medium containing a commercially available
serum replacement enables the clonal culture of hES cells on fibroblasts95. Recently, it
was reported that high doses of FGF-2 are adequate to maintain hES cells over 30
passages under feeder-free and serum-free growth conditions97. Wang et al. showed
that incubation of conditioned media from feeders with a neutralizing antibody against
FGF-2 abrogates the capacity of conditioned media to support hES cells, suggesting
that indeed FGF-2 is an essential factor produced by feeder cells97. The recent
observation that high dose FGF-2 (40ng/ml) can sustain hES cells has been
independently reported, thereby corroborating this important insight98;99. It has
recently been demonstrated that elevated levels of FGF-2, FGF-11, FGF-13 and all
four FGFRs are expressed in undifferentiated hES cells100-105. Correlating with
reported data, SymAtlas database analysis (Figure 1) demonstrates that most FGFs
(15 out of 22) are expressed in blastocysts and fertilized egg of the mouse genome.
The mechanism of action for FGF-2 in maintaining self-renewal of hES cells is still
not understood. Because expression of all four FGFRs was observed in cultured hES
cells106;107, one can speculate that FGF-2 may stimulate undifferentiated hES cell
proliferation directly. Alternatively, FGF-2 may block the differentiation of hES cells,
as FGF-2 has been shown to inhibit maturation of oligodendrocyte precursors108;109.
Together, it is now clear that FGF signaling is unconditionally required for the
sustained self-renewal and pluripotency of hES cells. This knowledge may serve as a
base for future developments in using FGFs to culture undifferentiated hES cells for
cell-based therapies to counteract the process of age-related diseases.
Concluding Remarks and Future Perspectives
The behavior of stem cells is carefully regulated to meet the demands of normal
homeostasis of the organism, ensuring that a balance between proliferation, survival
and differentiation exists. For many tissues, this balance is impeded during aging.
Data presented in this review describe the role of FGFs and their receptors in
promoting self-renewal, maintenance and proliferation of HSCs, ES cells and NSCs.
Many studies have shown striking similarities with respect to FGF biology shared
27
Fibroblast growth factors regulates stem cell self renewal and aging
between these three stem cell species. However, the molecular mechanisms by which
the effects of FGFs occur in all three types of stem cells remains unknown.
Although most stem cell studies that have been carried out were restricted to the use
of FGF-2. In total, 22 FGFs exist (not including spliced forms). Why has FGF-2
historically been the most commonly used growth factor? Given their pleiotropic
effects and sequence similarities it seems reasonable to argue that at least some other
members of the FGF family will possess interesting stem cell stimulating activity.
Clearly the next challenge will be to examine the effects of the remaining FGFs in
well characterized stem cell systems. Only then would we be able to begin to
understand the complete role of FGFs in regulating stem cell self renewal behavior
and its impact on cellular aging, tissue aging and indeed organismal aging.
28
Fibroblast growth factors regulates stem cell self renewal and aging
Acknowledgements
This work was supported by the National Institutes of Health (R01HL073710) and by
the Ubbo Emmius Foundation
29
Fibroblast growth factors regulates stem cell self renewal and aging
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