Regulatory Role of Fibroblast Growth Factors on Hematopoietic Stem Cells Yeoh, Joyce Siew Gaik

University of Groningen

Regulatory role of fibroblast growth factors on hematopoietic stem cells Yeoh, Joyce Siew Gaik

IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below. Document Version Publisher's PDF, also known as Version of record

Publication date: 2007

Link to publication in University of Groningen/UMCG research database

Citation for published version (APA): Yeoh, J. S. G. (2007). Regulatory role of fibroblast growth factors on hematopoietic stem cells. s.n.

Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).

Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim.

Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum.

Download date: 23-09-2021

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 turn- over 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 (FGF- 1), 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

Fgf1 gnf1m11999_at Fgf2 gnf1m01118_at Fgf4 gnf1m27000_at Fgf5 gnf1m11382_a_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 *225 *150 *130 *9,000

Relative Expression

Fgf10 gnf1m12419_at Fgf13 gnf1m00725_at Fgf14 gnf1m24788_at Fgf15 gnf1m01116_a_at

Brown fat Adipose tissue Adrenal gla nd 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 *50,000 *85 *900 *200

Relative Expression

Legend Fgf18 gnf1m27457_at Fg20 gnf1m27635_at Fgf23 gnf1m30275_at Brown fat Adipose tissue Testis Brown fat Adipose tissue Adrenal gla nd Adrenal gland Umbilical cord Bone Bone marrow Bone Uterus Amygdala Frontal cortex Preoptic Bone marrow Oocyte Trigeminal Cerebellum Amygdala Heart Cerebral cortex Dorsal root ganglia Frontal cortex Dorsal striatum Large intestine Hippocampus Hypothalamus Preoptic Small intestine Main olfactory epithelium Olfactory bulb Trigeminal Spinal cord lower B220+ B-cells Spinal cord upper Substantia nigra Cerebellum CD4+ T-cells Blastocysts Embryo day 10.5 Cerebral cortex CD8+ T-cells Embryo day 6.5 Embryo day 7.5 Embryo day 8.5 Dorsal root ganglia Liver Embryo day 9.5 Fertilized egg Dorsal striatum Lung Mammary gland (lact) Ovary Placenta Hippocampus Lymph node Prostate Testis Hypothalamus Skeletal muscle Umbilical cord Uterus Main olfactory epithelium Vomeronasal organ Oocyte Heart Large intestine Olfactory bulb Salivary gland Small intestine B220+ B-cells Spinal cord lower Tongue CD4+ T-cells CD8+ T-cells Liver Spinal cord upper Pancreas Lung Lymph node Substantia nigra Pituitary Skeletal muscle Vomeronasal organ Salivary gland Blastocysts Digits Tongue Pancreas Embryo day 10.5 Epidermis Pituitary Digits Embryo day 6.5 Epidermis Snout epidermis Snout epidermis Spleen Embryo day 7.5 Spleen Stomach Thymus Embryo day 8.5 Stomach Thyroid Trachea Bladder Embryo day 9.5 Thymus Kidney Retina Fertilized Egg

*300 Thyroid *450 *90 Mammary gland (lact) Trachea Relative Expression Ovary Bladder Placenta Kidney Prostate 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 that FGF-1 induced granulopoiesis31 and megakaryocytopoiesis32;33. 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 multi- lineage, 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 CFU- S39. 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 FGF- 2 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 FGF- 278. 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

References

1. Ornitz DM, Itoh N. Fibroblast growth factors. Genome Biology 2001;2:3005.1-3005.12.

2. Martin G. Making a vertebrate limb: new players enter from the wings. Bioessays 2001;23:865-868.

3. Ornitz DM, Marie PJ. FGF signaling pathways in endochondral and intramembranous bone development and human genetic disease. Genes Dev. 2002;16:1446-1465.

4. Ware LB, Matthay MA. Keratinocyte and hepatocyte growth factors in the lung: roles in lung development, inflammation, and repair. Am.J.Physiol Lung Cell Mol.Physiol 2002;282:L924-L940.

5. Basilico C, Moscatelli D. The FGF family of growth factors and oncogenes. Adv.Cancer Res. 1992;59:115-165.

6. Powers CJ, McLeskey SW, Wellstein A. Fibroblast growth factors, their receptors and signaling. Endocr.Relat Cancer 2000;7:165-197.

7. Abramson S, Miller RG, Phillips RA. The identification in adult bone marrow of pluripotent and restricted stem cells of the myeloid and lymphoid systems. J Exp.Med. 1977;145:1567-1579.

8. Till JE, McCulloch EA. A direct measurement of the radiation sensitivity of normal mouse bone marrow cells. Radiat.Res. 1961;14:213-222.

9. Alonso L, Fuchs E. Stem cells of the skin epithelium. Proc.Natl.Acad.Sci.U.S.A 2003;100 Suppl 1:11830-11835.

10. Ito M, Liu Y, Yang Z et al. Stem cells in the hair follicle bulge contribute to wound repair but not to homeostasis of the epidermis. Nat.Med. 2005;11:1351-1354.

11. Cotsarelis G, Sun TT, Lavker RM. Label-retaining cells reside in the bulge area of pilosebaceous unit: implications for follicular stem cells, hair cycle, and skin carcinogenesis. Cell 1990;61:1329-1337.

12. Lavker RM, Sun TT. Epidermal stem cells: properties, markers, and location. Proc.Natl.Acad.Sci.U.S.A 2000;97:13473-13475.

13. Bjerknes M, Cheng H. Clonal analysis of mouse intestinal epithelial progenitors. Gastroenterology 1999;116:7-14.

14. Hierlihy AM, Seale P, Lobe CG, Rudnicki MA, Megeney LA. The post-natal heart contains a myocardial stem cell population. FEBS Lett. 2002;530:239- 243.

15. Beltrami AP, Barlucchi L, Torella D et al. Adult cardiac stem cells are multipotent and support myocardial regeneration. Cell 2003;114:763-776.

30 Fibroblast growth factors regulates stem cell self renewal and aging

16. Lois C, Alvarez-Buylla A. Proliferating subventricular zone cells in the adult mammalian forebrain can differentiate into neurons and glia. Proc.Natl.Acad.Sci.U.S.A 1993;90:2074-2077.

17. Richards LJ, Kilpatrick TJ, Bartlett PF. De novo generation of neuronal cells from the adult mouse brain. Proc.Natl.Acad.Sci.U.S.A 1992;89:8591-8595.

18. Reynolds BA, Weiss S. Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system. Science 1992;255:1707- 1710.

19. Juckett DA. Cellular aging (the Hayflick limit) and species longevity: a unification model based on clonal succession. Mech.Ageing Dev. 1987;38:49- 71.

20. Rao MS, Mattson MP. Stem cells and aging: expanding the possibilities. Mech.Ageing Dev. 2001;122:713-734.

21. de Haan G. Hematopoietic stem cells: self-renewing or aging? Cells Tissues.Organs 2002;171:27-37.

22. Kamminga LM, de Haan G. Cellular memory and hematopoietic stem cell aging. Stem Cells 2006;24:1143-1149.

23. Itoh N, Ornitz DM. Evolution of the Fgf and Fgfr gene families. Trends Genet. 2004;20:563-569.

24. Boilly B, Vercoutter-Edouart AS, Hondermarck H, Nurcombe V, Le Bourhis X. FGF signals for cell proliferation and migration through different pathways. Cytokine & Growth Factor Reviews 2002;11:295-302.

25. Dailey L, Ambrosetti D, Mansukhani A, Basilico C. Mechanisms underlying differential responses to FGF signaling. Cytokine & Growth Factor Reviews 2005;16:233-247.

26. Su AI, Cooke MP, Ching KA et al. Large-scale analysis of the human and mouse transcriptomes. Proc.Natl.Acad.Sci.U.S.A 2002;99:4465-4470.

27. Adams GB, Scadden DT. The hematopoietic stem cell in its place. Nat.Immunol. 2006;7:333-337.

28. Arai F, Hirao A, Suda T. Regulation of hematopoietic stem cells by the niche. Trends Cardiovasc Med. 2005;15:75-79.

29. Arai F, Hirao A, Ohmura M et al. Tie2/angiopoietin-1 signaling regulates hematopoietic stem cell quiescence in the bone marrow niche. Cell 2004;118:149-161.

30. Kashiwakura I, Takahashi TA. Fibroblast growth factor and ex vivo expansion of hematopoietic progenitor cells. Leukemia & Lymphoma 2005;46:329-333.

31 Fibroblast growth factors regulates stem cell self renewal and aging

31. Yang M, Li K, Lam AC et al. Platelet-derived growth factor enhances granulopoiesis via bone marrow stromal cells. Int.J.Hematol. 2001;73:327- 334.

32. Bikfalvi A, Han ZC, Fuhrmann G. Interaction of fibroblast growth factor (FGF) with megakaryocytopoiesis and demonstration of FGF receptor expression in megakaryocytes and megakaryocytic-like cells. Blood 1992;80:1905-1913.

33. Chen QS, Wang ZY, Han ZC. Enhanced growth of megakaryocyte colonies in culture in the presence of heparin and fibroblast growth factor. Int.J.Hematol. 1999;70:155-162.

34. de Haan G, Weersing E, Dontje B et al. In vitro generation of long-term repopulating hematopoietic stem cells by fibroblast growth factor-1. Developmental Cell 2003;4:241-251.

35. Yeoh JS, van Os R, Weersing E et al. Fibroblast growth factor-1 and 2 preserve long-term repopulating ability of hematopoietic stem cells in serum- free cultures. Stem Cells 2006;24:1564-1572.

36. Crcareva A, Saito T, Kunisato A et al. Hematopoietic stem cells expanded by fibroblast growth factor-1 are excellent targets for retrovirus-mediated gene delivery. Exp.Hematol. 2005;33:1459-1469.

37. Zhang CC, Lodish HF. Murine hematopoietic stem cells change their surface phenotype during ex vivo expansion. Blood 2005;105:4314-4320.

38. Gabbianelli M, Sargiacomo M, Pelosi E et al. "Pure" human hematopoietic progenitors: permissive action of basic fibroblast growth factor. Science 1990;249:1561-1564.

39. Gallicchio VS, Hughes NK, Hulette BC, DellaPuca R, Noblitt L. Basic fibroblast growth factor (B-FGF) induces early- (CFU-s) and late-stage hematopoietic progenitor cell colony formation (CFU-gm, CFU-meg, and BFU-e) by synergizing with GM-CSF, Meg-CSF, and erythropoietin, and is a radioprotective agent in vitro. Int.J.Cell Cloning 1991;9:220-232.

40. Quito FL, Beh J, Bashayan O, Basilico C, Basch RS. Effects of fibroblast growth factor-4 (k-FGF) on long-term cultures of human bone marrow cells. Blood 1996;87:1282-1291.

41. Schofield R. The relationship between the spleen colony-forming cell and the haemopoietic stem cell. Blood Cells 1978;4:7-25.

42. Flaumenhaft R, Moscatelli D, Saksela O, Rifkin DB. Role of extracellular matrix in the action of basic fibroblast growth factor: matrix as a source of growth factor for long-term stimulation of plasminogen activator production and DNA synthesis. J.Cell Physiol 1989;140:75-81.

32 Fibroblast growth factors regulates stem cell self renewal and aging

43. Roberts R, Gallagher J, Spooncer E et al. Heparan sulphate bound growth factors: a mechanism for stromal cell mediated haemopoiesis. Nature 1988;332:376-378.

44. Brunner G, Nguyen H, Gabrilove J, Rifkin DB, Wilson EL. Basic fibroblast growth factor expression in human bone marrow and peripheral blood cells. Blood 1993;81:631-638.

45. Oliver LJ, Rifkin DB, Gabrilove J, Hannocks MJ, Wilson EL. Long-term culture of human bone marrow stromal cells in the presence of basic fibroblast growth factor. Growth Factors 1990;3:231-236.

46. Dooley DC, Oppenlander BK, Spurgin P et al. Basic fibroblast growth factor and epidermal growth factor downmodulate the growth of hematopoietic cells in long-term stromal cultures. J.Cell Physiol 1995;165:386-397.

47. Emami S, Merrill W, Cherington V et al. Enhanced growth of canine bone marrow stromal cell cultures in the presence of acidic fibroblast growth factor and heparin. In Vitro Cell Dev.Biol.Anim 1997;33:503-511.

48. Wilson EL, Rifkin DB, Kelly F, Hannocks MJ, Gabrilove JL. Basic fibroblast growth factor stimulates myelopoiesis in long-term human bone marrow cultures. Blood 1991;77:954-960.

49. Allouche M, Bikfalvi A. The role of fibroblast growth factor-2 (FGF-2) in hematopoiesis. Prog.Growth Factor Res. 1995;6:35-48.

50. Calvi LM, Adams GB, Weibrecht KW et al. Osteoblastic cells regulate the haematopoietic stem cell niche. Nature 2003;425:841-846.

51. Kuhn HG, ckinson-Anson H, Gage FH. Neurogenesis in the dentate gyrus of the adult rat: age-related decrease of neuronal progenitor proliferation. J Neurosci. 1996;16:2027-2033.

52. Kempermann G, Kuhn HG, Gage FH. Experience-induced neurogenesis in the senescent dentate gyrus. J Neurosci. 1998;18:3206-3212.

53. Gould E, Reeves AJ, Fallah M et al. Hippocampal neurogenesis in adult Old World primates. Proc.Natl.Acad.Sci.U.S.A 1999;96:5263-5267.

54. Cameron HA, McKay RD. Restoring production of hippocampal neurons in old age. Nat.Neurosci. 1999;2:894-897.

55. Kukekov VG, Laywell ED, Suslov O et al. Multipotent stem/progenitor cells with similar properties arise from two neurogenic regions of adult human brain. Exp.Neurol. 1999;156:333-344.

56. Gage FH. Mammalian neural stem cells. Science 2000;287:1433-1438.

57. Alvarez-Buylla A, Garcia-Verdugo JM, Tramontin AD. A unified hypothesis on the lineage of neural stem cells. Nat.Rev.Neurosci. 2001;2:287-293.

33 Fibroblast growth factors regulates stem cell self renewal and aging

58. Weiss S, Reynolds BA, Vescovi AL et al. Is there a neural stem cell in the mammalian forebrain? Trends Neurosci. 1996;19:387-393.

59. Seaberg RM, van der KD. Stem and progenitor cells: the premature desertion of rigorous definitions. Trends Neurosci. 2003;26:125-131.

60. Rao MS. Multipotent and restricted precursors in the central nervous system. Anat.Rec. 1999;257:137-148.

61. Reynolds BA, Tetzlaff W, Weiss S. A multipotent EGF-responsive striatal embryonic progenitor cell produces neurons and astrocytes. J.Neurosci. 1992;12:4565-4574.

62. Tropepe V, Sibilia M, Ciruna BG et al. Distinct neural stem cells proliferate in response to EGF and FGF in the developing mouse telencephalon. Dev.Biol. 1999;208:166-188.

63. Gritti A, Cova L, Parati EA, Galli R, Vescovi AL. Basic fibroblast growth factor supports the proliferation of epidermal growth factor-generated neuronal precursor cells of the adult mouse CNS. Neurosci.Lett. 1995;185:151-154.

64. Gritti A, Frolichsthal-Schoeller P, Galli R et al. Epidermal and fibroblast growth factors behave as mitogenic regulators for a single multipotent stem cell-like population from the subventricular region of the adult mouse forebrain. J Neurosci. 1999;19:3287-3297.

65. Morshead CM, Reynolds BA, Craig CG et al. Neural stem cells in the adult mammalian forebrain: a relatively quiescent subpopulation of subependymal cells. Neuron 1994;13:1071-1082.

66. Shihabuddin LS, Ray J, Gage FH. FGF-2 is sufficient to isolate progenitors found in the adult mammalian spinal cord. Exp.Neurol. 1997;148:577-586.

67. Weiss S, Dunne C, Hewson J et al. Multipotent CNS stem cells are present in the adult mammalian spinal cord and ventricular neuroaxis. J Neurosci. 1996;16:7599-7609.

68. Gritti A, Parati EA, Cova L et al. Multipotential stem cells from the adult mouse brain proliferate and self-renew in response to basic fibroblast growth factor. J.Neurosci. 1996;16:1091-1100.

69. Gage FH, Coates PW, Palmer TD et al. Survival and differentiation of adult neuronal progenitor cells transplanted to the adult brain. Proc.Natl.Acad.Sci.U.S.A 1995;92:11879-11883.

70. Doetsch F, Petreanu L, Caille I, Garcia-Verdugo JM, varez-Buylla A. EGF converts transit-amplifying neurogenic precursors in the adult brain into multipotent stem cells. Neuron 2002;36:1021-1034.

71. Zhao M, Momma S, Delfani K et al. Evidence for neurogenesis in the adult mammalian substantia nigra. Proc.Natl.Acad.Sci.U.S.A 2003;100:7925-7930.

34 Fibroblast growth factors regulates stem cell self renewal and aging

72. Reynolds BA, Weiss S. Clonal and population analyses demonstrate that an EGF-responsive mammalian embryonic CNS precursor is a stem cell. Dev.Biol. 1996;175:1-13.

73. Craig CG, Tropepe V, Morshead CM et al. In vivo growth factor expansion of endogenous subependymal neural precursor cell populations in the adult mouse brain. J.Neurosci. 1996;16:2649-2658.

74. Kuhn HG, Winkler J, Kempermann G, Thal LJ, Gage FH. Epidermal growth factor and fibroblast growth factor-2 have different effects on neural progenitors in the adult rat brain. J.Neurosci. 1997;17:5820-5829.

75. Vaccarino FM, Schwartz ML, Raballo R et al. Changes in cerebral cortex size are governed by fibroblast growth factor during embryogenesis. Nat.Neurosci. 1999;2:246-253.

76. Wagner JP, Black IB, Cicco-Bloom E. Stimulation of neonatal and adult brain neurogenesis by subcutaneous injection of basic fibroblast growth factor. J Neurosci. 1999;19:6006-6016.

77. Cheng Y, Black IB, Cicco-Bloom E. Hippocampal granule neuron production and population size are regulated by levels of bFGF. Eur.J Neurosci. 2002;15:3-12.

78. Jin K, Sun Y, Xie L et al. Neurogenesis and aging: FGF-2 and HB-EGF restore neurogenesis in hippocampus and subventricular zone of aged mice. Aging Cell 2003;2:175-183.

79. Ortega S, Ittmann M, Tsang SH, Ehrlich M, Basilico C. Neuronal defects and delayed wound healing in mice lacking fibroblast growth factor 2. Proc Natl Acad Sci U S A 1998;95:5672-5677.

80. Miller DL, Ortega S, Bashayan O, Basch R, Basilico C. Compensation by fibroblast growth factor 1 (FGF1) does not account for the mild phenotypic defects observed in FGF2 null mice. Mol.Cell Biol. 2000;20:2260-2268.

81. Feldman B, Poueymirou W, Papaioannou VE, DeChiara TM, Goldfarb M. Requirement of FGF-4 for postimplantation mouse development. Science 1995;267:246-249.

82. Meyers EN, Lewandoski M, Martin GR. An Fgf8 mutant allelic series generated by Cre- and Flp-mediated recombination. Nat.Genet. 1998;18:136- 141.

83. Reifers F, Bohli H, Walsh EC et al. Fgf8 is mutated in zebrafish acerebellar (ace) mutants and is required for maintenance of midbrain-hindbrain boundary development and somitogenesis. Development 1998;125:2381-2395.

84. Shanmugalingam S, Houart C, Picker A et al. Ace/Fgf8 is required for forebrain commissure formation and patterning of the telencephalon. Development 2000;127:2549-2561.

35 Fibroblast growth factors regulates stem cell self renewal and aging

85. Sun X, Meyers EN, Lewandoski M, Martin GR. Targeted disruption of Fgf8 causes failure of cell migration in the gastrulating mouse embryo. Genes Dev. 1999;13:1834-1846.

86. Colvin JS, Green RP, Schmahl J, Capel B, Ornitz DM. Male-to-female sex reversal in mice lacking fibroblast growth factor 9. Cell 2001;104:875-889.

87. Sekine K, Ohuchi H, Fujiwara M et al. Fgf10 is essential for limb and lung formation. Nature Genetics 1999;21:138-141.

88. Evans MJ, Kaufman MH. Establishment in culture of pluripotential cells from mouse embryos. Nature 1981;292:154-156.

89. Martin GR. Isolation of a pluripotent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells. Proc.Natl.Acad.Sci.U.S.A 1981;78:7634-7638.

90. Thomson JA, Itskovitz-Eldor J, Shapiro SS et al. Embryonic stem cell lines derived from human blastocysts. Science 1998;282:1145-1147.

91. Reubinoff BE, Pera MF, Fong CY, Trounson A, Bongso A. Embryonic stem cell lines from human blastocysts: somatic differentiation in vitro. Nat.Biotechnol. 2000;18:399-404.

92. Smith AG, Heath JK, Donaldson DD et al. Inhibition of pluripotential embryonic stem cell differentiation by purified polypeptides. Nature 1988;336:688-690.

93. Williams RL, Hilton DJ, Pease S et al. Myeloid leukaemia inhibitory factor maintains the developmental potential of embryonic stem cells. Nature 1988;336:684-687.

94. Humphrey RK, Beattie GM, Lopez AD et al. Maintenance of pluripotency in human embryonic stem cells is STAT3 independent. Stem Cells 2004;22:522- 530.

95. Amit M, Carpenter MK, Inokuma MS et al. Clonally derived human embryonic stem cell lines maintain pluripotency and proliferative potential for prolonged periods of culture. Dev.Biol. 2000;227:271-278.

96. Xu C, Inokuma MS, Denham J et al. Feeder-free growth of undifferentiated human embryonic stem cells. Nat.Biotechnol. 2001;19:971-974.

97. Wang L, Li L, Menendez P, Cerdan C, Bhatia M. Human embryonic stem cells maintained in the absence of mouse embryonic fibroblasts or conditioned media are capable of hematopoietic development. Blood 2005;105:4598-4603.

98. Xu RH, Peck RM, Li DS et al. Basic FGF and suppression of BMP signaling sustain undifferentiated proliferation of human ES cells. Nature Methods 2005;2:185-190.

36 Fibroblast growth factors regulates stem cell self renewal and aging

99. Xu C, Rosler E, Jiang J et al. Basic fibroblast growth factor supports undifferentiated human embryonic stem cell growth without conditioned medium. Stem Cells 2005;23:315-323.

100. Dvash T, Mayshar Y, Darr H et al. Temporal gene expression during differentiation of human embryonic stem cells and embryoid bodies. Hum.Reprod. 2004;19:2875-2883.

101. Ginis I, Luo Y, Miura T et al. Differences between human and mouse embryonic stem cells. Dev.Biol. 2004;269:360-380.

102. Rao RR, Calhoun JD, Qin X et al. Comparative transcriptional profiling of two human embryonic stem cell lines. Biotechnol.Bioeng. 2004;88:273-286.

103. Sato N, Sanjuan-Ignacio M, Heke M et al. Molecular signature of human embryonic stem cells and its comparison with the mouse. Developmental.Biology. 2003;260:404-413.

104. Sperger JM, Chen X, Draper JS et al. Gene expression patterns in human embryonic stem cells and human pluripotent germ cell tumors. Proc.Natl.Acad.Sci.U.S.A 2003;100:13350-13355.

105. Skottman H, Mikkola M, Lundin K et al. Gene expression signatures of seven individual human embryonic stem cell lines. Stem Cells 2005;23:1343-1356.

106. Rosler ES, Fisk GJ, Ares X et al. Long-term culture of human embryonic stem cells in feeder-free conditions. Dev.Dyn. 2004;229:259-274.

107. Carpenter MK, Rosler ES, Fisk GJ et al. Properties of four human embryonic stem cell lines maintained in a feeder-free culture system. Dev.Dyn. 2004;229:243-258.

108. McKinnon RD, Matsui T, Dubois-Dalcq M, Aaronson SA. FGF modulates the PDGF-driven pathway of oligodendrocyte development. Neuron 1990;5:603- 614.

109. Bogler O, Wren D, Barnett SC, Land H, Noble M. Cooperation between two growth factors promotes extended self-renewal and inhibits differentiation of oligodendrocyte-type-2 astrocyte (O-2A) progenitor cells. Proc.Natl.Acad.Sci.U.S.A 1990;87:6368-6372.