A Complex Role for FGF-2 in Self-Renewal, Survival, and Adhesion of Human Embryonic Stem Cells

Abstract

The transcription program that is responsible for the pluripotency of human ESCs (hESCs) is believed to be comaintained by exogenous fibroblast growth factor-2 (FGF-2), which activates FGF receptors (FGFRs) and stimulates the mitogen-activated protein kinase (MAPK) pathway. However, the same pathway is stimulated by insulin receptors, insulin-like growth factor 1 receptors, and epidermal growth factor receptors. This mechanism is further complicated by intracrine FGF signals. Thus, the molecular mechanisms by which FGF-2 promotes the undifferentiated growth of hESCs are unclear. Here we show that, in undifferentiated hESCs, exogenous FGF-2 stimulated the expression of stem cell genes while suppressing cell death and apoptosis genes. Inhibition of autocrine FGF signaling caused upregulation of differentiation-related genes and downregulation of stem cell genes. Thus, exogenous FGF-2 reinforced the pluripotency maintenance program of intracrine FGF-2 signaling. Consistent with this hypothesis, expression of endogenous FGF-2 decreased during hESC differentiation and FGF-2 knockdown-induced hESC differentiation. In addition, FGF-2 signaling via FGFR2 activated MAPK kinase/extracellular signal-regulated kinase and AKT kinases, protected hESC from stress-induced cell death, and increased hESC adhesion and cloning efficiency. This stimulation of self-renewal, cell survival, and adhesion by exogenous and endogenous FGF-2 may synergize to maintain the undifferentiated growth of hESCs. Disclosure of potential conflicts of interest is found at the end of this article.

Shown for reading. Its publisher allows quoting it, not republishing it.

References 46

1. 1.

   Dvorak P, Dvorakova D, Koskova S, et al. Expression and potential role of fibroblast growth factor 2 and its receptors in human embryonic stem cells. Stem Cells. 2005;23:1200-1211.

   Not in our library10.1634/stemcells.2004-0303

2. 2.

   Levenstein ME, Ludwig TE, Xu RH, et al. Basic fibroblast growth factor support of human embryonic stem cell self-renewal. Stem Cells. 2006;24:568-574.

   Not in our library10.1634/stemcells.2005-0247

3. 3.

   Vallier L, Alexander M, Pedersen RA. Activin/nodal and FGF pathways cooperate to maintain pluripotency of human embryonic stem cells. J Cell Sci. 2005;118:4495-4509.

   Not in our library10.1242/jcs.02553

4. 4.

   Beattie GM, Lopez AD, Bucay N, et al. Activin A maintains pluripotency of human embryonic stem cells in the absence of feeder layer. Stem Cells. 2005;23:489-495.

   Not in our library10.1634/stemcells.2004-0279

5. 5.

   Xiao L, Yuan X, Sharkis SJ. Activin A maintains self-renewal and regulates fibroblast growth factor, Wnt, and bone morphogenic protein pathways in human embryonic stem cells. Stem Cells. 2006;24:1476-1486.

   Not in our library10.1634/stemcells.2005-0299

6. 6.

   Amit M, Shariki C, Margulets V, et al. Feeder layer- and serum-free culture of human embryonic stem cells. Biol Reprod. 2004;70:837-845.

   Not in our library10.1095/biolreprod.103.021147

7. 7.

   Dravid G, Ye ZH, Hammond H, et al. Defining the role of Wnt/β-catenin signaling in the survival, proliferation, and self-renewal of human embryonic stem cells. Stem Cells. 2005;23:1489-1501.

   Not in our library10.1634/stemcells.2005-0034

8. 8.

   Lu J, Hou RH, Booth CJ, et al. Defined culture conditions of human embryonic stem cells. Proc Natl Acad Sci USA. 2006;103:5688-5693.

   Not in our library10.1073/pnas.0601383103

9. 9.

   Cai LH, Ye ZH, Zhou BY, et al. Promoting human embryonic stem cell renewal or differentiation by modulating Wnt signal and culture conditions. Cell Res. 2007;17:62-72.

   Not in our library10.1038/sj.cr.7310138

10. 10.

    Schenke-Layland K, Angelis E, Rhodes KE, et al. Collagen IV induces trophoectoderm differentiation of mouse embryonic stem cells. Stem Cells. 2007;25:1529-1538.

    Not in our library10.1634/stemcells.2006-0729

11. 11.

    Funa NS, Saldeen J, Akerblom B, et al. Interdependent fibroblast growth factor and activin A signaling promotes the expression of endodermal genes in differentiating mouse embryonic stem cells expressing Src homology 2-domain inactive Shb. Differentiation. 2008;76:443-453.

    Not in our library10.1111/j.1432-0436.2007.00249.x

12. 12.

    Shiraki N, Yoshida T, Araki K, et al. Guided differentiation of embryonic stem cells into Pdx1-expressing regional-specific definitive endoderm. Stem Cells. 2008;26:874-885.

    Not in our library10.1634/stemcells.2007-0608

13. 13.

    Yang S, Soonpaa MH, Adler ED, et al. Human cardiovascular progenitor cells develop from a KDR+ embryonic-stem-cell-derived population. Nature. 2008;453:524-528.

    Not in our library10.1038/nature06894

14. 14.

    Li J, Wang G, Wang C, et al. MEK/ERK signaling contributes to the maintenance of human embryonic stem cell self-renewal. Differentiation. 2007;75:299-307.

    Not in our library10.1111/j.1432-0436.2006.00143.x

15. 15.

    Greber B, Lehrach H, Adjaye J. Fibroblast growth factor 2 modulates transforming growth factor β signaling in mouse embryonic fibroblasts and human ESCs (hESCs) to support hESC self-renewal. Stem Cells. 2007;25:455-464.

    Not in our library10.1634/stemcells.2006-0476

16. 16.

    Eiselleova L, Peterkova I, Neradil J, et al. Comparative study of mouse and human feeder cells for human embryonic stem cells. Int J Dev Biol. 2008;52:353-363.

    Not in our library10.1387/ijdb.082590le

17. 17.

    Bendall SC, Stewart MH, Menendez P, et al. IGF and FGF cooperatively establish the regulatory stem cell niche of pluripotent human cells in vitro. Nature. 2007;448:1015-1021.

    Not in our library10.1038/nature06027

18. 18.

    Xu R, Sampsell-Barron TL, Gu F, et al. NANOG is a direct target of TGFβ/Activin-mediated SMAD signaling in human ESCs. Cell Stem Cell. 2008;3:196-206.

    Not in our library10.1016/j.stem.2008.07.001

19. 19.

    Jirmanova L, Pacholikova J, Krejci P, et al. O-linked carbohydrates are required for FGF-2-mediated proliferation of mouse embryonic stem cells. Int J Dev Biol. 1999;43:555-562.

    Not in our library

20. 20.

    Wang L, Schulz TC, Sherrer ES, et al. Self-renewal of human embryonic stem cells requires insulin-like growth factor-1 receptor and ERBB2 receptor signaling. Blood. 2007;110:4111-4119.

    Not in our library10.1182/blood-2007-03-082586

21. 21.

    Ying QL, Wray J, Nichols J, et al. The ground state of embryonic stem cell self-renewal. Nature. 2008;453:519-523.

    Not in our library10.1038/nature06968

22. 22.

    Yu P-J, Ferrari G, Galloway AC, et al. Basic fibroblast growth factor (FGF-2): The high molecular weight forms come of age. J Cell Biochem. 2007;100:1100-1108.

    Not in our library10.1002/jcb.21116

23. 23.

    Stachowiak MK, Maher P, Stachowiak EK. Integrative nuclear signaling in cell development: A role for FGF receptor-1. DNA Cell Biol. 2007;26:1-16.

    Not in our library10.1089/dna.2007.0664

24. 24.

    Adewumi O, Aflatoonian B, Ahrlund-Richter L, et al. Characterization of human embryonic stem cell lines by the International Stem Cell Initiative. Nat Biotechnol. 2007;25:803-816.

    Not in our library10.1038/nbt1318

25. 25.

    Al-Shahrour F, Minguez P, Tárraga J, et al. BABELOMICS: A systems biology perspective in the functional annotation of genome-scale experiments. Nucleic Acids Res. 2006;34:W472-W476.

    Not in our library10.1093/nar/gkl172

26. 26.

    Liu Y-P, Dambaeva SV, Dovzhenko V, et al. Stable plasmid-based siRNA silencing of gene expression in human embryonic stem cells. Stem Cells Dev. 2005;14:487-492.

    Not in our library10.1089/scd.2005.14.487

27. 27.

    Enver T, Soneji S, Joshi C, et al. Cellular differentiation hierarchies in normal and culture-adapted human embryonic stem cells. Hum Mol Genet. 2005;14:3129-3140.

    Not in our library10.1093/hmg/ddi345

28. 28.

    Stewart MH, Bosse M, Chadwick K, et al. Clonal isolation of hESCs reveals heterogeneity within the pluripotent stem cell compartment. Nat Methods. 2006;3:807-815.

    Not in our library10.1038/nmeth939

29. 29.

    Hasegawa K, Fujioka T, Nakamura Y, et al. A method for the selection of human embryonic stem cell sublines with high replating efficiency after single-cell dissociation. Stem Cells. 2006;24:2649-2660.

    Not in our library10.1634/stemcells.2005-0657

30. 30.

    Schamberger C, Gerner C, Cerni C. bFGF rescues 423-cells from serum starvation-induced apoptosis downstream of activated caspase-3. FEBS Lett. 2004;573:19-25.

    Not in our library10.1016/j.febslet.2004.07.053

31. 31.

    Couderc B, Prats H, Bayard F, et al. Potential oncogenic effects of basic fibroblast growth factor requires cooperation between CUG abd AUG-initiated forms. Cell Regul. 1991;2:709-718.

    Not in our library10.1091/mbc.2.9.709

32. 32.

    Quarto N, Fong KD, Longaker MT. Gene profiling of cells expressing different FGF-2 forms. Gene. 2005;356:49-68.

    Not in our library10.1016/j.gene.2005.05.014

33. 33.

    Søensen V, Nilsen T, Wiedlocha A. Functional diversity of FGF-2 isoforms by intracellular sorting. Bioessays. 2006;28:504-514.

    Not in our library10.1002/bies.20405

34. 34.

    Wang H, Dey SK. Roadmap to embryo implantation: Clues from mouse models. Nat Rev Genet. 2006;7:185-199.

    Not in our library10.1038/nrg1808

35. 35.
    Cellular and molecular responses of the uterus to embryo implantation can be elicited by locally applied growth factors · 2001

    Not checked
36. 36.

    Taniguchi F, Harada T, Yoshida S, et al. Paracrine effects of bFGF and KGF on the process of mouse blastocyst implantation. Mol Reprod Dev. 1998;50:54-62.

    Not in our library10.1002/(sici)1098-2795(199805)50:1<54::aid-mrd7>3.0.co;2-w

37. 37.

    Krejci P, Krakow D, Mekikian PB, et al. Fibroblast growth factors 1, 2, 17, and 19 are the predominant FGF ligands expressed in human fetal growth plate cartilage. Pediatr Res. 2007;61:267-272.

    Not in our library10.1203/pdr.0b013e318030d157

38. 38.

    Giannouli CC, Kletsas D. TGFβ regulates differentially the proliferation of fetal and adult human skin fibroblasts via the activation of PKA and the autocrine action of FGF-2. Cell Signal. 2006;18:1417-1429.

    Not in our library10.1016/j.cellsig.2005.11.002

39. 39.

    Billottet C, Elkhatib N, Thiery JP, et al. Targets of fibroblast growth factor 1 (FGF-1) and FGF-2 signaling involved in the invasive and tumorigenic behavior of carcinoma cells. Mol Biol Cell. 2004;15:4725-4734.

    Not in our library10.1091/mbc.e04-04-0336

40. 40.

    Mayshar Y, Rom E, Chumakov I, et al. Fibroblast growth factor 4 and its novel splice isoform have opposing effects on the maintenance of human embryonic stem cell self-renewal. Stem Cells. 2008;26:769-774.

    Not in our library10.1634/stemcells.2007-1037

Cited by papers we hold 4

• Molecular and clinical significance of fibroblast growth factor 2 (FGF2 /bFGF) in malignancies of solid and hematological cancers for personalized therapies · 2016
  No notice
• FGF, Insulin, and SMAD Signaling Cooperate for Avian Primordial Germ Cell Self-Renewal · 2015
  No notice
• Periodontal Ligament Stem Cells: Current Status, Concerns, and Future Prospects · 2015
  No notice
• An iPSC Line from Human Pancreatic Ductal Adenocarcinoma Undergoes Early to Invasive Stages of Pancreatic Cancer Progression · 2013
  Not checked

Reads

A person counts once a day per paper. We keep no cookie and no address: a reader is a hash that changes every day. Any month under five reads shows no number.