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Role of the Receptor-Mediated Signaling Pathways on the Proliferation and Differentiation of Pluripotent Stem Cells

  • Toshiaki Ishizuka
Chapter
Part of the Current Human Cell Research and Applications book series (CHCRA)

Abstract

Several receptor-mediated signaling pathways are involved in the self-renewal or differentiation of pluripotent stem cells such as embryonic stem (ES) cells or induced pluripotent stem (iPS) cells. The activation of the JAK/STAT pathway induced by leukemia inhibitory factor (LIF) plays a critical role in the self-renewal of mouse ES or iPS cells. However, it has been demonstrated that fibroblast growth factor 2 (FGF2) maintains self-renewal of human ES or iPS cells by supporting stable expression of the extracellular matrix proteins through the activation of the PI3K/Akt pathway. Recent studies confirm that both the MEK/ERK and the PI3K/Akt pathways are involved in the self-renewal of both mouse ES cells and iPS cells. We have also revealed that stimulation of either α1-adrenoceptor or angiotensin II type 1 receptor (AT1R) leads to an increase in human iPS cell proliferation via Gq-dependent MEK/ERK and PI3K/Akt signaling pathways independent of FGF2.

Activation of the Smad signaling pathway by bone morphogenetic proteins (BMPs) and activin/nodal has been shown to promote cardiovascular differentiation of mouse and human ES or iPS cells. In addition, treatment with isoproterenol (a β-adrenoceptor agonist) enhances the cardiovascular differentiation of human iPS cells exposed to activin A, BMP4, and FGF2. As stimulation with β-adrenoceptors promotes cAMP and PKA activation, the cardiovascular differentiation of the cells may be enhanced by cAMP/PKA-dependent signaling pathways.

It has been found that treatment with retinoic acid (RA) during embryoid body (EB) formation induces the differentiation of mouse ES cells into neural progenitor cells (NPCs). RA treatment increases the level of active cAMP response element-binding (CREB) protein by enhancing the activity of c-Jun N-terminal kinase (JNK). It has been revealed that stimulation of either β-adrenoceptors or 5-HT4 receptors enhances the RA-induced differentiation of mouse iPS cells into NPCs through activation of the cAMP/PKA signaling pathway and the enhancement of CREB phosphorylation.

This review focuses on the role of the receptor-mediated signaling pathways in the proliferation and differentiation of pluripotent stem cells. Understanding the receptor-mediated signaling pathways that influence the proliferation and differentiation of pluripotent stem cells may be useful in the development of culture conditions that promote the therapeutic effects of regenerative medicine.

Keywords

Guanine nucleotide-binding protein-coupled receptors (GPCR) Pluripotent stem cells Extracellular signal-regulated kinase (ERK) PI3K/Akt cAMP/PKA 

Notes

Acknowledgments

The results of our studies mentioned in this review were supported in part by a Grant-in-Aid for the Special Research Program from the National Defense Medical College and the Scientific Research Program from the Japan Society for the Promotion of Sciences to T.I.

References

  1. 1.
    Evans MJ, Kaufman MH. Establishment in culture of pluripotent stem cells from mouse embryos. Nature. 1981;292:154–6.CrossRefPubMedGoogle Scholar
  2. 2.
    Martin GR. Isolation of a pluripotent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells. Proc Natl Acad Sci USA. 1981;78:7634–8.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Thomson JA, Itskovitz-Eldor J, Shapiro SS, et al. Embryonic stem cell lines derived from human blastocysts. Science. 1998;282:1145–7.CrossRefPubMedGoogle Scholar
  4. 4.
    Takahashi K, Tanabe K, Ohnuki M, et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell. 2007;131:861–72.CrossRefPubMedGoogle Scholar
  5. 5.
    Kane NM, Xiao Q, Baker AH, et al. Pluripotent stem cell differentiation into vascular cells: A novel technology with promises for vascular re(generation). Pharmacol and Therapeutics. 2011;129:29–49.CrossRefGoogle Scholar
  6. 6.
    Smith AG, Hooper ML. Buffalo rat liver cells produce a diffusible activity which inhibits the differentiation of murine embryonal carcinoma and embryonic stem cells. Dev Biol. 1987;121:1–9.CrossRefPubMedGoogle Scholar
  7. 7.
    Smith AG, Heath JK, Donaldson DD, et al. Inhibition of pluripotential embryonic stem cell differentiation by purified polypeptides. Nature. 1988;336:688–90.CrossRefPubMedGoogle Scholar
  8. 8.
    Gearing DP, Gough NM, King JA, et al. Molecular cloning and expression of cDNA encoding a murine myeloid leukaemia inhibitory factor (LIF). EMBO J. 1987;6:3995–4002.PubMedPubMedCentralGoogle Scholar
  9. 9.
    Williams RL, Hilton DJ, Pease S, et al. Myeloid leukaemia inhibitory factor maintains the developmental potential of embryonic stem cells. Nature. 1988;336:684–7.CrossRefPubMedGoogle Scholar
  10. 10.
    Kristensen DM, Kalisz M, Nielsen JH. Cytokine signaling in embryonic stem cells. APMIS. 2005;113:756–72.CrossRefPubMedGoogle Scholar
  11. 11.
    Zhang JG, Owezarek CM, Ward LD, et al. Evidence for the formation of a heterotrimeric complex of leukaemia inhibitory factor with its receptor subunits in solution. Biochem J. 1997;325:693–700.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Kim MO, Na SI, Lee MY, et al. Epinephrine increases DNA synthesis via ERK1/2s through cAMP, Ca2+/PKC, and PI3K/Akt signaling pathways in mouse embryonic stem cells. J Cell Biochem. 2008;104:1407–20.CrossRefPubMedGoogle Scholar
  13. 13.
    Zhong H, Minneman KP. Alpha1-adrenoceptor subtypes. Eur J Pharmacol. 1999;375:261–76.CrossRefPubMedGoogle Scholar
  14. 14.
    Gonzalez GA, Montminy MR. Cyclic AMP stimulates somatostatin gene transcription by phosphorylation of CREB at serine133. Cell. 1989;59:675–80.CrossRefPubMedGoogle Scholar
  15. 15.
    Prenzel N, Zwick E, Daub H, et al. EGF receptor transactivation by G-protein-coupled receptors requires metalloproteinase cleavage of proHB-EGF. Nature. 1999;402:884–8.CrossRefPubMedGoogle Scholar
  16. 16.
    Han HJ, Han JY, Hao JS, et al. Ang II-stimulated DNA synthesis is mediated by Ang II receptor-dependent Ca2+/PKC as well as EGF receptor-dependent PI3K/Akt/mTOR/p70S6K1 signal pathways in mouse embryonic stem cells. J Cell Physiol. 2007;211:618–29.CrossRefPubMedGoogle Scholar
  17. 17.
    Ishizuka T, Watanabe Y. α1-adrenoceptor stimulation enhances leukemia inhibitory factor-induced proliferation of mouse-induced pluripotent stem cells. Eur J Pharmacol. 2011;668:42–56.CrossRefPubMedGoogle Scholar
  18. 18.
    Landgraf D, Barth M, Layer PG, et al. Acetylcholine as a possible signaling molecule in embryonic stem cells: studies on survival, proliferation and death. Chem Biol Interact. 2010;187:115–9.CrossRefPubMedGoogle Scholar
  19. 19.
    Heeschen C, Jang JJ, Weis M, et al. Nicotine stimulates angiogenesis and promotes tumor growth and atherosclerosis. Nat Med. 2001;7:833–9.CrossRefPubMedGoogle Scholar
  20. 20.
    Heeschen C, Chang E, Aicher A, et al. Endothelial progenitor cells participate in nicotine-mediated angiogenesis. J Am Coll Cardiol. 2006;48:2553–60.CrossRefPubMedGoogle Scholar
  21. 21.
    Ishizuka T, Ozawa A, Goshima H, et al. Involvement of nicotinic acetylcholine receptors in the proliferation of mouse induced pluripotent stem cells. Life Sciences. 2012;90:637–48.Google Scholar
  22. 22.
    Daheron L, Opitz SL, Zaehres H, et al. LIF/STAT3 signaling fails to maintain self-renewal of human embryonic stem cells. Stem Cells. 2004;22:770–8.CrossRefPubMedGoogle Scholar
  23. 23.
    Humphrey RK, Beatle GM, Lopez AD, et al. Maintenance of pluripotency in human embryonic stem cells is STAT3 independent. Stem Cells. 2004;22:522–30.CrossRefPubMedGoogle Scholar
  24. 24.
    Sumi T, Fujimoto Y, Nakatsuji N, et al. STAT3 is dispensable for maintenance of self-renewal in nonhuman primate embryonic stem cells. Stem Cells. 2004;22:861–72.CrossRefPubMedGoogle Scholar
  25. 25.
    Kim SJ, Cheon SH, Yoo SJ, et al. Contribution of the PI3K/Akt/PKB signal pathway to maintenance of self-renewal in human embryonic stem cells. FEBS Lett. 2005;579:534–40.CrossRefPubMedGoogle Scholar
  26. 26.
    Ishizuka T, Goshima H, Ozawa A, et al. Stimulation of α1-adrenoceptor or angiotensin type 1 receptor enhances DNA synthesis in human-induced pluripotent stem cells via Gq-coupled receptor-dependent signaling pathways. Eur J Pharmacol. 2013;714:202–9.CrossRefPubMedGoogle Scholar
  27. 27.
    Massague J, Chen YG. Controlling TGF-beta signaling. Genes Dev. 2000;14:627–44.PubMedGoogle Scholar
  28. 28.
    Valdimarsdottir G, Mummery C. Functions of the TGFbeta superfamily in human embryonic stem cells. Apmis. 2005;113:773–89.CrossRefPubMedGoogle Scholar
  29. 29.
    Beattie GM, Lopez AD, Bucay N, et al. Activin A maintains pluripotency of human embryonic stem cells in the absence of feeder layers. Stem cells. 2005;23:489–95.CrossRefPubMedGoogle Scholar
  30. 30.
    James D, Levine AJ, Besser D, et al. TGFbeta/ activin/ nodal signaling is necessary for the maintenance of pluripotency in human embryonic stem cells. Development. 2005;132:1273–82.CrossRefPubMedGoogle Scholar
  31. 31.
    Wang G, Zhang H, Zhao Y, et al. Noggin and bFGF cooperate to maintain the pluripotency of human embryonic stem cells in the absence of feeder layers. Biochem Biophys Res Commun. 2005;330:934–42.CrossRefPubMedGoogle Scholar
  32. 32.
    Xu RH, Peck RM, Li DS, et al. Basic FGF and suppression of BMP signaling sustain undifferentiated proliferation of human ES cells. Nat Methods. 2005;2:185–90.CrossRefPubMedGoogle Scholar
  33. 33.
    Zhang P, Li J, Tan Z, et al. Short-term BMP-4 treatment initiates mesoderm induction in human embryonic stem cells. Blood. 2008;111:1933–41.CrossRefPubMedGoogle Scholar
  34. 34.
    Chadwick K, Wang L, Li L, et al. Cytokines and BMP-4 promote hematopoietic differentiation of human embryonic stem cells. Blood. 2003;102:906–15.CrossRefPubMedGoogle Scholar
  35. 35.
    Klaus A, Sega Y, Taketo MM, et al. Distinct roles of Wnt/beta-catenin and Bmp signaling during early cardiogenesis. Proc Nat Acad Sci USA. 2007;104:18531–6.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Schulthesis TM, Burch JB, Lassar AB. A role for bone morphogenetic proteins in the induction of cardiac myogenesis. Genes Dev. 1997;11:451–62.CrossRefGoogle Scholar
  37. 37.
    Gadue P, Huber TL, Paddison PJ, et al. Wnt and TGF-beta signaling are required for the induction of an in vitro model of primitive streak formation using embryonic stem cells. Proc Nat Acad Sci USA. 2006;103:16806–11.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Kattman SJ, Huber TL, Keller GM. Multipotent Flk-1+ cardiovascular progenitor cells give rise to the cardiomyocyte, endothelial, and vascular smooth muscle lineages. Dev Cell. 2006;11:723–32.CrossRefPubMedGoogle Scholar
  39. 39.
    Kattman SJ, Witty AD, Gagliardi M, et al. Stage-specific optimization of activin/nodal and BMP signaling promotes cardiac differentiation of mouse and human pluripotent stem cell lines. Cell Stem Cell. 2011;8:228–40.CrossRefPubMedGoogle Scholar
  40. 40.
    Yang L, Soonpaa MH, Adler ED, et al. Human cardiovascular progenitor cells develop from a KDR+ embryonic-stem-cell- derived population. Nature. 2008;453:524–8.CrossRefPubMedGoogle Scholar
  41. 41.
    Bai H, Gao Y, Arzigian M, et al. BMP4 regulates vascular progenitor development in human embryonic stem cells through a Smad-dependent pathway. J Cell Biochem. 2010;109:363–74.PubMedPubMedCentralGoogle Scholar
  42. 42.
    Yan L, Jia Z, Cui J, et al. Beta-adrenergic signals regulate cardiac differentiation of mouse embryonic stem cells via mitogen-activated protein kinase pathways. Develop Growth Differ. 2011;53:772–9.CrossRefGoogle Scholar
  43. 43.
    Chen Y, Shao JZ, Xiang LX, et al. Cyclic adenosine 3′,5′-monophosphate induces differentiation of mouse embryonic stem cells into cardiomyocytes. Cell Biol Int. 2006;30:301–7.CrossRefPubMedGoogle Scholar
  44. 44.
    Drab M, Haller H, Bychkov R, et al. From totipotent embryonic stem cells to spontaneously contracting smooth muscle cells: A retinoic acid and db-cAMP in vitro differentiation model. FASEB J. 1997;11:905–15.CrossRefPubMedGoogle Scholar
  45. 45.
    Ishizuka T, Goshima H, Ozawa A, et al. Involvement of β-adrenoceptors in the differentiation of human induced pluripotent stem cells into mesodermal progenitor cells. Eur J Pharmacol. 2014;740:28–34.CrossRefPubMedGoogle Scholar
  46. 46.
    Ross SA, McCaffery PJ, Drager UC, et al. Retinoids in embryonal development. Physiol Rev. 2000;80:1021–54.CrossRefPubMedGoogle Scholar
  47. 47.
    Shan ZY, Shen JL, Li QM, et al. pCREB is involved in neural induction of mouse embryonic stem cells by RA. Anat Rec. 2008;291:519–26.CrossRefGoogle Scholar
  48. 48.
    Okada Y, Shimazaki T, Sobue G, et al. Retinoic-acid- concentration-dependent acquisition of neural cell identity during in vitro differentiation of mouse embryonic stem cells. Dev Biol. 2004;275:124–42.CrossRefPubMedGoogle Scholar
  49. 49.
    Chrivia JC, Kwok RP, Lamb N, et al. Phosphorylated CREB binds specifically to the nuclear protein CBP. Nature. 1993;365:855–9.CrossRefPubMedGoogle Scholar
  50. 50.
    Duman RS, Malberg J, Nakagawa S, et al. Neuronal plasticity and survival in mood disorders. Biol Psychiatry. 2000;48:732–9.CrossRefPubMedGoogle Scholar
  51. 51.
    Di-Gregorio A, Sancho W, Stucky DW, et al. BMP signaling inhibits premature neural differentiation in the mouse embryo. Development. 2007;134:3359–69.CrossRefPubMedGoogle Scholar
  52. 52.
    Kawasaki H, Mizuseki K, Nishikawa S, et al. Induction of midbrain dopaminergic neurons from ES cells by stromal cell-derived inducing activity. Neuron. 2000;28:31–40.CrossRefPubMedGoogle Scholar
  53. 53.
    Tropepe V, Hitoshi S, Sirard C, et al. Direct neural fate specification from embryonic stem cell: a primitive mammalian neural stem cell stage acquired through a default mechanism. Neuron. 2001;30:65–78.CrossRefPubMedGoogle Scholar
  54. 54.
    Ying QL, Nichols J, Chambers I, et al. BMP induction of Id proteins suppresses differentiation and sustains embryonic stem cell self-renewal in collaboration with STAT3. Cell. 2003;115:281–92.CrossRefPubMedGoogle Scholar
  55. 55.
    Zhang K, Li L, Huang C, et al. Distinct functions of BMP4 during different stages of mouse ES cell neural commitment. Development. 2010;137:2095–105.CrossRefPubMedGoogle Scholar
  56. 56.
    Chambers SM, Fasano CA, Papapetrou EP, et al. Highly efficient neural conversion of human ES and iPS cells by dual inhibition of SMAD signaling. Nat Biotechnol. 2009;27:275–80.CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Smith JR, Vallier L, Lupo G, et al. Inhibition of activin/nodal signaling promotes specification of human embryonic stem cells into neuroectoderm. Dev Biol. 2008;313:107–17.CrossRefPubMedGoogle Scholar
  58. 58.
    Matulka K, Lin HH, Hribkova H, et al. PTP1B is an effector of activin signaling and regulates neural specification of embryonic stem cells. Cell Stem Cell. 2013;13:706–19.CrossRefPubMedGoogle Scholar
  59. 59.
    Deng W, Ohrocka M, Fischer I, et al. In vitro differentiation of human marrow stromal cells into early progenitors of neural cells by conditions that increase intracellular cyclic AMP. Biochem Biophys Res Commun. 2001;282:148–52.CrossRefPubMedGoogle Scholar
  60. 60.
    Jori FP, Napolitano MA, Melone MA, et al. Molecular pathways involved in neural in vitro differentiation of marrow stromal stem cells. J Cell Biochem. 2005;94:645–55.CrossRefPubMedGoogle Scholar
  61. 61.
    Wang TT, Tio M, Lee W, et al. Neural differentiation of mesenchymal-like stem cells from cord blood is mediated by PKA. Biochem Biophys Res Commun. 2007;357:1021–7.CrossRefPubMedGoogle Scholar
  62. 62.
    Ishizuka T, Goshima H, Ozawa A, et al. β1-adrenoceptor stimulation enhances the differentiation of mouse induced pluripotent stem cells into neural progenitor cells. Neurosci. Lett. 2012;525:60–5.Google Scholar
  63. 63.
    Banasr M, Hery M, Printemps R, et al. Serotonin-induced increases in adult cell proliferation and neurogenesis are mediated through different and common 5-HT receptor subtypes in the dentate gyrus and the subventricular zone. Neuropsychopharmacology. 2004;29:450–60.CrossRefPubMedGoogle Scholar
  64. 64.
    Mahar I, Bambino FR, Mechawar N, et al. Stress, serotonin, and hippocampal neurogenesis in relation to depression and antidepressant effects. Neurosci Biobehav Rev. 2014;38:173–92.CrossRefPubMedGoogle Scholar
  65. 65.
    Sahay A, Hen R. Adult hippocampal neurogenesis in depression. Nat Neurosci. 2007;10:1110–5.CrossRefPubMedGoogle Scholar
  66. 66.
    Klempin F, Babu H, De Pietri Toneli D, et al. Oppositional effects of serotonin receptors 5-HT1a, 2, and 2c in the regulation of adult hippocampal neurogenesis. Front Mol Neurosci. 2010;3:1–11.Google Scholar
  67. 67.
    Zusso M, Debetto P, Guidolin D, et al. Fluoxetine-induced proliferation and differentiation of neural progenitor cells isolated from rat postnatal cerebellum. Biochem Pharmacol. 2008;76:391–403.CrossRefPubMedGoogle Scholar
  68. 68.
    Ishizuka T, Goshima H, Ozawa A, et al. Stimulation of 5-HT4 receptor enhances differentiation of mouse induced pluripotent stem cells into neural progenitor cells. Clin Exp Pharmacol Physiol. 2014;41:345–50.CrossRefPubMedGoogle Scholar
  69. 69.
    Reddy UR, Basu A, Bannerman P, et al. ZPK inhibits PKA induced transcriptional activation by CREB and blocks retinoic acid induced neuronal differentiation. Oncogene. 1999;18:4474–84.CrossRefPubMedGoogle Scholar

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© Springer Nature Singapore Pte Ltd. 2018

Authors and Affiliations

  1. 1.Department of PharmacologyNational Defense Medical CollegeSaitamaJapan

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