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

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


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.


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



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.


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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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