Erythropoietin facilitates definitive endodermal differentiation of mouse embryonic stem cells via activation of ERK signaling

Taku Kaitsuka, Kohei Kobayashi, Wakako Otsuka, Takuya Kubo, Farzana Hakim, Fan Yan Wei, Nobuaki Shiraki, Shoen Kume, Kazuhito Tomizawa

Research output: Contribution to journalArticlepeer-review

6 Citations (Scopus)


Artificially generated pancreatic β-cells from pluripotent stem cells are expected for cell replacement therapy for type 1 diabetes. Several strategies are adopted to direct pluripotent stem cells toward pancreatic differentiation. However, a standard differentiation method for clinical application has not been established. It is important to develop more effective and safer methods for generating pancreatic β-cells without toxic or mutagenic chemicals. In the present study, we screened several endogenous factors involved in organ development to identify the factor, which induced the efficiency of pancreatic differentiation and found that treatment with erythropoietin (EPO) facilitated the differentiation of mouse embryonic stem cells (ESCs) into definitive endoderm. At an early stage of differentiation, EPO treatment significantly increased Sox17 gene expression, as a marker of the definitive endoderm. Contrary to the canonical function of EPO, it did not affect the levels of phos-phorylated JAK2 and STAT5, but stimulated the phosphorylation of ERK1/2 and Akt. The MEK inhibitor U0126 significantly inhibited EPO-induced Sox17 expression. The differentiation of ESCs into definitive endoderm is an important step for the differentiation into pancreatic and other endodermal lineages. This study suggests a possible role of EPO in embryonic endodermal development and a new agent for directing the differentiation into endodermal lineages like pancreatic β-cells.

Original languageEnglish
Pages (from-to)C573-C582
JournalAmerican Journal of Physiology - Cell Physiology
Issue number5
Publication statusPublished - 2017 May


  • Definitive endoderm
  • Differentiation
  • Embryonic stem cell
  • ERK
  • Erythropoietin


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