Human embryonic stem cells with biological and epigenetic characteristics similar to those of mouse ESCs

Jacob Hanna, Albert W. Cheng, Krishanu Saha, Jongpil Kim, Christopher J. Lengner, Frank Soldner, John P. Cassady, Julien Muffat, Bryce W. Carey, Rudolf Jaenisch

Research output: Contribution to journalArticle

585 Scopus citations

Abstract

Human and mouse embryonic stem cells (ESCs) are derived from blastocyst-stage embryos but have very different biological properties, and molecular analyses suggest that the pluripotent state of human ESCs isolated so far corresponds to that of mouse-derived epiblast stem cells (EpiSCs). Here we rewire the identity of conventional human ESCs into a more immature state that extensively shares defining features with pluripotent mouse ESCs. This was achieved by ectopic induction of Oct4, Klf4, and Klf2 factors combined with LIF and inhibitors of glycogen synthase kinase 3β (GSK3β) and mitogen-activated protein kinase (ERK1/2) pathway. Forskolin, a protein kinase A pathway agonist which can induce Klf4 and Klf2 expression, transiently substitutes for the requirement for ectopic transgene expression. In contrast to conventional human ESCs, these epigenetically convertedcellshave growth properties,an X-chromosome activation state (XaXa), a gene expression profile, and a signaling pathway dependence that are highly similar to those of mouse ESCs. Finally, the same growth conditions allow the derivation of human induced pluripotent stem (iPS) cells with similar properties as mouse iPS cells. The generation of validated "naïve" human ESCs will allow the molecular dissection of a previously undefined pluripotent state in humans and may open up new opportunities for patient-specific, disease-relevant research.

Original languageEnglish (US)
Pages (from-to)9222-9227
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number20
DOIs
StatePublished - May 18 2010
Externally publishedYes

Keywords

  • Pluripotency
  • Reprogramming

ASJC Scopus subject areas

  • General

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