Robust cardiomyocyte differentiation from human pluripotent stem cells via temporal modulation of canonical Wnt signaling

Xiaojun Lian, Cheston Hsiao, Gisela Wilson, Kexian Zhu, Laurie B. Hazeltine, Samira M. Azarin, Kunil K. Raval, Jianhua Zhang, Timothy J. Kamp, Sean P. Palecek

Research output: Contribution to journalArticle

752 Scopus citations

Abstract

Human pluripotent stem cells (hPSCs) offer the potential to generate large numbers of functional cardiomyocytes from clonal and patient-specific cell sources. Here we show that temporal modulation of Wnt signaling is both essential and sufficient for efficient cardiac induction in hPSCs under defined, growth factor-free conditions. shRNA knockdown of β-catenin during the initial stage of hPSC differentiation fully blocked cardiomyocyte specification, whereas glycogen synthase kinase 3 inhibition at this point enhanced cardiomyocyte generation. Furthermore, sequential treatment of hPSCs with glycogen synthase kinase 3 inhibitors followed by inducible expression of β-catenin shRNA or chemical inhibitors of Wnt signaling produced a high yield of virtually (up to 98%) pure functional human cardiomyocytes from multiple hPSC lines. The robust ability to generate functional cardiomyocytes under defined, growth factor-free conditions solely by genetic or chemically mediated manipulation of a single developmental pathway should facilitate scalable production of cardiac cells suitable for research and regenerative applications.

Original languageEnglish (US)
Pages (from-to)E1848-E1857
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number27
DOIs
StatePublished - Jul 3 2012

Keywords

  • Chemically defined medium
  • Directed differentiation

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