Robust cardiomyocyte differentiation from human pluripotent stem cells via temporal modulation of canonical Wnt signaling
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- Xiaojun Lian
- Departments of aChemical and Biological Engineering and
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- Cheston Hsiao
- Departments of aChemical and Biological Engineering and
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- Gisela Wilson
- Medicine, University of Wisconsin, Madison, WI 53706; and
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- Kexian Zhu
- Departments of aChemical and Biological Engineering and
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- Laurie B. Hazeltine
- Departments of aChemical and Biological Engineering and
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- Samira M. Azarin
- Departments of aChemical and Biological Engineering and
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- Kunil K. Raval
- Medicine, University of Wisconsin, Madison, WI 53706; and
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- Jianhua Zhang
- Medicine, University of Wisconsin, Madison, WI 53706; and
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- Timothy J. Kamp
- Medicine, University of Wisconsin, Madison, WI 53706; and
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- Sean P. Palecek
- Departments of aChemical and Biological Engineering and
説明
<jats:p>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.</jats:p>
収録刊行物
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- Proceedings of the National Academy of Sciences
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Proceedings of the National Academy of Sciences 109 (27), E1848-, 2012-05-29
Proceedings of the National Academy of Sciences