Rapid induction and long-term self-renewal of primitive neural precursors from human embryonic stem cells by small molecule inhibitors

Wenlin Li, Woong Sun, Yu Zhang, Wanguo Wei, Rajesh Ambasudhan, Peng Xia, Maria Talantova, Tongxiang Lin, Janghwan Kim, Xiaolei Wang, Woon Ryoung Kim, Stuart A. Lipton, Kang Zhang, Sheng Ding

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224 Citations (Scopus)

Abstract

Human embryonic stem cells (hESCs) hold enormous promise for regenerative medicine. Typically, hESC-based applications would require their in vitro differentiation into a desirable homogenous cell population. A major challenge of the current hESC differentiation paradigm is the inability to effectively capture and, in the long-term, stably expand primitive lineage-specific stem/precursor cells that retain broad differentiation potential and, more importantly, developmental stage-specific differentiation propensity. Here, we report synergistic inhibition of glycogen synthase kinase 3 (GSK3), transforming growth factor β (TGF-β), and Notch signaling pathways by small molecules can efficiently convert monolayer cultured hESCs into homogenous primitive neuroepithelium within 1 wk under chemically defined condition. These primitive neuroepithelia can stably self-renew in the presence of leukemia inhibitory factor, GSK3 inhibitor (CHIR99021), and TGF-β receptor inhibitor (SB431542); retain high neurogenic potential and responsiveness to instructive neural patterning cues toward midbrain and hindbrain neuronal subtypes; and exhibit in vivo integration. Our work uniformly captures and maintains primitive neural stem cells from hESCs.

Original languageEnglish
Pages (from-to)8299-8304
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number20
DOIs
Publication statusPublished - 2011 May 17

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    Li, W., Sun, W., Zhang, Y., Wei, W., Ambasudhan, R., Xia, P., Talantova, M., Lin, T., Kim, J., Wang, X., Kim, W. R., Lipton, S. A., Zhang, K., & Ding, S. (2011). Rapid induction and long-term self-renewal of primitive neural precursors from human embryonic stem cells by small molecule inhibitors. Proceedings of the National Academy of Sciences of the United States of America, 108(20), 8299-8304. https://doi.org/10.1073/pnas.1014041108