TY - JOUR
T1 - Rapid induction and long-term self-renewal of primitive neural precursors from human embryonic stem cells by small molecule inhibitors
AU - Li, Wenlin
AU - Sun, Woong
AU - Zhang, Yu
AU - Wei, Wanguo
AU - Ambasudhan, Rajesh
AU - Xia, Peng
AU - Talantova, Maria
AU - Lin, Tongxiang
AU - Kim, Janghwan
AU - Wang, Xiaolei
AU - Kim, Woon Ryoung
AU - Lipton, Stuart A.
AU - Zhang, Kang
AU - Ding, Sheng
PY - 2011/5/17
Y1 - 2011/5/17
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=79957777958&partnerID=8YFLogxK
U2 - 10.1073/pnas.1014041108
DO - 10.1073/pnas.1014041108
M3 - Article
C2 - 21525408
AN - SCOPUS:79957777958
VL - 108
SP - 8299
EP - 8304
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 20
ER -