title: Rapid induction and long-term self-renewal of primitive neural precursors from human embryonic stem cells by small molecule inhibitors.
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.
authors.affiliation: Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Wenlin
authors.initials: W
authors.lastname: Li
authors.forename: Woong
authors.initials: W
authors.lastname: Sun
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.forename: Wanguo
authors.initials: W
authors.lastname: Wei
authors.forename: Rajesh
authors.initials: R
authors.lastname: Ambasudhan
authors.forename: Peng
authors.initials: P
authors.lastname: Xia
authors.forename: Maria
authors.initials: M
authors.lastname: Talantova
authors.forename: Tongxiang
authors.initials: T
authors.lastname: Lin
authors.forename: Janghwan
authors.initials: J
authors.lastname: Kim
authors.forename: Xiaolei
authors.initials: X
authors.lastname: Wang
authors.forename: Woon Ryoung
authors.initials: WR
authors.lastname: Kim
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Lipton
authors.forename: Kang
authors.initials: K
authors.lastname: Zhang
authors.forename: Sheng
authors.initials: S
authors.lastname: Ding
mesh_terms: D018929:Cell Culture Techniques; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors; D006801:Humans; D058953:Neural Stem Cells / Q000166:cytology*; D051880:Receptors, Notch / Q000037:antagonists & inhibitors; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors
chemical_list: D051880:Receptors, Notch; D016212:Transforming Growth Factor beta; D038362:Glycogen Synthase Kinase 3