Embryonic Stem Cells Neural Differentiation Qualifies the Role of Wnt/beta-Catenin Signals in Human Telencephalic Specification and Regionalization

作者：Nicoleau Camille; Varela Christine; Bonnefond Caroline; Maury Yves; Bugi Aurore; Aubry Laetitia; Viegas Pedro; Bourgois Rocha Fany; Peschanski Marc; Perrier Anselme L^*

来源：Stem Cells, 2013, 31(9): 1763-1774.

DOI：10.1002/stem.1462

• Pluripotent stem cells
• Developmental biology
• Striatum
• Neural differentiation
• Forebrain specification
• Huntington disease
• Cell therapy

Wnt-ligands are among key morphogens that mediate patterning of the anterior territories of the developing brain in mammals. We qualified the role of Wnt-signals in regional specification and subregional organization of the human telencephalon using human pluripotent stem cells (hPSCs). One step neural conversion of hPSCs using SMAD inhibitors leads to progenitors with a default rostral identity. It provides an ideal biological substrate for investigating the role of Wnt signaling in both anteroposterior and dorso-ventral processes. Challenging hPSC-neural derivatives with Wnt-antagonists, alone or combined with sonic hedgehog (Shh), we found that Wnt-inhibition promote both telencephalic specification and ventral patterning of telencephalic neural precursors in a dose-dependent manner. Using optimal Wnt-antagonist and Shh-agonist signals we produced human ventral-telencephalic precursors, committed to differentiation into striatal projection neurons both in vitro and in vivo after homotypic transplantation in quinolinate-lesioned rats. This study indicates that sequentially organized Wnt-signals play a key role in the development of human ventral telencephalic territories from which the striatum arise. In addition, the optimized production of hPSC-derived striatal cells described here offers a relevant biological resource for exploring and curing Huntington disease. Stem Cells2013;31:1763-1774

• 出版日期2013-9