Efficient Endoderm Induction from Human Pluripotent Stem Cells by Logically Directing Signals Controlling Lineage Bifurcations

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• 作者：Kyle聽M. Loh ; Lay聽Teng Ang ; Jingyao Zhang ; Vibhor Kumar ; Jasmin Ang ; Jun聽Qiang Auyeong ; Kian聽Leong Lee ; Siew聽Hua Choo ; Christina聽Y.Y. Lim ; Massimo Nichane ; Junru Tan ; Monireh聽Soroush Noghabi ; Lisa Azzola ; Elizabeth聽S. Ng ; Jens Durruthy-Durruthy ; Vittorio Sebastiano ; Lorenz Poellinger ; Andrew聽G. Elefanty ; Edouard聽G. Stanley ; Qingfeng Chen ; Shyam Prabhakar ; et al.
• 刊名：Cell Stem Cell
• 出版年：6 February, 2014
• 年：2014
• 卷：14
• 期：2
• 页码：237-252
• 全文大小：7257 K

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Summary

Human pluripotent stem cell (hPSC) differentiation typically yields heterogeneous populations. Knowledge of signals controlling embryonic lineage bifurcations could efficiently yield desired cell types through exclusion of alternate fates. Therefore, we revisited signals driving induction and anterior-posterior patterning of definitive endoderm to generate a coherent roadmap for endoderm differentiation. With striking temporal dynamics, BMP and Wnt initially specified anterior primitive streak (progenitor to endoderm), yet, 24聽hr later, suppressed endoderm and induced mesoderm. At lineage bifurcations, cross-repressive signals separated mutually exclusive fates; TGF-尾 and BMP/MAPK respectively induced pancreas versus liver from endoderm by suppressing the alternate lineage. We systematically blockaded alternate fates throughout multiple consecutive bifurcations, thereby efficiently differentiating multiple hPSC lines exclusively into endoderm and its derivatives. Comprehensive transcriptional and chromatin mapping of highly pure endodermal populations revealed that endodermal enhancers existed in a surprising diversity of 鈥減re-enhancer鈥?states before activation, reflecting the establishment of a permissive chromatin landscape as a prelude to differentiation.