| Literature DB >> 24412311 |
Kyle M Loh1, Lay Teng Ang2, Jingyao Zhang3, Vibhor Kumar3, Jasmin Ang3, Jun Qiang Auyeong3, Kian Leong Lee4, Siew Hua Choo3, Christina Y Y Lim3, Massimo Nichane3, Junru Tan3, Monireh Soroush Noghabi3, Lisa Azzola5, Elizabeth S Ng6, Jens Durruthy-Durruthy7, Vittorio Sebastiano7, Lorenz Poellinger4, Andrew G Elefanty6, Edouard G Stanley6, Qingfeng Chen8, Shyam Prabhakar3, Irving L Weissman7, Bing Lim9.
Abstract
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 hr later, suppressed endoderm and induced mesoderm. At lineage bifurcations, cross-repressive signals separated mutually exclusive fates; TGF-β 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 "pre-enhancer" states before activation, reflecting the establishment of a permissive chromatin landscape as a prelude to differentiation.Entities:
Mesh：
Substances：
Year: 2014 PMID： 24412311 PMCID： PMC4045507 DOI： 10.1016/j.stem.2013.12.007
Source DB: PubMed Journal: Cell Stem Cell ISSN： 1875-9777 Impact factor: 24.633