Efficient Endoderm Induction from Human Pluripotent Stem Cells by Logically Directing Signals Controlling Lineage Bifurcations
| Autor: | Elizabeth Ng, Edouard G. Stanley, Vittorio Sebastiano, Bing Lim, Andrew G. Elefanty, Jun Qiang Auyeong, Siew Hua Choo, Kian Leong Lee, Massimo Nichane, Lisa Azzola, Lorenz Poellinger, Jingyao Zhang, Lay Teng Ang, Jens Durruthy-Durruthy, Shyam Prabhakar, Jasmin Ang, Vibhor Kumar, Junru Tan, Kyle M. Loh, Monireh Soroush Noghabi, Christina Ying Yan Lim, Irving L. Weissman, Qingfeng Chen |
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| Rok vydání: | 2014 |
| Předmět: |
Pluripotent Stem Cells
Mesoderm animal structures Primitive Streak Transcription Genetic MAP Kinase Signaling System Molecular Sequence Data Biology Culture Media Serum-Free Article Epigenesis Genetic Mice Transforming Growth Factor beta medicine Genetics Animals Humans Cell Lineage Induced pluripotent stem cell Pancreas Embryonic Stem Cells Body Patterning Base Sequence Primitive streak Endoderm Embryogenesis Cell Biology Embryonic stem cell Chromatin Cell biology Fibroblast Growth Factors Wnt Proteins Gastrulation Enhancer Elements Genetic medicine.anatomical_structure Liver Bone Morphogenetic Proteins embryonic structures Molecular Medicine Digestive System Protein Binding Signal Transduction Definitive endoderm |
| Zdroj: | Cell Stem Cell. 14(2):237-252 |
| ISSN: | 1934-5909 |
| DOI: | 10.1016/j.stem.2013.12.007 |
| Popis: | SummaryHuman 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. |
| Databáze: | OpenAIRE |
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