Efficient endoderm induction from human pluripotent stem cells by logically directing signals controlling lineage bifurcations.
Efficient endoderm induction from human pluripotent stem cells by logically directing signals controlling lineage bifurcations.
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DOI：
10.1016/j.stem.2013.12.007
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发表时间：
2014-02-06
期刊：
影响因子：
23.9
通讯作者：
Lim, Bing
中科院分区：
文献类型：
--
作者：
Loh, Kyle M.;Ang, Lay Teng;Zhang, Jingyao;Kumar, Vibhor;Ang, Jasmin;Auyeong, Jun Qiang;Lee, Kian Leong;Choo, Siew Hua;Lim, Christina Y. Y.;Nichane, Massimo;Tan, Junru;Noghabi, Monireh Soroush;Azzola, Lisa;Ng, Elizabeth S.;Durruthy-Durruthy, Jens;Sebastiano, Vittorio;Poellinger, Lorenz;Elefanty, Andrew G.;Stanley, Edouard G.;Chen, Qingfeng;Prabhakar, Shyam;Weissman, Irving L.;Lim, Bing
人类多能干细胞（hPSC）分化通常产生异质群体。控制胚胎谱系分叉的信号的知识可以通过排除交替命运有效地产生所需的细胞类型。因此，我们重新审视了驱动诱导和确定内胚层前后模式的信号，以生成内胚层分化的连贯路线图。在惊人的时间动态下，BMP和Wnt最初指定前原始条纹（内胚层的祖细胞），但24小时后抑制内胚层并诱导中胚层。在谱系分叉处，交叉抑制信号分离了相互排斥的命运：TGFβ和BMP/MAPK分别通过抑制交替谱系诱导胰腺和肝脏从内胚层分化。我们系统地阻断了多个连续分叉的交替命运，从而有效地将多个hPSC细胞系专门分化为内胚层及其衍生物。对高纯度内胚层群体的全面转录和染色质定位揭示了内胚层增强子在激活前以令人惊讶的多样性“前增强子”状态存在，反映了作为分化前奏的允许染色质景观的建立。
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 hours later suppressed endoderm and induced mesoderm. At lineage bifurcations, cross-repressive signals separated mutually-exclusive fates: TGFβ 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 establishment of a permissive chromatin landscape as a prelude to differentiation.
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