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信号通路调控增强人类原始多能性诱导的原则。

Principles of signaling pathway modulation for enhancing human naive pluripotency induction.

机构信息

Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 7610001, Israel.

Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 7610001, Israel.

出版信息

Cell Stem Cell. 2021 Sep 2;28(9):1549-1565.e12. doi: 10.1016/j.stem.2021.04.001. Epub 2021 Apr 28.

DOI:10.1016/j.stem.2021.04.001
PMID:33915080
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8423434/
Abstract

Isolating human MEK/ERK signaling-independent pluripotent stem cells (PSCs) with naive pluripotency characteristics while maintaining differentiation competence and (epi)genetic integrity remains challenging. Here, we engineer reporter systems that allow the screening for defined conditions that induce molecular and functional features of human naive pluripotency. Synergistic inhibition of WNT/β-CATENIN, protein kinase C (PKC), and SRC signaling consolidates the induction of teratoma-competent naive human PSCs, with the capacity to differentiate into trophoblast stem cells (TSCs) and extraembryonic naive endodermal (nEND) cells in vitro. Divergent signaling and transcriptional requirements for boosting naive pluripotency were found between mouse and human. P53 depletion in naive hPSCs increased their contribution to mouse-human cross-species chimeric embryos upon priming and differentiation. Finally, MEK/ERK inhibition can be substituted with the inhibition of NOTCH/RBPj, which induces alternative naive-like hPSCs with a diminished risk for deleterious global DNA hypomethylation. Our findings set a framework for defining the signaling foundations of human naive pluripotency.

摘要

分离具有原始多能性特征的人 MEK/ERK 信号独立多能干细胞（PSCs），同时保持分化能力和（表观遗传）遗传完整性仍然具有挑战性。在这里，我们设计了报告系统，允许筛选出诱导人原始多能性的分子和功能特征的定义条件。WNT/β-CATENIN、蛋白激酶 C（PKC）和 SRC 信号的协同抑制可巩固致瘤性原始人类 PSCs 的诱导，这些细胞具有体外分化为滋养层干细胞（TSCs）和胚胎外原始内胚层（nEND）细胞的能力。在增强原始多能性方面，鼠与人之间存在不同的信号和转录要求。在原始 hPSC 中耗尽 P53 可增加其在启动和分化后对鼠-人异种嵌合胚胎的贡献。最后，MEK/ERK 抑制可以用 NOTCH/RBPj 的抑制来替代，NOTCH/RBPj 诱导具有降低的有害全基因组低甲基化风险的替代性原始样 hPSC。我们的研究结果为定义人类原始多能性的信号基础奠定了框架。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4672/8423434/a8c8a15b0d71/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4672/8423434/e9c06ef03cd3/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4672/8423434/aa172d114549/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4672/8423434/fb888723c6d9/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4672/8423434/be39f123325c/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4672/8423434/34ba753f8460/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4672/8423434/3837d6b519ee/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4672/8423434/48f8c4bd865a/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4672/8423434/a8c8a15b0d71/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4672/8423434/e9c06ef03cd3/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4672/8423434/aa172d114549/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4672/8423434/fb888723c6d9/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4672/8423434/be39f123325c/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4672/8423434/34ba753f8460/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4672/8423434/3837d6b519ee/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4672/8423434/48f8c4bd865a/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4672/8423434/a8c8a15b0d71/gr7.jpg

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