在体外利用原始多能干细胞捕获人类滋养层细胞的发育。

Capturing human trophoblast development with naive pluripotent stem cells in vitro.

机构信息

Department of Life Science Frontiers, CiRA, Kyoto University, Kyoto 606-8507, Japan; Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan; Japan Society for the Promotion of Science, Tokyo 102-0083, Japan.

Department of Life Science Frontiers, CiRA, Kyoto University, Kyoto 606-8507, Japan.

出版信息

Cell Stem Cell. 2021 Jun 3;28(6):1023-1039.e13. doi: 10.1016/j.stem.2021.03.013. Epub 2021 Apr 7.

DOI:10.1016/j.stem.2021.03.013

PMID:33831365

Abstract

Trophoblasts are extraembryonic cells that are essential for maintaining pregnancy. Human trophoblasts arise from the morula as trophectoderm (TE), which, after implantation, differentiates into cytotrophoblasts (CTs), syncytiotrophoblasts (STs), and extravillous trophoblasts (EVTs), composing the placenta. Here we show that naïve, but not primed, human pluripotent stem cells (PSCs) recapitulate trophoblast development. Naive PSC-derived TE and CTs (nCTs) recreated human and monkey TE-to-CT transition. nCTs self-renewed as CT stem cells and had the characteristics of proliferating villous CTs and CTs in the cell column of the first trimester. Notably, although primed PSCs differentiated into trophoblast-like cells (BMP4, A83-01, and PD173074 [BAP]-treated primed PSCs [pBAPs]), pBAPs were distinct from nCTs and human placenta-derived CT stem cells, exhibiting properties consistent with the amnion. Our findings establish an authentic paradigm for human trophoblast development, demonstrating the invaluable properties of naive human PSCs. Our system provides a platform to study the molecular mechanisms underlying trophoblast development and related diseases.

摘要

滋养层细胞是胚胎外细胞，对于维持妊娠至关重要。人类滋养层细胞起源于桑葚胚的滋养外胚层（TE），在着床后，它分化为细胞滋养层细胞（CTs）、合体滋养层细胞（STs）和绒毛外滋养层细胞（EVTs），构成胎盘。在这里，我们表明幼稚的，但不是初始的，人类多能干细胞（PSCs）能够重现滋养层细胞的发育。幼稚的 PSC 衍生的 TE 和 CT（nCTs）再现了人类和猴子的 TE-CT 转变。nCTs 自我更新为 CT 干细胞，并具有增殖性绒毛 CT 和早孕期细胞柱 CT 的特征。值得注意的是，尽管初始的 PSCs 分化为滋养层样细胞（BMP4、A83-01 和 PD173074 [BAP]处理的初始 PSCs [pBAPs]），但 pBAPs 与 nCTs 和源自人类胎盘的 CT 干细胞不同，表现出与羊膜一致的特性。我们的发现为人类滋养层细胞的发育建立了一个真实的范例，展示了幼稚的人类 PSCs 的宝贵特性。我们的系统为研究滋养层细胞发育和相关疾病的分子机制提供了一个平台。