Overcoming Autocrine FGF Signaling-Induced Heterogeneity in Naive Human ESCs Enables Modeling of Random X Chromosome Inactivation.

Overcoming Autocrine FGF Signaling-Induced Heterogeneity in Naive Human ESCs Enables Modeling of Random X Chromosome Inactivation. Cell Stem Cell. 2020 Jul 08;: Authors: An C, Feng G, Zhang J, Cao S, Wang Y, Wang N, Lu F, Zhou Q, Wang H Abstract Primed and naive human embryonic stem cells (hESCs) do not fully recapitulate the X chromosome status observed in human preimplantation epiblast and fail to initiate random X chromosome inactivation (XCI) upon differentiation. Therefore, an ideal system for studying XCI during early human development is yet to be established. We show that incomplete blocking of autocrine fibroblast growth factor 2 (FGF2) signaling in naive hESCs drives significant heterogeneity in X chromosome and pluripotency status. We derived homozygous XaXa naive hESCs with dual allelic XIST expression and high levels of TFCP2L1, whose transcriptome and X chromosome states are similar to human preimplantation epiblast. Random XCI was initiated upon naive-to-primed conversion of these cells, and both pre- and post-XCI primed hESCs were obtained. We observed random XCI in all cells upon further differentiation of pre-XCI primed hESCs. Together, these findings enable derivation of homogeneous naive hESCs and establish a powerful platform to study human XCI. PMID: 32673569 [PubMed - as supplied by publisher]
Source: Cell Stem Cell - Category: Stem Cells Authors: Tags: Cell Stem Cell Source Type: research