GATA3 Mediates a Fast, Irreversible Commitment to BMP4-Driven Differentiation in Human Embryonic Stem Cells

Abstract

Summary During early development, extrinsic triggers prompt pluripotent cells to begin the process of differentiation. When and how human embryonic stem cells (hESCs) irreversibly commit to differentiation is a fundamental yet unanswered question. By combining single-cell imaging, genomic approaches, and mathematical modeling, we find that hESCs commit to exiting pluripotency unexpectedly early. We show that bone morphogenetic protein 4 (BMP4), an important differentiation trigger, induces a subset of early genes to mirror the sustained, bistable dynamics of upstream signaling. Induction of one of these genes, GATA3, drives differentiation in the absence of BMP4. Conversely, GATA3 knockout delays differentiation and prevents fast commitment to differentiation. We show that positive feedback at the level of the GATA3-BMP4 axis induces fast, irreversible commitment to differentiation. We propose that early commitment may be a feature of BMP-driven fate choices and that interlinked feedback is the molecular basis for an irreversible transition from pluripotency to differentiation.

Higher BMP Expression in Tendon Stem/Progenitor Cells Contributes to the Increased Heterotopic Ossification in Achilles Tendon With Aging

“…In this study, the expression levels of BMPs in TSPC was increased with aging and upon osteogenic induction, indicating the intimate relationship between BMP expression and osteogenic differentiation potential of TSPC. In addition, BMP-2 could increase the osteogenic differentiation potential of TSPCs in this study, and BMPs also regulated differentiation ability of other cell species, such as tenocytes (Sato et al, 1988), embryonic stem cells (Gunne-Braden et al, 2020), and MSCs (Zhang et al, 2019). At the same time, we have tested the effect of noggin on the osteogenic differentiation of TSPCs in vitro, and the results showed that the addition of noggin could inhibit BMP-induced enhancement of osteogenic differentiation of TSPCs.…”

Centimeter-scale quorum sensing dictates collective survival of differentiating embryonic stem cells

“…This, combined with our study, suggests that one will likely find global community effects among ex vivo embryonic structures, in which large numbers of multicellular structures (e.g., blastocysts) communicate amongst them on a plate. Using our type of systematic approach, one may uncover such global community effects which may involve both secreted molecules (3,(57)(58)(59)(60)(61)(62) and cellcell contact-mediated communication (63)(64)(65)(66). The latter did not enter our analysis as we sparsely seeded near-single cells.…”

Translating Embryogenesis to Generate Organoids: Novel Approaches to Personalized Medicine

“…Dual SMAD signaling (BMP4 and TGF-β) activation leads to PS formation in ESCs while blocking ectodermal commitment. BMP4 in the presence of FGF2 is the critical regulator that leads to the upregulation of mesoderm-related genes ( Brachyury, Cdx2, Tbx3, and Gata4 ) in hESCs ( Gunne-Braden et al., 2020 ), whereas TGF-β inhibition accelerates mesoderm formation from PS and blocks endoderm specification ( Loh et al., 2014 ). This strategy was used to differentiate ESCs into hematopoietic precursor ( Pearson et al., 2008 ; Zhang et al., 2008 ) and endothelial progenitors ( Goldman et al., 2009 ) that was instrumental in the formation of cardiac organoids resembling human fetal hearts ( Voges et al., 2017 ).…”