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Summary Understanding epigenetic mechanisms regulating embryonic stem cell (ESC) differentiation to endothelial cells may lead to increased efficiency of generation of vessel wall endothelial cells needed for vascular engineering. Here we demonstrated that the histone demethylases KDM4A and KDM4C played an indispensable but independent role in mediating the expression of fetal liver kinase (Flk)1 and VE-cadherin, respectively, and thereby the transition of mouse ESCs (mESCs) to endothelial cells. KDM4A was shown to bind to histones associated with the Flk1 promoter and KDM4C to bind to histones associated with the VE-cadherin promoter. KDM4A and KDM4C were also both required for capillary tube formation and vasculogenesis in mice. We observed in zebrafish that KDM4A depletion induced more severe vasculogenesis defects than KDM4C depletion, reflecting the early involvement of KDM4A in specifying endothelial cell fate. These findings together demonstrate the essential role of KDM4A and KDM4C in orchestrating mESC differentiation to endothelial cells through the activation of Flk1 and VE-cadherin promoters, respectively., Highlights • Histone demethylases KDM4A and KDM4C are upregulated in endothelial differentiation • KDM4A and KDM4A bind to histones associated with Flk1 and VE-cadherin promoters • Depletion of either KDM4A or KDM4C in mESCs prevented endothelial differentiation • Depletion of KDM4A and KDM4C prevented blood vessel formation in zebrafish, In this article, Malik, Rehman, and colleagues show that the histone demethylases KDM4A and KDM4C are upregulated during the differentiation of mouse embryonic stem cells into vascular endothelial cells. Depletion of these two histone demethylases suppressed endothelial differentiation and angiogenesis in vitro as well as vascular development in a zebrafish model.

Summary Culture-expanded human mesenchymal stem cells (MSCs) are increasingly used in clinics, yet full characterization of the genomic compositions of these cells is lacking. We present a whole-genome investigation on the genetic dynamics of cultured MSCs under ex vivo establishment (passage 1 [p1]) and serial expansion (p8 and p13). We detected no significant changes in copy-number alterations (CNAs) and low levels of single-nucleotide changes (SNCs) until p8. Strikingly, a significant number (677) of SNCs were found in p13 MSCs. Using a sensitive Droplet Digital PCR assay, we tested the nonsynonymous SNCs detected by whole-genome sequencing and found that they were preexisting low-frequency mutations in uncultured mononuclear cells (∼0.01%) and early-passage MSCs (0.1%–1% at p1 and p8) but reached 17%–36% in p13. Our data demonstrate that human MSCs maintain a stable genomic composition in the early stages of ex vivo culture but are subject to clonal growth upon extended expansion., Graphical Abstract, Highlights • Whole-genome investigation reveals variances of cultured MSCs along serial passages • Human MSCs maintain a stable genomic composition in early stages of ex vivo culture • Human MSCs are subject to clonal growth upon extended expansion • The “new” SNCs present in the expanded MSCs preexist in the early cell population, Wang, Cheng, and colleagues present a whole-genome analysis on genetic dynamics of cultured MSCs under ex vivo establishment (passage 1) and serial expansion (passages 8 and 13). The data demonstrate that human MSCs maintain a stable genomic composition in the early stages of ex vivo culture but are subject to clonal growth upon extended expansion.