Chemokine CCL2 Activates Hypoxia Response Factors Regulating Pluripotency and Directed Endothelial Differentiation of Human Pluripotent Stem Cells

Abstract—Human pluripotent stem cell (PSC) research is currently focused on selecting conditions and growth factors that better mimic preimplantation development and germ cell differentiation, which is important for disease modeling using PSC. Previously, it was shown that, in the presence of the chemokine CCL2, human PSCs acquire properties attributable for preimplantation blastomeres, namely, they activate the JAK-STAT3 signaling pathway and increase the mRNA level of the hypoxic response genes. However, CCL2 is hardly used in human PSCs cultivation, and its effect is described in a single study. We continued to study the effect of CCL2 on human PSC and showed that human embryonic and induced pluripotent stem cells cultured with CCL2 have an increased level of the oxygen-dependent protein subunits HIF1A and HIF2A, which are necessary to trigger the hypoxic response, as well as elevated levels of the key pluripotency transcription factor proteins OCT4, NANOG, KLF4, SOX2, and TFCP2L1. In addition, the presence of CCL2 had a positive effect on directed endothelial differentiation, accelerating the maturation of progenitors and enhancing the angiogenic potential of differentiated derivatives.