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 signalling pathway and increase the mRNA level of the hypoxic response genes. However, CCL2 is practically not used in the human PSCs cultivation, and its effect is described in a single study. We continued to study the CCL2 effect on human PSC and showed that human embryonic and induced pluripotent stem cells cultured with CCL2 have an increased protein level of the oxygen-dependent subunits HIF1A and HIF2A, which are necessary to trigger the hypoxic response, as well as elevated protein levels of the key pluripotency transcription factors 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.