Vascular endothelial growth factor/kinase insult domain receptor (KDR)/fetal liver kinase 1 (FLK1)-mediated skin-epithelial progenitor cells reprogramming.

Abstract

Vascular endothelial growth factor (VEGF) is an angiogenic protein that has effects on damaged neurons. We investigated VEGF function and found that it effectively induces the transition of skin-derived epithelial progenitor cells (EPCs) to more primitive stem cells. This change was accompanied by the epigenetic reprogramming of many genes. Among these genes are several stem-cell-associated transcription factors, such as Rex1, Oct4, Nanog, and Sox2. The VEGF-induced reprogramming of EPCs occurred through the FLK1 receptor and Janus kinase (JAK)/signal transducer- and activator of transcription 3 (STAT3) phosphorylation. When we engrafted VEGF-sensitized EPCs into sites of brain trauma, both engrafted VEGF/EPCs and endogenous cells showed functionally active neurogenesis and potent immunomodulatory function. These results indicate that VEGF actively induces the reprogramming of EPCs to become more primitive stem cells that display active cell growth, neurogenesis, migration, and survival behaviors, which may lead to a novel therapeutic strategy for central nervous system disorders.