Elucidation of mesenchymal to epithelial transition mechanism of bone marrow mesenchymal stem cells and application to regenerative medicine.

点击翻译按钮获取中文摘要

Previously, we had shown that bone marrow-derived mesenchymal stem/progenitor cells contribute regeneration of detached epithelia in the skin of epidermolysis bullosa (EB), a intractable genetic skin disease. With such background, in this study, we aimed to investigate precise mechanism of mesenchymal to epithelial transition (MET) of bone marrow-derived mesenchymal cells in the EB skin, and to apply the obtained results for developing novel regenerative medicine. In 2012, we found that injured epithelia of EB skin release abundant high mobility group box 1 (HMGB1) to stimulate and mobilize lineage-/PDGFR.+/c-kit- (L-P+K-) bone marrow cells into the circulation, and the circulating L-P+K- cells are then accumulate to the injured skin via CXCR4/SDF-1. axis to provide bone marrow-derived epithelial cells by MET. In 2013, we further investigated particular cell surface marker for identifying MET-capable cell in L-P+K- population, and clarified that SSEA3 is an exclusive maker for specifically identifying the MET-capable cells in the L-P+K- cell population. We also proved that L-P+K- bone marrow-derived cells are essential for regeneration of EB skin by blocking accumulation of those cells by systemic inoculating CXCR4 antagonist in EB mouse model, resulting in persistent severe cutaneous injury. In 2014, we examined efficacy of systemic administration of HMGB1 on regeneration processes of cutaneous injury, and found that HMGB1 administration significantly accelerate tissue regeneration by inducing accumulation of L-P+K- cells in the injury, which then provide potent anti-inflammatory molecules and regenerate the injured epithelia by MET.