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

以前，我们已经表明，骨髓来源的间充质干细胞/祖细胞有助于表皮大疱症（EB），一种难治性遗传性皮肤病的皮肤脱落上皮细胞的再生。在这样的背景下，在本研究中，我们的目的是研究EB皮肤中骨髓来源的间充质细胞的间充质向上皮转化（MET）的确切机制，并将所获得的结果应用于开发新的再生医学。2012年，我们发现EB皮肤损伤的上皮细胞释放丰富的高迁移率族蛋白1（HMGB 1），以刺激和动员谱系-/PDGFR。c-kit-（L-P+K-）骨髓细胞进入循环，然后循环的L-P+K-细胞通过CXCR 4/SDF-1积聚到受损皮肤。轴，以通过MET提供骨髓来源的上皮细胞。2013年，我们进一步研究了用于鉴定L-P+K-细胞群中具有MET能力的细胞的特定细胞表面标记物，并阐明SSEA 3是特异性鉴定L-P+K-细胞群中具有MET能力的细胞的唯一标记物。我们还证明了L-P+K-骨髓来源的细胞是EB皮肤再生所必需的，通过在EB小鼠模型中全身性的CXCR 4拮抗剂阻断这些细胞的积累，导致持续的严重皮肤损伤。在2014年，我们检查了全身施用HMGB 1对皮肤损伤的再生过程的功效，并且发现HMGB 1施用通过诱导损伤中L-P+K-细胞的积累显著加速组织再生，所述L-P+K-细胞然后提供有效的抗炎分子并通过MET使损伤的上皮细胞再生。

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.