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

阐明骨髓间充质干细胞间充质到上皮细胞的转化机制及其在再生医学中的应用。

• 批准号: 22390217
• 负责人: TAMAI Katsuto
• 金额: $ 12.15万
• 依托单位: Osaka University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2010
• 资助国家: 日本
• 起止时间: 2010 至 2012
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-22390217/
• 关键词: 骨髄間葉系幹細胞; 間葉上皮転換(MET); HMGB1; CXCL12; CXCR4; 間葉系幹細胞; 表皮水疱症; VII型コラーゲン; SDF-1α; 間葉-上皮転換; SSEA3; ケラチン5; 再生誘導; 皮膚損傷

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.

先前，我们已经证明骨髓来源的间充质干细胞/祖细胞有助于大疱性表皮松解症（EB）皮肤中分离上皮的再生，EB是一种难治性遗传性皮肤病。在此背景下，本研究旨在探讨EB皮肤骨髓间充质细胞间充质向上皮转化（MET）的确切机制，并将所得结果应用于新型再生医学的开发。2012年，我们发现EB皮肤损伤上皮释放大量高迁移性组框1 (HMGB1)，刺激和调动lineage-/PDGFR。+/c-kit- (L-P+K-)骨髓细胞进入循环，然后循环中的L-P+K-细胞通过CXCR4/SDF-1积聚到损伤皮肤。通过MET提供骨髓源性上皮细胞。2013年，我们进一步研究了L-P+K-细胞群体中MET-capable细胞的特异性细胞表面标记，明确了SSEA3是L-P+K-细胞群体中特异性识别MET-capable细胞的独家制造者。我们还通过在EB小鼠模型中系统接种CXCR4拮抗剂阻断L-P+K-骨髓源性细胞的积累，证明了L-P+K-骨髓源性细胞对EB皮肤再生至关重要，从而导致持续严重的皮肤损伤。2014年，我们研究了全身给药HMGB1对皮肤损伤再生过程的影响，发现HMGB1通过诱导损伤组织中L-P+K-细胞的积累，从而提供有效的抗炎分子，并通过MET再生损伤上皮，从而显著加速组织再生。

项目成果

Serum anti-BPAG1 auto-antibody is a novel marker for human melanoma.

• DOI: 10.1371/journal.pone.0010566
• 发表时间: 2010-05-10
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Shimbo T;Tanemura A;Yamazaki T;Tamai K;Katayama I;Kaneda Y
• 通讯作者: Kaneda Y

教育講演6 研究を目指す若手皮膚科医のために 臨床医にとって研究とは? 臨床と研究は皮膚科学一卵性双生児である.

教育讲座 6 对于致力于研究的年轻皮肤科医生 研究对临床医生意味着什么？临床实践和研究在皮肤病学中是同卵双胞胎。

• 发表时间: 2012
• 作者: Masahiro Katsura;Kazunori Matsumoto;Tomohiro Uchida;Noriyuki Ohmuro;Tatsuo Kikuchi;Chika Obara;Yumiko Hamaie;Emi Sunakawa;Hiroo Matsuoka;玉井克人
• 通讯作者: 玉井克人

HMGB1 mobilized PDGFRa-positive cells from bone marrow to regenerate injured epithelia

HMGB1动员骨髓中的PDGFRa阳性细胞来再生受损的上皮细胞

• 发表时间: 2011
• 作者: Miyake;K.;Katsuto Tamai
• 通讯作者: Katsuto Tamai

Problems and future perspectives for gene therapy of genetic skin diseases

遗传性皮肤病基因治疗存在的问题及未来展望

• 发表时间: 2011
• 作者: Kawamura Y;Ishiwata T;Takizawa M;Ishida H;Asano Y;Nonoyama S.;Katsuto Tamai
• 通讯作者: Katsuto Tamai

骨髄由来細胞による表皮水疱症皮膚再生医療

利用骨髓来源细胞的大疱性表皮松解症皮肤再生药物

• 发表时间: 2011
• 作者: Kamae C;Nakagawa N;Sato H;Honma K;Mitsuiki N;Ohara O;Kanegane H;Pasic S;Pan-Hammarstrom Q;MC van Zelm;Morio T;Imai K;Nonoyama S;Noriyuki Ohmuro;玉井克人
• 通讯作者: 玉井克人