Tu Tran Cam, Yamashita Toshiharu, Kato Toshiki, Nagano Masumi, Trinh Nhu Thuy, Hamada Hiromi, Sato Fujio, Ohneda Kinuko, Matsuo-Takasaki Mami, Ohneda Osamu
Graduate School of Comprehensive Human Sciences, Laboratory of Regenerative Medicine and Stem Cell Biology, University of Tsukuba, 1-1-1 Tsukuba, 305-8575 Japan.
Graduate School of Comprehensive Human Sciences, Laboratory of Regenerative Medicine and Stem Cell Biology, University of Tsukuba, 1-1-1 Tsukuba, 305-8575 Japan; Ph.D. Program in Human Biology, School of Integrative and Global Majors, University of Tsukuba, 1-1-1 Tsukuba, 305-8575 Japan.
Biochem Biophys Res Commun. 2016 Aug 12;477(1):68-75. doi: 10.1016/j.bbrc.2016.06.022. Epub 2016 Jun 6.
Mesenchymal stem cells (MSCs) are defined as multipotent cells that can give rise to various kinds of differentiated mesenchymal cells, and are thus considered to be useful for clinical therapy. However, the big hurdles of MSC therapy are the inability of MSCs to reach the appropriate tissues or sites with high efficiency and engraftment after transplantation. In this study, we investigated how adipose tissue-derived MSCs (AT-MSCs) improve their homing ability after intravenous injection. We previously found that human endothelial progenitor cells with low aldehyde dehydrogenase activity (Alde-Low EPCs) are suitable for the treatment of ischemic tissues. In addition, we demonstrated that microvesicles (MVs) derived from Alde-Low EPCs possessed the ability to improve the homing ability of non-functional Alde-High EPCs, resulting in wound healing. We initially transfected MVs derived from Alde-Low EPCs (EMVs) to human AT-MSCs, which were originally unable to cure ischemic tissues by intravenous transplantation. Remarkably, AT-MSC transfected EMVs dramatically repaired the ischemic skin flap compared with AT-MSC derived-MV (MMVs) transfected AT-MSCs or control AT-MSCs. We then found that the expression of CXCR4, an important chemokine receptor for cell migration, was highly elevated in EMV-transfected AT-MSCs. Moreover, AT-MSCs transfected with EMVs, but not control AT-MSCs, migrated to wound sites after intravenous injection. Consequently, CD45(+) inflammatory cells were successfully recruited at the wound sites after the injection of EMV-transfected AT-MSCs. These results demonstrate that EMVs are a useful source to improve the homing ability and wound healing ability of MSCs at the wound sites.
间充质干细胞(MSCs)被定义为能够产生各种分化间充质细胞的多能细胞,因此被认为对临床治疗有用。然而,MSC治疗的重大障碍是MSC在移植后无法高效地到达合适的组织或部位并植入。在本研究中,我们调查了脂肪组织来源的MSCs(AT-MSCs)在静脉注射后如何提高其归巢能力。我们之前发现醛脱氢酶活性低的人内皮祖细胞(Alde-Low EPCs)适用于缺血组织的治疗。此外,我们证明来自Alde-Low EPCs的微泡(MVs)具有提高无功能的Alde-High EPCs归巢能力的作用,从而促进伤口愈合。我们最初将来自Alde-Low EPCs的MVs(EMVs)转染到人AT-MSCs中,这些AT-MSCs原本无法通过静脉移植治愈缺血组织。值得注意的是,与AT-MSC来源的MVs(MMVs)转染的AT-MSCs或对照AT-MSCs相比,转染EMVs的AT-MSC显著修复了缺血皮瓣。然后我们发现细胞迁移的重要趋化因子受体CXCR4的表达在转染EMVs的AT-MSCs中高度升高。此外,转染EMVs的AT-MSCs,而不是对照AT-MSCs,在静脉注射后迁移到伤口部位。因此,在注射转染EMVs的AT-MSCs后,CD45(+)炎性细胞成功募集到伤口部位。这些结果表明,EMVs是提高MSCs在伤口部位的归巢能力和伤口愈合能力的有用来源。
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