Department of Nephrology, Hiroshima University Hospital, 1-2-3 Kasumi, Minami-ku, Hiroshima, Hiroshima, 734-8551, Japan.
Department of Stem Cell Biology and Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, Hiroshima, 734-8553, Japan.
Sci Rep. 2021 Jan 13;11(1):850. doi: 10.1038/s41598-020-79664-6.
Mesenchymal stem cells (MSCs) administered for therapeutic purposes can be activated by interferon-γ (IFN-γ) secreted from natural killer cells in injured tissues and exert anti-inflammatory effects. These processes require a substantial period of time, leading to a delayed onset of MSCs' therapeutic effects. In this study, we investigated whether pretreatment with IFN-γ could potentiate the anti-fibrotic ability of MSCs in rats with ischemia-reperfusion injury (IRI) and unilateral ureter obstruction. Administration of MSCs treated with IFN-γ strongly reduced infiltration of inflammatory cells and ameliorated interstitial fibrosis compared with control MSCs without IFN-γ treatment. In addition, conditioned medium obtained from IFN-γ-treated MSCs decreased fibrotic changes in cultured cells induced by transforming growth factor-β1 more efficiently than that from control MSCs. Most notably, secretion of prostaglandin E2 from MSCs was significantly increased by treatment with IFN-γ. Increased prostaglandin E2 in conditioned medium obtained from IFN-γ-treated MSCs induced polarization of immunosuppressive CD163 and CD206-positive macrophages. In addition, knockdown of prostaglandin E synthase weakened the anti-fibrotic effects of MSCs treated with IFN-γ in IRI rats, suggesting the involvement of prostaglandin E2 in the beneficial effects of IFN-γ. Administration of MSCs treated with IFN-γ might represent a promising therapy to prevent the progression of renal fibrosis.
间充质干细胞（MSCs）经治疗用途给药后，可被损伤组织中自然杀伤细胞分泌的干扰素-γ（IFN-γ）激活，并发挥抗炎作用。这些过程需要相当长的时间，导致 MSCs 治疗效果的延迟出现。在这项研究中，我们研究了 IFN-γ 预处理是否可以增强 MSCs 在缺血再灌注损伤（IRI）和单侧输尿管梗阻大鼠中的抗纤维化能力。与未用 IFN-γ 处理的对照 MSCs 相比，用 IFN-γ 处理的 MSCs 给药强烈减少了炎症细胞的浸润，并改善了间质纤维化。此外，IFN-γ 处理的 MSCs 产生的条件培养基比对照 MSCs 更有效地减少转化生长因子-β1诱导的培养细胞的纤维化变化。值得注意的是，IFN-γ 处理显著增加了 MSCs 前列腺素 E2 的分泌。IFN-γ 处理的 MSCs 产生的条件培养基中前列腺素 E2 的增加诱导了免疫抑制性 CD163 和 CD206 阳性巨噬细胞的极化。此外，前列腺素 E 合酶的敲低削弱了 IFN-γ 处理的 MSCs 在 IRI 大鼠中的抗纤维化作用，表明前列腺素 E2 参与了 IFN-γ 的有益作用。IFN-γ 处理的 MSCs 的给药可能代表一种有前途的疗法，可预防肾纤维化的进展。
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