A scaffold laden with mesenchymal stem cell-derived exosomes for promoting endometrium regeneration and fertility restoration through macrophage immunomodulation
A scaffold laden with mesenchymal stem cell-derived exosomes for promoting endometrium regeneration and fertility restoration through macrophage immunomodulation
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载有间充质干细胞衍生的外泌体的支架，通过巨噬细胞免疫调节促进子宫内膜再生和生育力恢复
DOI：
10.1016/j.actbio.2020.06.029
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发表时间：
2020-09-01
影响因子：
9.7
通讯作者：
Zhang, Songying
中科院分区：
文献类型：
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作者：
Xin, Liaobing;Lin, Xiaona;Zhang, Songying
子宫内膜创伤可能会导致宫腔粘连（IUAs），导致不孕。临床上的常规方法已不能解决严重病例的子宫内膜再生问题。脐带来源的间充质干细胞（UC-MSC）为基础的疗法已经显示出一些有前途的成就，在治疗宫内节育器。但其潜在的致瘤性、低输注率和低滞留率等局限性仍存在争议，限制了MSCs的临床应用。相比之下，UC-MSC衍生的外泌体表现出与其源细胞相似的功能，并且有望克服这些限制。因此，本研究提出了一种新的和可行的无细胞治疗策略，即通过UC-MSC衍生的外泌体。在此，我们设计了一种用于大鼠子宫内膜损伤模型中的子宫内膜再生的外泌体和胶原支架（CS/Exos）的构建体，并通过巨噬细胞免疫调节研究了再生机制。CS/Exos移植有效诱导（i）子宫内膜再生，（ii）胶原重塑，（iii）增加雌激素受体α/孕激素受体的表达，和（iv）恢复生育力。从机制上讲，CS/Exos促进了体内和体外CD 163（+）M2巨噬细胞极化，减轻了炎症，并增加了抗炎反应。通过RNAseq，富集在外泌体中的miRNA是外泌体诱导的巨噬细胞极化的主要介质。总之，我们证明CS/Exos治疗通过miRNAs的免疫调节功能促进子宫内膜再生和生育力恢复。我们的研究突出了CS/Exos用于管理IUAs的治疗前景。意义声明严重的子宫内膜创伤常导致宫腔粘连（IUAs）和不孕。传统方法在临床上的效果有限，因此开发新的子宫内膜再生和生育力恢复策略非常重要。在这项研究中，设计了载有外泌体的支架（CS/Exos），并且CS/Exos的移植有效地诱导了（i）子宫内膜再生，（ii）胶原蛋白重塑，（iii）增加雌激素受体α/孕酮受体的表达，以及（iv）恢复生育力。在机制上，CS/Exos构建体促进M2巨噬细胞极化，减轻炎症，并增加抗炎反应。此外，外泌体中富集的miRNA是外泌体诱导的巨噬细胞极化的主要介质。这项研究强调了CS/Exos的治疗前景和严重IUAs管理的转化应用。(C)2020 Acta Materialia Inc.由爱思唯尔有限公司出版。保留所有权利。
Endometrial traumas may cause intrauterine adhesions (IUAs), leading to infertility. Conventional methods in clinic have not solved the problem of endometrial regeneration in severe cases. Umbilical cord-derived mesenchymal stem cell (UC-MSC)-based therapies have shown some promising achievements in the treatment of IUAs. However, the limitations of potential tumorigenicity, low infusion and low retention are still controversial and restricted the clinical application of MSCs. In contrast, UC-MSC-derived exosomes exhibit a similar function to their source cells and are expected to overcome these limitations. Therefore, a novel and viable cell-free therapeutic strategy by UC-MSC-derived exosomes was proposed in this study. Here, we designed a construct of exosomes and collagen scaffold (CS/Exos) for endometrial regeneration in a rat endometrium-damage model, and investigated the regeneration mechanism through macrophage immunomodulation. The CS/Exos transplantation potently induced (i) endometrium regeneration, (ii) collagen remodeling, (iii) increased the expression of the estrogen receptor alpha/progesterone receptor, and (iv) restored fertility. Mechanistically, CS/Exos facilitated CD163(+) M2 macrophage polarization, reduced inflammation, and increased anti-inflammatory responses in vivo and in vitro. By RNAseq, miRNAs enriched in exosomes were the main mediator for exosomes-induced macrophage polarization. Overall, we demonstrated that CS/Exos treatment facilitated endometrium regeneration and fertility restoration by immunomodulatory functions of miRNAs. Our research highlights the therapeutic prospects of CS/Exos for the management of IUAs.Statement of significanceSevere endometrial traumas always result in intrauterine adhesions (IUAs) and infertility. The limited outcomes by conventional methods in the clinic make it very important to develop new strategies for endometrium regeneration and fertility restoration. In this study, an exosome-laden scaffold (CS/Exos) was designed and the transplantation of CS/Exos potently induced (i) endometrium regeneration, (ii) collagen remodeling, (iii) increased the expression of the estrogen receptor a/progesterone receptor, and (iv) restored fertility. In mechanism, the construct of CS/Exos facilitated M2 macrophage polarization, reduced inflammation, and increased anti-inflammatory responses. Furthermore, miRNAs enriched in exosomes were the main mediator for exosome-induced macrophage polarization. This study highlights the therapeutic prospects of CS/Exos and the translational application for the management of severe IUAs. (C) 2020 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.