Department of Prosthodontics, Peking University School and Hospital of Stomatology, 22 Zhongguancun South Avenue, Beijing, 100081, China.
National Center of Stomatology, National Clinical Research Center for Oral Diseases, National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing Key Laboratory of Digital Stomatology, Research Center of Engineering and Technology for Computerized Dentistry Ministry of Health, Peking University School and Hospital of Stomatology, Beijing, 100081, China.
Stem Cell Res Ther. 2022 Jul 16;13(1):323. doi: 10.1186/s13287-022-03004-w.
In tissue engineering, mesenchymal stem cells (MSCs) are common seed cells because of abundant sources, strong proliferation ability and immunomodulatory function. Numerous researches have demonstrated that MSC-macrophage crosstalk played a key role in the tissue engineering. Macrophages could regulate the differentiation of MSCs via different molecular mechanisms, including extracellular vesicles. Apoptotic macrophages could generate large amounts of apoptotic vesicles (apoVs). ApoVs are rich in proteins, RNA (microRNAs, mRNAs, ncRNAs, etc.) and lipids, and are a key intercellular communication mediator that can exert different regulatory effects on recipient cells. MiRNAs account for about half of the total RNAs of extracellular vesicles, and play important roles in biological processes such as cell proliferation and differentiation, whereas the functions of macrophage-derived apoVs remain largely unknown. There was no research to clarify the role of macrophage-derived apoVs in MSC fate choices. In this study, we aimed to characterize macrophage-derived apoVs, and investigate the roles of macrophage-derived apoVs in the fate commitment of MSCs.
We characterized macrophage-derived apoVs, and investigated their role in MSC osteogenesis and adipogenesis in vitro and in vivo. Furthermore, we performed microRNA loss- and gain-of-function experiments and western blot to determine the molecular mechanism.
Macrophages could produce a large number of apoVs after apoptosis. MSCs could uptake apoVs. Then, we found that macrophage-derived apoVs inhibited osteogenesis and promoted adipogenesis of MSCs in vitro and in vivo. In mechanism, apoVs were enriched for microRNA155 (miR155), and apoVs regulated osteogenesis and adipogenesis of MSCs by delivering miR155. Besides, miR155 regulated osteogenesis and adipogenesis of MSCs cultured with macrophage-derived apoVs via the SMAD2 signaling pathway.
Macrophage-derived apoVs could regulate the osteogenesis and adipogenesis of MSCs through delivering miR155, which provided novel insights for MSC-mediated tissue engineering.
在组织工程中，间充质干细胞（MSCs）由于来源丰富、增殖能力强、免疫调节功能强，是常见的种子细胞。大量研究表明，MSC-巨噬细胞相互作用在组织工程中起着关键作用。巨噬细胞可以通过不同的分子机制调节 MSCs 的分化，包括细胞外囊泡。凋亡的巨噬细胞可以产生大量的凋亡小体（apoVs）。apoVs 富含蛋白质、RNA（microRNAs、mRNAs、ncRNAs 等）和脂质，是一种关键的细胞间通讯介质，对受体细胞可以发挥不同的调节作用。miRNAs 约占细胞外囊泡总 RNA 的一半，在细胞增殖和分化等生物学过程中发挥重要作用，而巨噬细胞来源的 apoVs 的功能在很大程度上尚不清楚。目前还没有研究阐明巨噬细胞来源的 apoVs 在 MSC 命运选择中的作用。在这项研究中，我们旨在表征巨噬细胞来源的 apoVs，并研究其在 MSC 成骨和成脂命运中的作用。
我们对巨噬细胞来源的 apoVs 进行了表征，并研究了它们在 MSC 体外和体内成骨和成脂分化中的作用。此外，我们进行了 microRNA 缺失和获得功能实验以及 Western blot 实验，以确定分子机制。
巨噬细胞凋亡后可产生大量 apoVs。MSCs 可以摄取 apoVs。然后，我们发现巨噬细胞来源的 apoVs 在体外和体内抑制 MSC 的成骨和促进其成脂。在机制上，apoVs 富含 microRNA155（miR155），并且 apoVs 通过递送 miR155 调节 MSC 的成骨和成脂。此外，miR155 通过 SMAD2 信号通路调节培养有巨噬细胞来源 apoVs 的 MSC 的成骨和成脂。
巨噬细胞来源的 apoVs 可以通过递送 miR155 来调节 MSC 的成骨和成脂，这为 MSC 介导的组织工程提供了新的见解。
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