Hofer Heidi R, Tuan Rocky S
Center for Cellular and Molecular Engineering, Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, 450 Technology Drive, Room 221, Pittsburgh, PA, 15219, USA.
Stem Cell Res Ther. 2016 Sep 9;7(1):131. doi: 10.1186/s13287-016-0394-0.
Adult mesenchymal stem cells (MSCs) represent a subject of intense experimental and biomedical interest. Recently, trophic activities of MSCs have become the topic of a number of revealing studies that span both basic and clinical fields. In this review, we focus on recent investigations that have elucidated trophic mechanisms and shed light on MSC clinical efficacy relevant to musculoskeletal applications. Innate differences due to MSC sourcing may play a role in the clinical utility of isolated MSCs. Pain management, osteochondral, nerve, or blood vessel support by MSCs derived from both autologous and allogeneic sources have been examined. Recent mechanistic insights into the trophic activities of these cells point to ultimate regulation by nitric oxide, nuclear factor-kB, and indoleamine, among other signaling pathways. Classic growth factors and cytokines-such as VEGF, CNTF, GDNF, TGF-β, interleukins (IL-1β, IL-6, and IL-8), and C-C ligands (CCL-2, CCL-5, and CCL-23)-serve as paracrine control molecules secreted or packaged into extracellular vesicles, or exosomes, by MSCs. Recent studies have also implicated signaling by microRNAs contained in MSC-derived exosomes. The response of target cells is further regulated by their microenvironment, involving the extracellular matrix, which may be modified by MSC-produced matrix metalloproteinases (MMPs) and tissue inhibitor of MMPs. Trophic activities of MSCs, either resident or introduced exogenously, are thus intricately controlled, and may be further fine-tuned via implant material modifications. MSCs are actively being investigated for the repair and regeneration of both osteochondral and other musculoskeletal tissues, such as tendon/ligament and meniscus. Future rational and effective MSC-based musculoskeletal therapies will benefit from better mechanistic understanding of MSC trophic activities, for example using analytical "-omics" profiling approaches.
成人间充质干细胞（MSCs）是实验和生物医学领域备受关注的研究对象。近年来，MSCs的营养活性已成为基础和临床领域众多有启发性研究的主题。在本综述中，我们重点关注了近期的研究，这些研究阐明了营养机制，并揭示了与肌肉骨骼应用相关的MSCs临床疗效。由于MSCs来源不同而产生的固有差异可能在分离的MSCs的临床应用中发挥作用。已对源自自体和异体来源的MSCs在疼痛管理、骨软骨、神经或血管支持方面进行了研究。最近对这些细胞营养活性的机制性见解表明，除其他信号通路外，一氧化氮、核因子-κB和吲哚胺对其有最终调控作用。经典的生长因子和细胞因子，如血管内皮生长因子（VEGF）、睫状神经营养因子（CNTF）、胶质细胞源性神经营养因子（GDNF）、转化生长因子-β（TGF-β）、白细胞介素（IL-1β、IL-6和IL-8）以及C-C配体（CCL-2、CCL-5和CCL-23），作为旁分泌控制分子，由MSCs分泌或包装到细胞外囊泡或外泌体中。最近的研究还表明，MSCs来源的外泌体中所含的微小RNA也参与信号传导。靶细胞的反应进一步受其微环境的调控，微环境涉及细胞外基质，而细胞外基质可能会被MSCs产生的基质金属蛋白酶（MMPs）和MMPs组织抑制剂所修饰。因此，无论是驻留的还是外源性引入的MSCs的营养活性都受到复杂的控制，并且可以通过植入材料的修饰进一步微调。目前正在积极研究MSCs用于骨软骨和其他肌肉骨骼组织（如肌腱/韧带和半月板）的修复和再生。未来基于MSCs的合理有效的肌肉骨骼治疗将受益于对MSCs营养活性的更好的机制理解，例如使用分析性“组学”分析方法。
