Aktas Erdem, Chamberlain Connie S, Saether Erin E, Duenwald-Kuehl Sarah E, Kondratko-Mittnacht Jaclyn, Stitgen Michael, Lee Jae Sung, Clements Anna E, Murphy William L, Vanderby Ray
Department of Orthopedics, Ankara Oncology Research and Training Hospital, Ankara, Turkey.
Department of Orthopedics and Rehabilitation, University of Wisconsin, Madison, Wisconsin, 53705.
J Orthop Res. 2017 Feb;35(2):269-280. doi: 10.1002/jor.23258. Epub 2016 Apr 25.
Tendon healing is a complex coordinated series of events resulting in protracted recovery, limited regeneration, and scar formation. Mesenchymal stem cell (MSC) therapy has shown promise as a new technology to enhance soft tissue and bone healing. A challenge with MSC therapy involves the ability to consistently control the inflammatory response and subsequent healing. Previous studies suggest that preconditioning MSCs with inflammatory cytokines, such as IFN-γ, TNF-α, and IL-1β may accelerate cutaneous wound closure. The objective of this study was to therefore elucidate these effects in tendon. That is, the in vivo healing effects of TNF-α primed MSCs were studied using a rat Achilles segmental defect model. Rat Achilles tendons were subjected to a unilateral 3 mm segmental defect and repaired with either a PLG scaffold alone, MSC-seeded PLG scaffold, or TNF-α-primed MSC-seeded PLG scaffold. Achilles tendons were analyzed at 2 and 4 weeks post-injury. In vivo, MSCs, regardless of priming, increased IL-10 production and reduced the inflammatory factor, IL-1α. Primed MSCs reduced IL-12 production and the number of M1 macrophages, as well as increased the percent of M2 macrophages, and synthesis of the anti-inflammatory factor IL-4. Primed MSC treatment also increased the concentration of type I procollagen in the healing tissue and increased failure stress of the tendon 4 weeks post-injury. Taken together delivery of TNF-α primed MSCs via 3D PLG scaffold modulated macrophage polarization and cytokine production to further accentuate the more regenerative MSC-induced healing response. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:269-280, 2017.
肌腱愈合是一系列复杂且相互协调的事件，会导致恢复过程漫长、再生受限以及瘢痕形成。间充质干细胞（MSC）疗法已展现出作为一种增强软组织和骨愈合的新技术的潜力。MSC疗法面临的一个挑战是持续控制炎症反应及后续愈合的能力。先前的研究表明，用炎性细胞因子（如IFN-γ、TNF-α和IL-1β）对MSC进行预处理可能会加速皮肤伤口闭合。因此，本研究的目的是阐明这些作用在肌腱中的情况。也就是说，使用大鼠跟腱节段性缺损模型研究了TNF-α预处理的MSC的体内愈合效果。将大鼠跟腱造成单侧3毫米节段性缺损，并用单独的PLG支架、接种MSC的PLG支架或接种TNF-α预处理的MSC的PLG支架进行修复。在损伤后2周和4周对跟腱进行分析。在体内，无论是否进行预处理，MSC都会增加IL-10的产生并减少炎性因子IL-1α。预处理的MSC减少了IL-12的产生以及M1巨噬细胞的数量，同时增加了M2巨噬细胞的百分比和抗炎因子IL-4的合成。预处理的MSC治疗还增加了愈合组织中I型前胶原的浓度，并增加了损伤后4周肌腱的破坏应力。综上所述，通过3D PLG支架递送TNF-α预处理的MSC可调节巨噬细胞极化和细胞因子产生，以进一步强化MSC诱导的更具再生性的愈合反应。©2016骨科研究协会。由Wiley Periodicals, Inc.出版。《矫形外科学研究》35:269 - 280, 2017。
