Chamberlain Connie S, Saether Erin E, Aktas Erdem, Vanderby Ray
Department of Orthopedics and Rehabilitation, University of Wisconsin-Madison, Madison, Wisconsin 53705, USA.
Department of Orthopedics, Ankara Oncology Research and Training Hospital, Ankara, Turkey.
J Cytokine Biol. 2017 May;2(1). Epub 2017 Jan 7.
A normal healing response after ligament and tendon rupture results in scar formation and an inferior tissue that fails to emulate its original structure, composition, and function. More regenerative healing (closer to the original) can be obtained through early suppression of inflammatory cells and associated cytokines. Examination of the immune mediated response of mesenchymal stem/stromal cells (MSCs) during healing indicates that MSCs reprogram macrophages from a pro-inflammatory M1 phenotype to an anti-inflammatory M2 phenotype. Based on these studies our objective was to treat ligament and tendon injuries with MSCs in order to modulate their inflammatory response. Our initial studies using allogeneic cells demonstrated an dose dependency of MSCs on ligament healing. Medial collateral ligaments (MCLs) treated with 1 × 10 (low dose) MSCs exhibited less inflammation and a reduced number of M1 macrophages compared to ligaments treated with 4 × 10 (high dose) MSCs. Strength of ligament was also improved with the low dose treatment. We then examined the effects of MSCs that had been preconditioned to be more anti-inflammatory. Treatment with these preconditioned MSCs was compared with normally processed (unconditioned) MSCs using the rat Achilles tendon and MCL healing models. Pre-conditioned MSCs significantly reduced inflammation by increasing the M2 macrophages and decreasing the M1 macrophages. Most importantly, treatment with pre-conditioned MSCs improved tissue strength to levels comparable to intact tissue. Overall, pre-conditioned MSC-treatment out-performed unconditioned MSCs to improve ligament and tendon healing by stimulating a more robust, paracrine-mediated immunosuppressive response.
韧带和肌腱断裂后的正常愈合反应会导致瘢痕形成，形成的组织质量较差，无法恢复其原始结构、组成和功能。通过早期抑制炎症细胞和相关细胞因子，可以实现更接近原始状态的再生愈合。对间充质干细胞（MSC）在愈合过程中免疫介导反应的研究表明，MSC可将巨噬细胞从促炎的M1表型重编程为抗炎的M2表型。基于这些研究，我们的目标是用MSC治疗韧带和肌腱损伤，以调节其炎症反应。我们最初使用同种异体细胞的研究表明，MSC对韧带愈合存在剂量依赖性。与用4×10（高剂量）MSC处理的韧带相比，用1×10（低剂量）MSC处理的内侧副韧带（MCL）炎症较轻，M1巨噬细胞数量减少。低剂量治疗还提高了韧带的强度。然后，我们研究了经过预处理以增强抗炎能力的MSC的效果。在大鼠跟腱和MCL愈合模型中，将这些预处理的MSC与正常处理（未预处理）的MSC的治疗效果进行了比较。预处理的MSC通过增加M2巨噬细胞和减少M1巨噬细胞，显著减轻了炎症。最重要的是，用预处理的MSC进行治疗可将组织强度提高到与完整组织相当的水平。总体而言，预处理的MSC治疗在改善韧带和肌腱愈合方面优于未预处理的MSC，因为它能刺激更强有力的、旁分泌介导的免疫抑制反应。
