The Therapeutic Effect of iMSC-Derived Small Extracellular Vesicles on Tendinopathy Related Pain Through Alleviating Inflammation: An in vivo and in vitro Study

Abstract

Background Tendinopathy is a common cause of tendon pain. However, there is a lack of effective therapies for managing tendinopathy pain, despite the pain being the most common complaint of patients. This study aimed to evaluate the therapeutic effect of small extracellular vesicles released from induced pluripotent stem cell-derived mesenchymal stem cells (iMSC-sEVs) on tendinopathy pain and explore the underlying mechanisms. Methods Rat tendinopathy model was established and underwent the injection of iMSC-sEVs to the quadriceps tendon one week after modeling. Pain-related behaviors were measured for the following four weeks. Tendon histology was assessed four weeks after the injection. To further investigate the potential mechanism, tenocytes were stimulated with IL-1β to mimic tendinopathy in vitro. The effect of iMSC-sEVs on tenocyte proliferation and the expression of proinflammatory cytokines were measured by CCK-8, RT-qPCR, and ELISA. RNA-seq was further performed to systematically analyze the related global changes and underlying mechanisms. Results Local injection of iMSC-sEVs was effective in alleviating pain in the tendinopathy rats compared with the vehicle group. Tendon histology showed ameliorated tendinopathy characteristics. Upon iMSC-sEVs treatment, significantly increased tenocyte proliferation and less expression of proinflammatory cytokines were observed. Transcriptome analysis revealed that iMSC-sEVs treatment upregulated the expression of genes involved in cell proliferation and downregulated the expression of genes involved in inflammation and collagen degeneration. Conclusion Collectively, this study demonstrated iMSC-sEVs protect tenocytes from inflammatory stimulation and promote cell proliferation as well as collagen synthesis, thereby relieving pain derived from tendinopathy. As a cell-free regenerative treatment, iMSC-sEVs might be a promising therapeutic candidate for tendinopathy.

Irreversible Electroporation Improves Tendon Healing in a Rat Model of Collagenase-Induced Achilles Tendinopathy

“…Second, tendon healing was evaluated for only 77 days after IRE, and there were no long-term observational results. Third, methods to quantify pain have recently been used in tendinopathy research, 9,22,43 but the accuracy of these methods requires further validation.…”

Large extracellular vesicles secreted by human iPSC-derived MSCs ameliorate tendinopathy via regulating macrophage heterogeneity

“…A total of thirty adult male Sprague Dawley rats (200–300 g) underwent sham surgery or tendinopathy-modeling surgery were randomly and averagely divided into four groups [ 1 ]: Sham group [ 2 ]; Model + PBS group [ 3 ]; Model + sEVs group [ 4 ]; Model + lEVs group. The rat tendinopathy model was established by a single injection of carrageenan solution according to previous studies [ [22] , [23] , [24] , [25] ]. Briefly, we dissolved carrageenan powder (Sigma-Aldrich/Merck KGaA, Germany) with sterile PBS to obtain a 4% carrageenan solution.…”

Stem cell- derived extracellular vesicles as new tools in regenerative medicine - Immunomodulatory role and future perspectives

“…In another report, intra-articular administration of secretome obtained from BM-MSCs stimulated with TNF-α and IFN-γ and ameliorated pain in the murine model of osteoarthritis ( 238 ). Moreover, EVs secreted by iPSCs-derived MSCs decreased tendinopathy-related pain symptoms in rat model in vivo , alleviating inflammation and enhancing proliferation of tenocytes ( 239 ). Not only EVs from SCs, but also immune cells may have the ability to reduce inflammation-related pain symptoms.…”