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      VEGFA-Enriched Exosomes from Tendon-Derived Stem Cells Facilitate Tenocyte Differentiation, Migration, and Transition to a Fibroblastic Phenotype


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          Tendon-derived stem cells (TDSCs) play a vital role in repair of rotator cuff tear injuries by secreting paracrine proteins that regulate resident cell functions. Secreted exosomes may play a role in tendon injury repair by mediating intercellular communication; however, the detailed mechanisms by which TDSC-derived exosomes affect tenocyte development remain unknown. Here, we examined the effects of exosomes isolated from conditioned medium of TDSCs on tenocyte differentiation, migration, and transition to a fibroblastic phenotype in vitro. Successful isolation of exosomes from TDSCs was confirmed by high expression levels of CD81, CD63, CD9, and TSG101. Treatment with TDSC-derived exosomes promoted the growth and migration of cultured rat tenocytes, and increased the levels of the fibrosis markers collagen I, collagen III, scleraxis, tenascin C, and α-smooth muscle actin. Furthermore, vascular endothelial growth factor A (VEGFA) expression was higher in TDSC-derived exosomes than in TDSCs, and genetic knockdown of VEGFA suppressed the stimulatory effect of TDSC-derived exosomes on tenocyte development. Overall, these results demonstrate that VEGFA-enriched exosomes isolated from TDSCs promote differentiation and migration of cultured tenocytes and their transition to a fibroblastic phenotype. These data provide a new potential clinical treatment strategy for tendon injury.

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          Identification of tendon stem/progenitor cells and the role of the extracellular matrix in their niche.

          The repair of injured tendons remains a great challenge, largely owing to a lack of in-depth characterization of tendon cells and their precursors. We show that human and mouse tendons harbor a unique cell population, termed tendon stem/progenitor cells (TSPCs), that has universal stem cell characteristics such as clonogenicity, multipotency and self-renewal capacity. The isolated TSPCs could regenerate tendon-like tissues after extended expansion in vitro and transplantation in vivo. Moreover, we show that TSPCs reside within a unique niche predominantly comprised of an extracellular matrix, and we identify biglycan (Bgn) and fibromodulin (Fmod) as two critical components that organize this niche. Depletion of Bgn and Fmod affects the differentiation of TSPCs by modulating bone morphogenetic protein signaling and impairs tendon formation in vivo. Our results, while offering new insights into the biology of tendon cells, may assist in future strategies to treat tendon diseases.
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            MSC exosomes mediate cartilage repair by enhancing proliferation, attenuating apoptosis and modulating immune reactivity.

            Mesenchymal stem cell (MSC) exosome was previously shown to be effective in repairing critical size osteochondral defects in an immunocompetent rat model. Here we investigate the cellular processes modulated by MSC exosomes and the mechanism of action underlying the exosome-mediated responses in cartilage repair. We observed that exosome-mediated repair of osteochondral defects was characterised by increased cellular proliferation and infiltration, enhanced matrix synthesis and a regenerative immune phenotype. Using chondrocyte cultures, we could attribute the rapid cellular proliferation and infiltration during exosome-mediated cartilage repair to exosomal CD73-mediated adenosine activation of AKT and ERK signalling. Inhibitors of AKT or ERK phosphorylation suppressed exosome-mediated increase in cell proliferation and migration but not matrix synthesis. The role of exosomal CD73 was confirmed by the attenuation of AKT and ERK signalling by AMPCP, a CD73 inhibitor and theophylline, an adenosine receptor antagonist. Exosome-treated defects also displayed a regenerative immune phenotype characterised by a higher infiltration of CD163+ regenerative M2 macrophages over CD86+ M1 macrophages, with a concomitant reduction in pro-inflammatory synovial cytokines IL-1β and TNF-α. Together, these observations demonstrated that the efficient osteochondral regeneration by MSC exosomes was effected through a coordinated mobilisation of multiple cell types and activation of several cellular processes.
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              miR-100-5p-abundant exosomes derived from infrapatellar fat pad MSCs protect articular cartilage and ameliorate gait abnormalities via inhibition of mTOR in osteoarthritis


                Author and article information

                Biomed Res Int
                Biomed Res Int
                BioMed Research International
                9 September 2022
                : 2022
                1Department of Bone and Joint Surgery and Sports Medicine Center, The First Affiliated Hospital, Jinan University, Guangzhou 510630, China
                2Department of Orthopedics, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China
                3Department of Orthopedic Trauma and Hand Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, China
                Author notes

                Academic Editor: Valentina Russo

                Copyright © 2022 Zhaowen Xue et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                Research Article


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