The roles and therapeutic potentialof mesenchymal stem/stromal cells and their extracellular vesicles in tendinopathies

Abstract

Tendinopathies encompass a highly prevalent, multi-faceted spectrum of disorders, characterized by activity-related pain, compromised function, and propensity for an extended absence from sport and the workplace. The pathophysiology of tendinopathy continues to evolve. For decades, it has been related primarily to repetitive overload trauma but more recently, the onset of tendinopathy has been attributed to the tissue’s failed attempt to heal after subclinical inflammatory and immune challenges (failed healing model). Conventional tendinopathy management produces only short-term symptomatic relief and often results in incomplete repair or healing leading to compromised tendon function. For this reason, there has been increased effort to develop therapeutics to overcome the tissue’s failed healing response by targeting the cellular metaplasia and pro-inflammatory extra-cellular environment. On this basis, stem cell-based therapies have been proposed as an alternative therapeutic approach designed to modify the course of the various tendon pathologies. Mesenchymal stem/stromal cells (MSCs) are multipotent stem cells often referred to as “medicinal signaling cells” due to their immunomodulatory and anti-inflammatory properties that can produce a pro-regenerative microenvironment in pathological tendons. However, the adoption of MSCs into clinical practice has been limited by FDA regulations and perceived risk of adverse events upon infusion in vivo. The introduction of cell-free approaches, such as the extracellular vesicles of MSCs, has encouraged new perspectives for the treatment of tendinopathies, showing promising short-term results. In this article, we review the most recent advances in MSC-based and MSC-derived therapies for tendinopathies. Preclinical and clinical studies are included with comment on future directions of this rapidly developing therapeutic modality, including the importance of understanding tissue loading and its relationship to any treatment regimen.

Stem Cell‐Based Therapies and Tissue Engineering Innovations for Tendinopathy: A Comprehensive Review of Current Strategies and Future Directions

“…This condition also involves the dysregulated recruitment of immune cells and inflammatory mediators, eventually leading to increased cellular apoptosis ( Figure A). [ 4a,65 ] The adult tendon contains densely packed collagen fibrils responsible for transmitting force from muscle to bone. [ 66 ] Tendinopathy occurs due to tendon rupture and repetitive mechanical loading, forming scars as tendons fail to heal completely or regain their mechanical function.…”

Injectable self-assembled GDF5-containing dipeptide hydrogels for enhanced tendon repair

“…Tendon stem/progenitor cells (TSPCs) are self-renewing pluripotent cells present in tendons and are an important cell source for tendon tissue repair and regeneration [ 13 , 14 ]. TSPCs exhibit can not only differentiate into various cell types, including bone cells, chondrocytes, and adipocytes, but also regulate immune responses and play an important role in maintaining the physiological functions of tendons, including elasticity, flexibility, and tensile strength [ 15 , 16 ]. Rui et al [ 17 ] and Zhang et al [ 18 ] successfully isolated and cultured TSPCs in the tendon tissues of rats and rabbits, respectively, and found that these cells could differentiate toward tendon formation under certain conditions [ 17 ].…”