Abstract
Mesenchymal stromal/stem cells (MSCs) are increasingly employed for tissue regeneration, largely mediated through paracrine actions. Currently, extracellular vesicles (EVs) released by MSCs are major mediators of these paracrine effects. We evaluated whether rat-bone-marrow-MSC-derived EVs (rBMSCs-EVs) can ameliorate tendon injury in an in vivo rat model. Pro-collagen1A2 and MMP14 protein are expressed in rBMSC-EVs, and are important factors for extracellular-matrix tendon-remodeling. In addition, we found pro-collagen1A2 in rBMSC-EV surface-membranes by dot blot. In vitro on cells isolated from Achilles tendons, utilized as rBMSC -EVs recipient cells, EVs at both low and high doses induce migration of tenocytes; at higher concentration, they induce proliferation and increase expression of Collagen type I in tenocytes. Pretreatment with trypsin abrogate the effect of EVs on cell proliferation and migration, and the expression of collagen I. When either low- or high-dose rBMSCs-EVs were injected into a rat-Achilles tendon injury-model (immediately after damage), at 30 days, rBMSC-EVs were found to have accelerated the remodeling stage of tendon repair in a dose-dependent manner. At histology and histomorphology evaluation, high doses of rBMSCs-EVs produced better restoration of tendon architecture, with optimal tendon-fiber alignment and lower vascularity. Higher EV-concentrations demonstrated greater expression of collagen type I and lower expression of collagen type III. BMSC-EVs hold promise as a novel cell-free modality for the management of tendon injuries.
Highlights
The incidence of tendon injuries has markedly increased over the past few decades
extracellular vesicles (EVs) play a role in tendon-healing by modulating inflammatory responses [9, 10, 11]. This pilot study explores the effect of rBMSC-EVs on an Achilles tendon injury in a rat model to evaluate whether high and low concentrations of EVs derived from rat bone marrow stromal/ stem cells without any further supplementation would improve repair of the injured tendon
Biophysical analysis data indicate that enriched EV populations were obtained from rBMSCs
Summary
The incidence of tendon injuries has markedly increased over the past few decades. To date, no viable therapeutic options provide fully successful, long-term solutions; reliable, effective, safe, innovative therapies are required. This pilot study explores the effect of rBMSC-EVs on an Achilles tendon injury in a rat model to evaluate whether high and low concentrations of EVs derived from rat bone marrow stromal/ stem cells without any further supplementation would improve repair of the injured tendon. Biophysical analysis data indicate that enriched EV populations were obtained from rBMSCs. The purity, size distribution and number of separated EVs were revealed by Atomic Force Microscopy (AFM) and Colloidal nanoplasmonic (CONAN) assay (Fig 2F, 2G and 2H).
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