Abstract
BackgroundPulmonary fibrosis (PF), the end point of interstitial lung diseases, is characterized by myofibroblast over differentiation and excessive extracellular matrix accumulation, leading to progressive organ dysfunction and usually a terminal outcome. Studies have shown that umbilical cord-derived mesenchymal stromal cells (uMSCs) could alleviate PF; however, the underlying mechanism remains to be elucidated.MethodsThe therapeutic effects of uMSC-derived extracellular vesicles (uMSC-EVs) on PF were evaluated using bleomycin (BLM)-induced mouse models. Then, the role and mechanism of uMSC-EVs in inhibiting myofibroblast differentiation were investigated in vivo and in vitro.ResultsTreatment with uMSC-EVs alleviated the PF and enhanced the proliferation of alveolar epithelial cells in BLM-induced mice, thus improved the life quality, including the survival rate, body weight, fibrosis degree, and myofibroblast over differentiation of lung tissue. Moreover, these effects of uMSC-EVs on PF are likely achieved by inhibiting the transforming growth factor-β (TGF-β) signaling pathway, evidenced by decreased expression levels of TGF-β2 and TGF-βR2. Using mimics of uMSC-EV-specific miRNAs, we found that miR-21 and miR-23, which are highly enriched in uMSC-EVs, played a critical role in inhibiting TGF-β2 and TGF-βR2, respectively.ConclusionThe effects of uMSCs on PF alleviation are likely achieved via EVs, which reveals a new role of uMSC-EV-derived miRNAs, opening a novel strategy for PF treatment in the clinical setting.
Highlights
Pulmonary fibrosis (PF), the end point of interstitial lung diseases, is characterized by myofibroblast over differentiation and excessive extracellular matrix accumulation, leading to progressive organ dysfunction and usually a terminal outcome
The present study investigated the antifibrotic effect of umbilical cord-derived mesenchymal stromal cells (uMSCs)-extracellular vesicles (EVs) using a bleomycin (BLM)-induced mouse model, and our results demonstrated that uMSC-EVs alleviated PF through inhibiting the transforming growth factor-β (TGF-β) signaling pathway
Results uMSC-EV treatment alleviated pulmonary fibrosis in the BLM-induced mice uMSCs were confirmed using flow cytometry (FCM) and IF staining, and the results showed that uMSCs were positive to CD73, CD90, and CD105, negative to CD34 and CD45 (Fig. 1a, b). uMSC-EVs were confirmed using a transmission electron microscope, NanoSight, and western blot analysis
Summary
Pulmonary fibrosis (PF), the end point of interstitial lung diseases, is characterized by myofibroblast over differentiation and excessive extracellular matrix accumulation, leading to progressive organ dysfunction and usually a terminal outcome. Pulmonary fibrosis (PF), the end point interstitial lung diseases, is described as the deposition of excessive collagen and other extracellular matrix molecules within the alveolar septa (thickening of the septal interstitium), with or without structural lung damage and fibrotic masses, depending on the severity [1,2,3]. One currently assumed pathogenesis of PF is fibroblast-to-myofibroblast transition (FMT) initiated and driven by the transforming growth factor-β (TGF-β) signaling pathway [4, 5]. The downstream genes of the TGF-β signaling pathway, including TGF-β receptor and Smad, are activated, which leads to the extensive expression of α-smooth muscle actin (α-SMA) and collagen, thereby promoting FMT [6].
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