Extracellular vesicles derived from umbilical cord mesenchymal stromal cells alleviate pulmonary fibrosis by means of transforming growth factor-β signaling inhibition

Abstract

Background 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. Studies have shown that umbilical cord-derived mesenchymal stromal cells (uMSCs) could alleviate PF; however, the underlying mechanism remains to be elucidated. Methods The 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. Results Treatment 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. Conclusion The 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.

Mesenchymal Stem Cell-Derived Extracellular Vesicles as Idiopathic Pulmonary Fibrosis Microenvironment Targeted Delivery

“…In fact, the clinical transition to MSC-EVs is still in its infancy and needs to face many challenges. Here, we summarize the studies of MSC-EVs administration in pulmonary fibrosis in vivo in Table 2 [ 20 , 108 , 117 , 124 , 125 , 126 , 127 , 128 , 129 , 130 , 131 , 132 , 133 , 134 , 135 , 136 , 137 , 138 , 139 ] and an overview of therapeutic modalities of MSC-EVs for IPF in Figure 3 .…”

Extracellular vesicles in idiopathic pulmonary fibrosis: pathogenesis and therapeutics

“…They demonstrated that human UC-MSC-derived EVs alleviate pulmonary fibrosis by repressing the TGF-β signaling pathway. Mechanistically, miR-21 and miR-23 in the EVs play crucial elements that contribute to anti-myofibroblast differentiation by downregulating TGF-β2 and TGF-βR2 expression [ 53 ]. While studies on MSC-derived EVs have dramatically increased, the development of clinical medicines is still in its infancy.…”

“…Since stem cell-derived EVs naturally contain various bioactive molecules derived from stem cells, the EV-based therapeutics have several advantages in clinical therapies. Currently, various types of cell-derived EVs have been studied in experimental pulmonary fibrosis models, such as MSCs [50][51][52][53][54], adult stem cells [55], fibroblasts [56,57], bronchial epithelial cells [10], and lung tissue spheroid cells [11] (Table 2).…”

Roles of exosomes and exosome-derived miRNAs in pulmonary fibrosis

“…However, exosomal miR-23a inhibited myofibroblast differentiation through inhibition of the TGF-β/SMAD pathway during wound healing ( Fang et al, 2016 ), and was thus used in the experimental treatment of PF ( Tan et al, 2018 ). Moreover, extracellular vesicles derived from umbilical cord MSCs enriched with miR-23 alleviated PF by inhibition of TGF-β signaling ( Shi et al, 2021 ). The precise effect and mechanism of the miR-23 family requires further investigation ( Table 10 ).…”