Microvesicles derived from human Wharton’s jelly mesenchymal stem cells enhance autophagy and ameliorate acute lung injury via delivery of miR-100

Abstract

Objectives: Microvesicles (MVs) derived from human Wharton's jelly mesenchymal stem cells (MSC-MVs) were demonstrated to ameliorate acute lung injury (ALI). We have previously found that MSC-MV-transferred hepatocyte growth factor was partly involved in their therapeutic effects. Since MSC-MVs also contained a substantial quantity of miR-100, which plays an important role in lung cancer and injury, we speculated that miR-100 might similarly account for a part of the therapeutic effects of MSC-MVs.Methods: MSCs were transfected with miR-100 inhibitor to downregulate miR-100 in MSC-MVs. A rat model of ALI and cell injury in rat type II alveolar epithelial cell line (L2) was induced by bleomycin (BLM). A co-culture model of alveolar epithelial cells and MSC-MVs was utilized to examine the therapeutic role of MSC-MVs and mechanism.Results: MSC-MV treatment attenuated BLM-induced apoptosis and inflammation in BLM-treated L2 cells and ameliorated BLM-induced lung apoptosis, inflammation, and fibrosis in BLM-induced ALI rats. The beneficial effect of MSC-MVs was partly eliminated when miR-100 was knocked down in MSCs. Moreover, MSC-MV-transferred miR-100 mediated the therapeutic effect of MSC-MVs in ALI through enhancing autophagy by targeting mTOR.Conclusion: MSC-MVs enhance autophagy and ameliorate ALI partially via delivery of miR-100.

Effects of Mesenchymal Stromal Cell-Derived Extracellular Vesicles in Lung Diseases: Current Status and Future Perspectives

“…Characteristics of MSC treatments in lung diseases (completed clinical trials) EVs also transferred miR27a-3p / miR146a to modulate macrophage polarization[59,62]. Besides miRNAs, Zhu et al and Tang et al have demonstrated that MSC-EVs (30.9 ± 17.0μg protein/30ul or isolated from 3*10 6 MSCs/30ul) are capable of reducing inflammatory cell influx, protein permeability, MIP2 production, extravascular lung water, and increasing IL-10 secretion in the LPS-induced mouse models[63,64].…”

Review of the potential of mesenchymal stem cells for the treatment of infectious diseases

“…Silencing of mTOR or overexpression of autophagy-related proteins in epithelial cells reduced the production of cytokines IL-6 and IL-8[ 109 ]. Chen et al [ 110 ] found that miR-100 present in human WJ-MSCs-derived exosomes (extracellular vesicles, EVs) downregulated mTOR in rat AT-II cells. Treatment with MSCs-derived EVs activated autophagy but inhibited apoptosis and secretion of pro-inflammatory cytokines in bleomycin-treated rat epithelial cells through mTOR downregulation[ 110 ].…”

“…Chen et al [ 110 ] found that miR-100 present in human WJ-MSCs-derived exosomes (extracellular vesicles, EVs) downregulated mTOR in rat AT-II cells. Treatment with MSCs-derived EVs activated autophagy but inhibited apoptosis and secretion of pro-inflammatory cytokines in bleomycin-treated rat epithelial cells through mTOR downregulation[ 110 ]. The protective and repair functions of the MSCs were found to be mediated by p70S6K1[ 111 ], an isoform of S6K1, which is the downstream target of mTOR[ 65 ].…”

Pulmonary gene delivery—Realities and possibilities

“…144 A potential drawback is that cellular components internal to cellularly-produced exosomes may also be delivered along with any loaded cargo. 142,150–152 Exosomes have been used in mice for delivery to brain 144 and lymph nodes 151 without noticeable toxicity as long as the cell source was syngeneic. Safety studies will be the first major hurdle for exosome delivery to humans since unapproved exosome containing products (from the cells in which the exosomes are produced) have been warned against by the FDA.…”