sEVs from tonsil-derived mesenchymal stromal cells alleviate activation of hepatic stellate cells and liver fibrosis through miR-486-5p

Abstract

Mesenchymal stromal cells (MSCs) are considered as a promising therapeutic tool for liver fibrosis, a main feature of chronic liver disease. Because small extracellular vesicles (sEVs) harboring a variety of proteins and RNAs are known to have similar functions with their derived cells, MSC-derived sEVs carry out the regenerative capacities of MSCs. Human tonsil-derived MSCs (T-MSCs) are reported as a novel source of MSCs, but their effects on liver fibrosis remain unclear. In the present study, we investigated the effects of T-MSC-derived sEVs on liver fibrosis. The expression of profibrotic genes decreased in human primary hepatic stellate cells (pHSCs) co-cultured with T-MSCs. Treatment of T-MSC-sEVs inactivated human and mouse pHSCs. Administration of T-MSC-sEVs ameliorated hepatic injuries and fibrosis in chronically damaged liver induced by carbon tetrachloride (CCl 4 ). miR-486-5p highly enriched in T-MSC-sEVs targeting the hedgehog receptor, smoothened (Smo), was upregulated, whereas Smo and Gli2, the hedgehog target gene, were downregulated in pHSCs and liver tissues treated with T-MSC-sEVs or miR-486-5p mimic, indicating that sEV-miR-486 inactivates HSCs by suppressing hedgehog signaling. Our results showed that T-MSCs attenuate HSC activation and liver fibrosis by delivering sEVs, and miR-486 in the sEVs inactivates hedgehog signaling, suggesting that T-MSCs and their sEVs are novel anti-fibrotic therapeutics for treating chronic liver disease.

Extracellular Vesicles in Organ Fibrosis: Mechanisms, Therapies, and Diagnostics

“…The EVs elicited similar effects when added to TGF-β1-treated HL7702 [ 280 ] or CCl 4 -treated L-02 hepatic cells in vitro [ 279 ]. EVs from human tonsil-derived mesenchymal stromal cells reduced expression of αSMA , TGF-β , CCN2 and vimentin in human LX2 HSC in vitro and attenuated collagen deposition and profibrotic gene expression in CCl 4 -induced liver fibrosis in mice, with the therapeutic effect attributed to elevated levels of EV miR-486-5p which suppressed Smo Hh receptor expression and signaling in HSC [ 281 ]. EVs from human umbilical cord perivascular cells were antifibrotic and inhibited fibrosis-related gene expression in TAA-induced hepatic fibrosis in vivo but these effects were augmented upon prior loading of the EVs with IGF-1 by adenoviral transduction of the donor cells [ 282 ].…”

Mesenchymal Stem Cells: Therapeutic Mechanisms for Stroke

“…Compared with BMSCs, the yield of ADSCs is not affected by age [ 9 ]. In addition, MSCs can be derived from multiple tissues, such as umbilical cord blood (UCB), umbilical cord (UC) [ 8 ], tonsils [ 10 ], olfactory mucosa [ 11 ], and dental tissue [ 12 ]. Depending on the cell source, different dosing times may result in different therapeutic effects [ 13 ].…”

The emerging roles of extracellular vesicles as intercellular messengers in liver physiology and pathology

“…132 In addition to EVs obtained from BM-MSCs to promote liver regeneration, 132 tonsil MSCs-released EVs enriched with miR-486-5p also attenuate liver fibrosis by inhibiting hedgehog signaling after intravenous administration to CCl4induced liver fibrosis mice. 133 EVs can be engineered to enhance their sustainability and increase the amount of therapeutic cargo molecules. Embedding MSC-derived EVs in polyethylene glycol hydrogels prolongs EV retention in the body.…”