Unravelling the reversion mechanisms of activated hepatic stellate cell properties by extracellular vesicles from mesenchymal stem cells

Table 1 Role of anti-fibrotic microRNAs in liver fibrosis by modulating specific pathway(s)

miRNA	Target protein/pathway	Mechanism	Ref.
miR-29a/b/c	TIMP, SMAD, TGF-β, PDGF, Wnt, MMP, HMGB-1, TLR-4	Directly targets collagen genes, reduces ECM production, increases MMPs via TIMP suppression, inhibits Wnt signaling	[12,155,156,162]
miR-146a	NF-κB, IL-6, TNF-α, IL-1β, MCP-1, TGF-β, Wnt	Targets IRAK1, TRAF6 to inhibit NF-κB pathway; reduces pro-inflammatory cytokines, inhibits HSC activation	[40,222]
miR-125b	TGF-β, SMAD, Wnt	Targets SIRT7, suppresses TGF-β/SMAD and Wnt pathways, regulate Hedgehog signaling	[152]
miR-122	Collagen I/III, TIMP, α-SMA	Downregulated in fibrosis; restoration reduces collagen and HSC activation	[153,154]
let-7 g	TGF-β, SMAD	Inhibits TGF-β signaling, reduces ECM production, inhibit migration of HCC	[157]
miR-30a/e	TGF-β, α-SMA	Targets Beclin-1 and autophagy pathways, suppresses HSC activation	[158]
miR-133b	TGF-β	Directly targets TGF-β, inhibits HSC activation	[159]
miR-19b	TGFβR2	May inhibit TGF-β pathway via receptor targeting, inhibit fibrogenesis	[160]
miR-26a	Notch, TGF-β	Inhibits HSC proliferation, collagen production, EMT	[223]
miR-15a/b, miR-16	Bcl-2, TGF-β/SMAD, Notch, Wnt	Inhibit HSC proliferation and collagen expression	[224]
miR-126	p5, PI3K-AKT	Maintains endothelial integrity; fibrosis role less defined; regulates HSCs cycle and maintains HSCs	[225]
miR-199a/199a-3p	Collagen I/III, caveolin-2, GSK, MAPK	Improve chemo-sensitivity through mTOR pathway	[151,163]
miR-200	EMT, TGF-β, SMAD	Inhibits EMT and TGF-β induced fibrogenesis through SMAD pathway	[161]
miR-223	NF-κB, PDGF, MCP-1, HMGB1	Inhibits inflammasome activation, reduces inflammation and fibrosis	[226-228]
miR-150-5p/miR-150	TGF-β, c-Myb	Suppresses HSC activation	[229]
miR-486-5p	Hedgehog signaling	Suppresses HSC activation and fibrosis	[148]

miRNA: MicroRNA; TIMP: Tissue inhibitors of matrix metalloproteinase; SMAD: Small mother against decapentaplegic; TGF-β: Transforming growth factor-β; PDGF: Platelet derived growth factor; MMP: Matrix metalloproteinase; HMGB-1: High-mobility group box-1; TLR-4: Toll-like receptor 4; ECM: Extracellular matrix; NF-κB: Nuclear factor-kappa B; IL-6: Interleukin-6; TNF-α: Tumor necrosis factor-α; IL-1β: Interleukin-1β; MCP-1: Monocyte chemotactic protein-1; IRAK1: Interleukin-1 receptor associated kinase 1; TRAF6: Tumor necrosis factor receptor associated factor 6; HSC: Hepatic stellate cell; SIRT7: Sirtuin7; α-SMA: Alpha-smooth muscle actin; HCC: Hepatocellular carcinoma; TGFβR2: Transforming growth factor-beta receptor 2; EMT: Epithelial-mesenchymal transition; PI3K: Phosphoinositide 3-kinase; AKT: Protein kinase B; GSK: Glycogen synthase kinase; MAPK: Mitogen-activated protein kinase; mTOR: Mammalian target of rapamycin.