Human Placental Mesenchymal Stem Cells Ameliorate Liver Fibrosis in Mice by Upregulation of Caveolin1 in Hepatic Stellate Cells

Abstract

Background: Liver fibrosis (LF) is a common pathological process characterized by the activation of hepatic stellate cells (HSCs) and accumulation of extracellular matrix. Severe LF causes cirrhosis and even liver failure, a major cause of morbidity and mortality worldwide. Transplantation of human placental mesenchymal stem cells (hPMSCs) has been considered as an alternative therapy, replacing liver transplantation in clinical trials, to treat LF. However, the underlying mechanisms and the appropriate time window for hPMSC transplantation are not well understood. Methods: We established mouse models of CCL4-injured LF, and administered hPMSCs once a week for 2 weeks. The therapeutic effect of hPMSCs on LF was investigated, according to histopathological and blood biochemical analyses. What’s more, the culture supernatant of hPMSCs were isolated, and the effect of the culture supernatant on the inhibition of activated HSCs was also assessed. RNA sequencing (RNA-seq) analysis, Real-time PCR array, and western blotting were performed to explore possible signaling pathways involved in treatment of IF with hPMSCs. Results: hPMSC treatment can alleviate experimental hepatic fibrosis, restore liver function, and inhibit inflammation. Furthermore, the therapeutic effect of hPMSCs against mild to moderate LF was significantly greater than against severe disease. Mechanistic dissection studies suggested ameliorating LF using hPMSCs occur partly by restoring Caveolin-1 (Cav1) in activated hepatic stellate cells (HSCs). Upregulation of Cav1 can inhibit the TGF-β/Smad signaling pathway, mainly by reducing Smad2 phosphorylation, resulting in the inhibition of activated HSCs, whereas this effect could be abated if Cav1 was silenced in advance by siRNAs. Conclusions: Our findings suggest that hPMSCs could provide multifaceted therapeutic benefits for the treatment of LF, and the TGF-β/Cav1 pathway might act as a therapeutic target for hPMSCs in the treatment of LF.

Therapeutic efficacy of human adipose mesenchymal stem cells in Crohn’s colon fibrosis is improved by IFN-γ and kynurenic acid priming through indoleamine 2,3-dioxygenase-1 signaling

“…Additionally, if substantial inflammation is confirmed, physicians should initially attempt anti-inflammatory therapy, which might decrease bowel wall edema and thickness, with subsequent relief of the obstructive symptom [26]. Our previous studies have also shown that the anti-inflammatory effect of MSCs is very important in the treatment of liver fibrosis [27]. The above experiments indicated that primed hADSCs of IDO-1 expression increased had significant anti-inflammatory and antifibrotic effects than untreated hADSCs.…”

The role of bile acid receptor TGR5 in regulating inflammatory signalling

“…TGR5 up-regulation participates in human placental mesenchymal stem cell transplantation-relieved primary sclerosing cholangitis. 123 TGR5 KO or inhibition leads to more abundant pro-inflammatory subtype of macrophages and suppressed tumour progression in NSCLC 65 ; TGR5 activation ameliorates motor deficits and cognitive impairment in a subchronic Parkinson's disease mouse model 124 ; and DCA induces gastric intestinal metaplasia by activating TGR5/STAT3/KLF5 axis. 125 Tgr5 KO mice show greater steatosis and inflammation by increasing liver macrophages recruitment 59 ; Tgr5 KO mice show decreased hair area and length, skin thickness, and the ratio of anagen and telogen, collagen, and mast cell number and loss the bone mass than WT group.…”

Small-molecule natural products for reversing liver fibrosis based on modulation of HSCs activation: an update

“…FGF21 inhibits further activation of HSCs by suppressing the TGF-β/Smad3C signaling pathway, thereby stopping the progression of LF. Furthermore, it has been found that upregulation of Cav1 inhibits the TGF-β/Smad signaling pathway, mainly by decreasing the phosphorylation of Smad2, thereby inhibiting activated HSCs [26] . High mobility group box 1 protein (HMGB1) and toll-like receptor 4 (TLR4) are key mediators of the pro-inflammatory response.…”