Abstract
Non-alcoholic steatohepatitis (NASH) occurrence has been increasing and is becoming a major cause of liver cirrhosis and liver cancer. However, effective treatments for NASH are still lacking. We examined the benefits of serum-free conditioned medium from stem cells derived from human exfoliated deciduous teeth (SHED-CM) on a murine non-alcoholic steatohepatitis (NASH) model induced by a combination of Western diet (WD) and repeated administration of low doses of carbon tetrachloride intraperitoneally, focusing on the gut-liver axis. We showed that repeated intravenous administration of SHED-CM significantly ameliorated histological liver fibrosis and inflammation in a murine NASH model. SHED-CM inhibited parenchymal cell apoptosis and reduced the activation of inflammatory macrophages. Gene expression of pro-inflammatory and pro-fibrotic mediators (such as Tnf-α, Tgf-β, and Ccl-2) in the liver was reduced in mice treated with SHED-CM. Furthermore, SHED-CM protected intestinal tight junctions and maintained intestinal barrier function, while suppressing gene expression of the receptor for endotoxin, Toll-like receptor 4, in the liver. SHED-CM promoted the recovery of Caco-2 monolayer dysfunction induced by IFN-γ and TNF-α in vitro. Our findings suggest that SHED-CM may inhibit NASH fibrosis via the gut-liver axis, in addition to its protective effect on hepatocytes and the induction of macrophages with unique anti-inflammatory phenotypes.
Highlights
Non-alcoholic steatohepatitis (NASH) occurrence has been increasing and is becoming a major cause of liver cirrhosis and liver cancer
Morphometric analysis revealed that the positive area with Sirius red staining of the livers was significantly lower in the SHEDCM group (2.75 ± 0.31%) than in the Dulbecco’s modified Eagle’s medium (DMEM) group (7.43 ± 1.57%, P < 0.05) (Fig. 2A,B)
In fluorescence immunostaining of liver, the positive area for α-smooth muscle actin (α-SMA) was significantly lower in the Stem cells from human exfoliated deciduous teeth (SHEDs)-CM group (0.97 ± 0.65%) than in the DMEM group (4.57 ± 0.89%) (Fig. 2A,D)
Summary
Non-alcoholic steatohepatitis (NASH) occurrence has been increasing and is becoming a major cause of liver cirrhosis and liver cancer. We examined the benefits of serum-free conditioned medium from stem cells derived from human exfoliated deciduous teeth (SHED-CM) on a murine non-alcoholic steatohepatitis (NASH) model induced by a combination of Western diet (WD) and repeated administration of low doses of carbon tetrachloride intraperitoneally, focusing on the gut-liver axis. Mesenchymal stem cells (MSCs) with multipotent differentiation potential and low antigenicity self-renew and differentiate into adipocytes, cartilage, and bone, and secrete a wide range of nutritional and immunomodulatory factors These soluble factors can be collected as serum-free conditioned medium. We have previously reported that serum-free conditioned medium from stem cells derived from human exfoliated deciduous teeth (SHED-CM) exerts a protective effect on hepatocytes, and is effective in a rat model of D-galactosamine-induced acute liver failure[8] and in a murine model of carbon tetrachloride (CCl4)-induced liver fibrosis[9]. There have been no reports regarding the effects of SHED-CM in fatty liver models
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