Abstract
The limitations of stem cells have led researchers to investigate the secretome, which is the secretory materials in stem cells, since the principal mechanism of action of stem cells is mediated by the secretome. In this study, we determined the antifibrotic potential of the secretome released from miR-150-transfected adipose-derived stromal cells (ASCs). The secretome released from ASCs that were transfected with antifibrotic miR-150 was obtained (referred to as the miR-150 secretome). To validate the antifibrotic effects of the miR-150 secretome, we generated in vitro and in vivo models of liver fibrosis by treating human hepatic stellate cells (LX2 cells) with thioacetamide (TAA) and subcutaneous injection of TAA into mice, respectively. In the in vitro model, more significant reductions in the expression of fibrosis-related markers, such as TGFβ, Col1A1, and α-SMA, were observed by using the miR-150 secretome than the control secretome, specifically in TAA-treated LX2 cells. In the in vivo model, infusion of the miR-150 secretome into mice with liver fibrosis abrogated the increase in serum levels of systemic inflammatory cytokines, such as IL-6 and TNF-α, and induced increased expression of antifibrotic, proliferation, and antioxidant activity markers in the liver. Our in vitro and in vivo experiments indicate that the miR-150 secretome is superior to the naive secretome in terms of ameliorating liver fibrosis, minimizing systemic inflammatory responses, and promoting antioxidant enzyme expression. Therefore, we conclude that miR-150 transfection into ASCs has the potential to induce the release of secretory materials with enhanced antifibrotic, proliferative, and antioxidant properties.
Highlights
Advanced liver fibrosis is one of the major causes of mortality and morbidity worldwide because it leads to liver cirrhosis, portal hypertension, hepatocellular carcinoma, and hepatic failure
The values are presented as the mean ± standard deviation of three independent experiments. *P < 0.05. α-SMA alphasmooth muscle actin, COL1A1 collagen type I alpha 1 chain, Ct control, MMP2 metalloproteinases-2, Sec the secretome obtained from adipose-derived stromal cells (ASCs) after 48 h of incubation, TAA thioacetamide, t-ASC miR-150-transfected adipose-tissue derived stem cell, TGF-β transforming growth factor-β, TIMP-1 tissue inhibitor of metalloproteinases-1, t-Sec the secretome released from miR-150-transfected ASCs
Mice with liver fibrosis were intravenously infused with normal saline (n = 12), the control secretome (n = 12), or the miR-150 secretome (n = 12) three times a week for 1 week. b RT-PCR results showing the mRNA expression of MMP2, α-SMA, and TGF-β1 in liver specimens in each group
Summary
Advanced liver fibrosis is one of the major causes of mortality and morbidity worldwide because it leads to liver cirrhosis, portal hypertension, hepatocellular carcinoma, and hepatic failure. Liver transplantation is considered the only curative option. In the past few decades, advances in stem cell research have provided hope that stem cells could ameliorate liver fibrosis. Safety concerns are one of the main obstacles to the clinical application of stem cells because the stability of transplanted stem cells cannot be guaranteed. Several researchers have turned to their attention to the secretome, which are the molecules that are secreted or surface-shed by stem cells[8,9]. Numerous studies have demonstrated that the secretome has similar potential to that of stem cells because the principal mechanism of action of these cells is mediated by the secretome[10,11,12,13,14,15,16,17]. We have performed several experiments that validated the therapeutic
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