A novel antifibrotic strategy utilizing conditioned media obtained from miR-150-transfected adipose-derived stem cells: validation of an animal model of liver fibrosis

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 fibrosisrelated 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.

Adipose Tissue Fibrosis: Mechanisms, Models, and Importance

“…The SVF consists of all non-adipocyte cell types, including ASCs, endothelial cells, immune cells, and fibroblasts. ASCs are an attractive therapeutic option as they secrete growth factors, cytokines, proteins, and exosomes that promote regeneration [ 161 , 162 ] and have been used to treat systemic sclerosis, as well as dermal, liver, cardiac, renal, muscular, and lung fibrosis [ 163 , 164 , 165 , 166 , 167 , 168 , 169 , 170 , 171 , 172 ]. For example, injecting hASCs systemically reduced kidney fibrosis, improved renal functions, and reduced profibrotic gene expression [ 168 , 169 ].…”

Application of adipose-derived stem cells in treating fibrosis

“…MiR-150 is a representative anti-fibrotic miRNA, which can inhibit the activation of hepatic stellate cells through the inhibition of C-X-C motif chemokine ligand 1 (CXCL1), and is a natural component of ASCs EVs[ 35 ]. Paik et al [ 36 ] transfected ASCs with miR-150 to explore whether additional miR-150 secretion could boost the anti-fibrotic ability. As expected, transfected ASCs better alleviated liver fibrosis both in vitro and in vivo , due to elevated secretion of anti-fibrotic miRs[ 36 ].…”

“…Paik et al [ 36 ] transfected ASCs with miR-150 to explore whether additional miR-150 secretion could boost the anti-fibrotic ability. As expected, transfected ASCs better alleviated liver fibrosis both in vitro and in vivo , due to elevated secretion of anti-fibrotic miRs[ 36 ].…”

Recent Advances of Adipose-Derived Stem Cell-Based Therapies

“…Liver is one of the sources of MSCs, but what is the effect of ADSCs in the treatment for liver failure? Recently, Paik and his teamwork has proposed novel antifibrotic strategy utilizing conditioned media obtained from miR-150transfected ADSCs in an animal model of liver fibrosis [58]. Banas et al discussed ADSCs repairing liver damage.…”