Mesenchymal stromal cell-derived exosome-rich fractionated secretome confers a hepatoprotective effect in liver injury

Abstract

BackgroundMesenchymal stromal cells (MSCs) are an attractive therapeutic agent in regenerative medicine. Recently, there has been a paradigm shift from differentiation of MSCs to their paracrine effects at the injury site. Several reports elucidate the role of trophic factors secreted by MSCs toward the repair of injured tissues. We hypothesize that fractionating the MSC secretome will enrich exosomes containing soluble bioactive molecules, improving its therapeutic potential for liver failure.MethodsRat bone marrow MSCs were isolated and the conditioned media filtered, concentrated and ultracentrifuged to generate fractionated secretome. This secretome was characterized for the presence of exosomes and recovery from liver injury assessed in in-vitro liver injury models. The results were further validated in vivo.ResultsStudies on in-vitro liver injury models using acetaminophen and hydrogen peroxide show better cell recovery and reduced cytotoxicity in the presence of fractionated as opposed to unfractionated secretome. Further, the cells showed reduced oxidative stress in the presence of fractionated secretome, suggesting a potential antioxidative effect. These results were further validated in vivo in liver failure models, wherein improved liver regeneration in the presence of fractionated secretome (0.819 ± 0.035) was observed as compared to unfractionated secretome (0.718 ± 0.042).ConclusionsThe work presented is a proof of concept that fractionating the secretome enriches certain bioactive molecules involved in the repair and recovery of injured liver tissue.Graphical abstractExosome enriched mesenchymal stromal cell-derived fractionated secretome potentiates recovery upon injection in injured liverElectronic supplementary materialThe online version of this article (10.1186/s13287-017-0752-6) contains supplementary material, which is available to authorized users.

Co-encapsulation of HNF4α Overexpressing UMSCs and Human Primary Hepatocytes Ameliorates Mouse Acute Liver Failure

“…Previous studies have demonstrated that co-transplantation of hepatocytes and MSCs exerted a signi cant therapeutic effect on ALF animal models, in which MSCs support hepatocellular metabolism and stabilization in ALF. (38) In the current study, in the co-capsulation system of UMSCs and hepatocytes, in vitro, UMSCs promoted the synthesis and secretion of human primary hepatocytes and enhanced the viability and function of hepatocytes ( Fig.1D-1E). In vivo, UMSC-HEP-APA reduced decreased mortality rate, hepatic apoptosis and necrotic level (Fig.2), inhibited in ammatory response including an alleviated neutrophil and macrophage in ltration in the liver, in ammatory factors levels (Fig.3).…”

Intranasal delivery of mesenchymal stem cell‐derived exosomes reduces oxidative stress and markedly inhibits ethanol consumption and post‐deprivation relapse drinking.

“…The size and concentration of exosomes were analyzed by NanoTracking System Analysis using the NanoSight NS500 equipment (NanoSight Ltd, Amesbury, United Kingdom) and by transmission electron microscopy with a Phillips Morgagni electron microscope as previously reported (Damania et al . ). Gel electrophoresis and Western blots were performed to confirm the enrichment of exosome markers (GM130, ALIX, Flotilin and EpCAM) in exosome samples compared to whole cell lysate using the Exosomal Marker Ab sampler kit (Cell Signaling Technology, Danvers, MA).…”

“…Additional studies both in vitro and in vivo have shown the marked ability of MSC‐derived exosomes to reduce oxidative stress and cell damage in several pathological conditions including hydrogen peroxide incubation, carbon tetrachloride administration, acetaminophen tissue injury and ischemic cardiomyopathy (Damania et al . ; Shi et al . ).…”

Transplantation of mesenchymal stem cells and their derivatives effectively promotes liver regeneration to attenuate acetaminophen-induced liver injury

“…Intriguingly, Wu et al demonstrated that MSCderived exosomes promoted the conversion of hepatocytes into hepatic oval cells to promote liver regeneration [94]. Exosomes improve cell recovery and reduce cytotoxicity in APAP-and hydrogen peroxide-treated hepatocytes [95]. MSC-derived exosomes significantly inhibit APAPinduced apoptosis of hepatocytes via upregulation of Bcl-xL levels but not through modulation of oxidative stress in vitro [96].…”