Extracellular Vesicles from Bone Marrow-Derived Mesenchymal Stem Cells Improve Survival from Lethal Hepatic Failure in Mice

Abstract

Background and Aims Stem cell-based therapies have potential for treatment of liver injury by contributing to regenerative responses, through functional tissue replacement or paracrine effects. The release of extracellular vesicles (EV) from cells has been implicated in intercellular communication, and may contribute to beneficial paracrine effects of stem-cell based therapies. Methods Therapeutic effects of bone-marrow derived mesenchymal stem cells (MSC) and vesicles released by these cells were examined in a lethal murine model of hepatic failure induced by D-Galactosamine/TNF-α. Results Systemically administered EV derived from MSC accumulated within the injured liver following systemic administration, reduced hepatic injury, and modulated cytokine expression. Moreover, survival was dramatically increased by EV derived from either murine or human MSC. Similar results were observed with the use of cryopreserved mMSC-EV after 3 months. Y-RNA-1 was identified as a highly enriched non-coding RNA within hMSC-EV compared to cells of origin. Moreover, siRNA mediated knockdown of Y-RNA-1 reduced the protective effects of MSC-EV on TNFα/Act D-mediated hepatocyte apoptosis in vitro. Conclusions These data support a critical role for MSC derived EV in mediating reparative responses following hepatic injury, and provide compelling evidence to support the therapeutic use of MSC derived EV in fulminant hepatic failure.

Amelioration of Ductular Reaction by Stem Cell Derived Extracellular Vesicles in MDR2 Knockout Mice via Lethal‐7 microRNA

“…Recently, many studies have been performed with stem cell–derived EVs and liver injury. EVs derived from mesenchymal stem cells (MSCEVs) have been shown to improve the survival of mice with d‐galactosamine/TNF‐α‐induced lethal hepatic failure . MSCEVs have also been shown to be a protective treatment when administered before ischemic‐reperfusion liver injury in mice .…”

Beneficial Effects of Human Mesenchymal Stromal Cells on Porcine Hepatocyte Viability and Albumin Secretion

“…The mechanism how MSC exert their beneficial effects needs further investigations and might not solely be due to paracrine effects. Interestingly, the systemic injection of extracellular vesicles, derived from bone marrow MSC after in vitro culture, reduced hepatic injury and improved mice survival [25], suggesting that such vesicles contain molecules either acting directly on liver cells or modulating the immune system. Moreover, the evaluation of the secretome of human MSC evidenced a correlation between vascular endothelial growth factor and cell proliferation, development processes, and immune processes.…”

Mesenchymal stem cell derived extracellular vesicles: a promising new therapeutic approach for hepatic injury

“…The use of mesenchymal stem cell (MSC) based therapy is a promising new strategy for the treatment of organ injury, and one that may have applications for acute hepatic injury (1–3). MSC have several unique properties such as their inherent capacity for regeneration and multipotency that support their use for tissue replacement therapy.…”

“…These include the cost, time required for their generation, and the need for a consistent supply of cells with a stable phenotype (4). Other limitations include toxicity, loss of viability, rejection or unwanted engraftment, for example, within the pulmonary microvasculature after their systemic administration (3). …”

“…Haga et al reported that the administration of EV isolated from bone marrow derived MSC dramatically improved survival and abrogated cytokine-mediated hepatic injury induced by systemic administration of D-galactosamine/TNF-α. A reduction in biochemical and histological hepatic injury, apoptosis and mortality from liver failure was observed (3). In another study carried out by the same group, a protective effect of BM-MSC-EV was observed with experimental hepatic ischemia/ reperfusion injury in vivo .…”