Hepatocyte exosomes mediate liver repair and regeneration via sphingosine-1-phosphate

Abstract

Background & Aims Exosomes are small membrane vesicles involved in intercellular communication. Hepatocytes are known to release exosomes, but little is known about their biological function. We sought to determine if exosomes derived from hepatocytes contribute to liver repair and regeneration after injury. Methods Exosomes derived from primary murine hepatocytes were isolated and characterized biochemically and biophysically. Using cultures of primary hepatocytes, we tested whether hepatocyte exosomes induced proliferation of hepatocytes in vitro. Using models of ischemia/reperfusion injury and partial hepatectomy, we evaluated whether hepatocyte exosomes promote hepatocyte proliferation and liver regeneration in vivo. Results Hepatocyte exosomes, but not exosomes from other liver cell types, induce dose-dependent hepatocyte proliferation in vitro and in vivo. Mechanistically, hepatocyte exosomes directly fuse with target hepatocytes and transfer neutral ceramidase and sphingosine kinase 2 (SK2) causing increased synthesis of sphingosine-1-phosphate (S1P) within target hepatocytes. Ablation of exosomal SK prevents the proliferative effect of exosomes. After ischemia/reperfusion injury, the number of circulating exosomes with proliferative effects increases. Conclusions Our data shows that hepatocyte-derived exosomes deliver the synthetic machinery to form S1P in target hepatocytes resulting in cell proliferation and liver regeneration after ischemia/reperfusion injury or partial hepatectomy. These findings represent a potentially novel new contributing mechanism of liver regeneration and have important implications for new therapeutic approaches to acute and chronic liver disease.

Exosome Adherence and Internalization by Hepatic Stellate Cells Triggers Sphingosine 1-Phosphate-dependent Migration

“…3C). Other extracellular matrix (ECM) proteins have been reported within exosomes (44,45). To examine whether other ECM proteins could be responsible for integrin activation by exosomes, we blotted lysed exosomes for collagen I, which was not detected in our serum-derived exosomes.…”

Hepatocytes release ceramide-enriched pro-inflammatory extracellular vesicles in an IRE1α-dependent manner

“…EVs are a route for cell-derived cargo to be shed from cells, and a mechanism for delivery of specifi c cargoes from donor cells to recipient cells, thus acting as carriers of a stress-stimulated message. Recently, studies have demonstrated an increase in circulating EV release under in vitro lipotoxic conditions, circulating EVs in mouse models of NASH and ischemia/reperfusion injury, and in patients with chronic hepatitis C and NASH (11)(12)(13). Furthermore, it has been reported that ceramides are needed for the formation of EVs via the multivesicular body (MVB) endosomal traffi cking pathway ( 14 ).…”

Exosome: An Emerging Participant in the Development of Liver Disease

“…Hiroyuki et al discovered that exosomes derived from hepatocytes can promote the proliferation and regeneration of liver tissue both in vitro and in mice models of liver ischemia/reperfusion injury or partial hepatectomy (22). The researchers believed that the underlying mechanism involves sphingosine 1-phosphate (S1P).…”

“…The researchers believed that the underlying mechanism involves sphingosine 1-phosphate (S1P). Hepatocyte-derived exosomes carrying neutral ceramidase and sphingosine kinase 2 (SK2) are captured by adjacent hepatocytes and raise the intracellular level of sphingosine-1-phosphate, thus promoting hepatocyte proliferation (22).…”