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

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• 作者：Hiroyuki Nojima¹ ; Christopher M. Freeman¹ ; Rebecca M. Schuster¹ ; Lukasz Japtok² ; Burkhard Kleuser² ; Michael J. Edwards¹ ; Erich Gulbins¹ ; ³ ; Alex B. Lentsch¹ ; ^{alex.lentsch@uc.edu" class="auth_mail" title="E-mail the corresponding author}
• 关键词：SK ; sphingosine kinase ; S1P ; sphingosine-1-phosphate ; BrdU ; 5-bromo-2-deoxyuridine ; I/R ; ischemia/reperfusion ; ELISA ; enzyme-linked immunosorbant assay ; PCNA ; proliferating cell nuclear antigen ; H3-P ; phosphorylated histone H3 ; FSBA ; fluorosulfonylbenzoyladenosine
• 刊名：Journal of Hepatology
• 出版年：2016
• 出版时间：January 2016
• 年：2016
• 卷：64
• 期：1
• 页码：60-68
• 全文大小：2404 K

文摘

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.