Hepatocyte exosomes mediate liver repair and regeneration via sphingosine-1-phosphate.
Hepatocyte exosomes mediate liver repair and regeneration via sphingosine-1-phosphate.
复制标题
DOI：
10.1016/j.jhep.2015.07.030
复制
发表时间：
2016-01
影响因子：
25.7
通讯作者：
Lentsch AB
中科院分区：
文献类型：
--
作者：
Nojima H;Freeman CM;Schuster RM;Japtok L;Kleuser B;Edwards MJ;Gulbins E;Lentsch AB
外来体是参与细胞间通讯的小膜囊泡。已知肝细胞释放外泌体，但对其生物学功能知之甚少。我们试图确定来源于肝细胞的外泌体是否有助于损伤后的肝修复和再生。分离衍生自原代鼠肝细胞的外泌体，并进行生化和生物药理学表征。使用原代肝细胞的培养物，我们测试了肝细胞外来体是否在体外诱导肝细胞增殖。使用缺血/再灌注损伤和部分肝切除模型，我们评估肝细胞外泌体是否促进体内肝细胞增殖和肝再生。肝细胞外泌体，而不是来自其他肝细胞类型的外泌体，在体外和体内诱导剂量依赖性肝细胞增殖。从机制上讲，肝细胞外泌体直接与靶肝细胞融合，并转移中性神经酰胺酶和鞘氨醇激酶2（SK 2），导致靶肝细胞内鞘氨醇-1-磷酸（S1 P）的合成增加。外泌体SK的消融防止了外泌体的增殖作用。在缺血/再灌注损伤后，具有增殖作用的循环外泌体的数量增加。我们的数据显示，肝细胞衍生的外泌体递送合成机制以在靶肝细胞中形成S1 P，导致缺血/再灌注损伤或部分肝切除术后的细胞增殖和肝再生。这些发现代表了一种潜在的新的肝再生机制，并对急性和慢性肝病的新治疗方法具有重要意义。
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. 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. 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. 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.
影响因子：
8.3
作者：
Limaye V;Vadas MA;Pitson SM;Gamble JR
通讯作者：
Gamble JR