Hepatic progenitor cells of biliary origin with liver repopulation capacity.
Hepatic progenitor cells of biliary origin with liver repopulation capacity.
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DOI：
10.1038/ncb3203
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发表时间：
2015-08
影响因子：
21.3
通讯作者：
Forbes SJ
中科院分区：
文献类型：
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作者：
Lu WY;Bird TG;Boulter L;Tsuchiya A;Cole AM;Hay T;Guest RV;Wojtacha D;Man TY;Mackinnon A;Ridgway RA;Kendall T;Williams MJ;Jamieson T;Raven A;Hay DC;Iredale JP;Clarke AR;Sansom OJ;Forbes SJ
肝细胞和胆管细胞在肝损伤后自我更新。严重损伤后肝细胞逐渐衰老，肝祖细胞（HPC）是否有助于肝再生尚不清楚。在这里，我们描述了一种小鼠模型，其中Mdm 2在超过98%的肝细胞中诱导缺失，导致几乎所有肝细胞表达p21的凋亡、坏死和衰老。这导致了旺盛的HPC活化，这是生存所必需的，随后是完整的功能性肝脏重建。使用细胞表面标记从遗传正常小鼠中分离的HPC在体外具有高度可扩展性和表型稳定性。将这些HPC移植到肝细胞Mdm 2重复缺失的成年小鼠肝脏中，建立非竞争性再增殖试验。移植的HPC显著促进肝实质的恢复、肝细胞和胆管上皮的再生，突出了它们在体内的谱系效力。因此，HPC是肝细胞或肝移植治疗肝病的潜在替代方案。
Hepatocytes and cholangiocytes self renew following liver injury. Following severe injury hepatocytes are increasingly senescent, whether Hepatic Progenitor Cells (HPCs) then contribute to liver regeneration is unclear. Here, we describe a mouse model where Mdm2 is inducibly deleted in over 98% of hepatocytes, causing apoptosis, necrosis and senescence with nearly all hepatocytes expressing p21. This results in florid HPC activation, which is necessary for survival, followed by complete, functional liver reconstitution. HPCs isolated from genetically normal mice, using cell surface markers, were highly expandable and phenotypically stable in vitro. These HPCs were transplanted into adult mouse livers where hepatocyte Mdm2 was repeatedly deleted, creating a non-competitive repopulation assay. Transplanted HPCs contributed significantly to restoration of liver parenchyma, regenerating hepatocytes and biliary epithelia, highlighting their in vivo lineage potency. HPCs are therefore a potential future alternative to hepatocyte or liver transplantation for liver disease.