惠利健研究组Hepatology解析凋亡抑制基因新功能

中科院生物化学与细胞生物学研究所惠利健研究组报道了凋亡抑制基因Survivin（存活素）在肝脏发育和肝脏干细胞增殖过程中的功能及机制。

　　

2013年7月1日，国际知名学术期刊《Hepatology》（肝脏学）在线发表了中科院生物化学与细胞生物学研究所惠利健研究组题为“Hepatic loss of Survivin impairs postnatal liver development and promotes expansion of hepatic progenitor cells”的研究论文，报道了凋亡抑制基因Survivin（存活素）在肝脏发育和肝脏干细胞增殖过程中的功能及机制。

在肝炎，肝纤维化和肝硬化等多种肝脏疾病发展过程中，肝细胞的增殖和代偿能力逐渐受到抑制，肝功能无法正常维持。肝脏干细胞具有胆管细胞和肝细胞双向分化潜能。在肝损伤情况下，肝脏干细胞会增殖和替换肝脏受损细胞，形成新的肝组织。但是以往研究所利用的化学物诱导模型或者基因缺失模型，肝脏干细胞仅部分替换受损肝组织，因而对肝脏干细胞修复肝脏的潜力无法全面评估。

存活素是凋亡抑制蛋白家族的一员，在细胞凋亡和有丝分裂过程中起重要的调控作用，目前存活素在肝脏发育和肝脏稳态维持过程中的作用仍然是未知的。博士研究生李丹在惠利健研究员指导下，发现在存活素缺失会导致新生小鼠肝细胞增殖停滞，多倍化和凋亡，进而刺激了肝脏干细胞的迅速增殖。肝脏干细胞在一个确定的短时间内完全替换原有受损肝细胞，形成正常的肝组织形态，并维持肝功能，从而首次证明了肝脏干细胞在病理条件下替换整个肝脏，并为研究肝脏干细胞的再生潜力提供了很好的模型。

此外，该研究还发现存活素缺失对成年肝细胞生存，稳态维持和功能没有明显影响。由于存活素在肝癌细胞中高表达，提示存活素可能是一个特异性高的肝癌治疗靶点。

该工作得到了国家科技部、国家自然科学基金委和中国科学院的资助。

原文摘要：

Hepatic loss of Survivin impairs postnatal liver development and promotes expansion of hepatic progenitor cells

Hepatocytes possess a remarkable capacity to regenerate and reconstitute the parenchyma after liver damage. However, in case of chronic injury, their proliferative potential is impaired and hepatic progenitor cells (HPCs) are activated, resulting in a ductular reaction known as oval cell response. Proapoptotic and survival signals maintain a precise balance to spare hepatocytes and progenitors from hyperplasia and cell death during regeneration. Survivin, a member of the family of inhibitor of apoptosis proteins (IAPs), plays key roles in proliferation and apoptosis of various cell types. Here we characterized the in vivo function of Survivin in regulating postnatal liver development and homeostasis using mice carrying conditional Survivin alleles. Hepatic perinatal loss of Survivin causes impaired mitosis, increased genome ploidy and enlarged cell size in postnatal livers, which eventually leads to hepatocyte apoptosis and triggers tissue damage and inflammation. Subsequently, HPCs that retain genomic Survivin alleles are activated, which finally differentiate into hepatocytes and reconstitute the whole liver. By contrast, inducible ablation of Survivin in adult hepatocytes does not affect HPC activation and liver homeostasis during a long life period. Conclusion: Our data demonstrate that perinatal Survivin deletion impairs hepatic mitosis in postnatal liver development, which induces HPCs activation and reconstitution in the liver, therefore providing a novel HPC induction model. (HEPATOLOGY 2013.)