The Polyploid State Restricts Hepatocyte Proliferation and Liver Regeneration in Mice.
The Polyploid State Restricts Hepatocyte Proliferation and Liver Regeneration in Mice.
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DOI：
10.1002/hep.30286
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发表时间：
2019-03
期刊：
影响因子：
--
通讯作者：
Duncan AW
中科院分区：
文献类型：
--
作者：
Wilkinson PD;Delgado ER;Alencastro F;Leek MP;Roy N;Weirich MP;Stahl EC;Otero PA;Chen MI;Brown WK;Duncan AW
肝脏含有具有二倍体或多倍体（四倍体、八倍体等）核含量的肝细胞混合物。多倍体肝细胞常见于成年哺乳动物，占啮齿动物整个肝池的约 90%。调节多倍体化的细胞和分子机制已得到充分表征；然而，尚不清楚二倍体和多倍体肝细胞在多种情况下是否具有相似的功能。回答这个问题一直具有挑战性，因为增殖的肝细胞可以增加或减少倍性，而具有健康的仅二倍体肝脏的动物模型尚未可用。最近据报道，肝脏中缺乏 E2f7 和 E2f8 的小鼠 (LKO) 存在多倍体化缺陷，但在其他方面都很健康。在此，对 LKO 小鼠的肝脏进行了严格的表征，证明二倍体肝细胞增加了 20 倍，并且即使在广泛增殖后仍维持二倍体状态。 LKO 小鼠的肝脏保持正常功能，但在受到促肿瘤刺激时变得高度致瘤，这表明 LKO 小鼠的肿瘤至少部分是由能够快速增殖的二倍体肝细胞驱动的。事实上，LKO 小鼠的肝细胞增殖速度更快，并且在竞争中胜过对照肝细胞，尤其是在竞争性再增殖研究中。此外，还检查了野生型小鼠的二倍体或多倍体肝细胞，以消除与 E2f7/E2f8 缺陷相关的潜在混杂效应。野生型二倍体细胞还表现出增殖优势，无论是在体外还是在肝再生过程中，都比多倍体细胞更快地进入和完成细胞周期。二倍体和多倍体肝细胞对肝丝裂原的反应相似，表明增殖动力学与对生长刺激的差异反应无关。二倍体肝细胞的增殖速度比多倍体快，表明多倍体状态起到生长抑制剂的作用，限制大多数肝细胞的增殖。
The liver contains a mixture of hepatocytes with diploid or polyploid (tetraploid, octaploid, etc.) nuclear content. Polyploid hepatocytes are commonly found in adult mammals, representing ~90% of the entire hepatic pool in rodents. The cellular and molecular mechanisms that regulate polyploidization have been well-characterized; however, it is unclear if diploid and polyploid hepatocytes function similarly in multiple contexts. Answering this question has been challenging because proliferating hepatocytes can increase or decrease ploidy, and animal models with healthy diploid-only livers have not been available. Mice lacking E2f7 and E2f8 in the liver (LKO) were recently reported to have a polyploidization defect but were otherwise healthy. Herein, livers from LKO mice were rigorously characterized, demonstrating a 20-fold increase in diploid hepatocytes and maintenance of the diploid state even after extensive proliferation. Livers from LKO mice maintained normal function but became highly tumorigenic when challenged with tumor-promoting stimuli, suggesting that tumors in LKO mice were driven, at least in part, by diploid hepatocytes capable of rapid proliferation. Indeed, hepatocytes from LKO mice proliferate faster and out-compete control hepatocytes, especially in competitive repopulation studies. In addition, diploid or polyploid hepatocytes from wild-type mice were examined to eliminate potentially confounding effects associated with E2f7/E2f8 deficiency. The wild-type diploid cells also showed a proliferative advantage, entering and progressing through the cell cycle faster than polyploid cells, both in vitro and during liver regeneration. Diploid and polyploid hepatocytes responded similarly to hepatic mitogens, indicating that proliferation kinetics are unrelated to differential response to growth stimuli. Diploid hepatocytes proliferate faster than polyploids, suggesting that the polyploid state functions as a growth suppressor to restrict proliferation by the majority of hepatocytes.
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影响因子：
46.9
作者：
Azuma, Hisaya;Paulk, Nicole;Grompe, Markus
通讯作者：
Grompe, Markus
DOI：
10.1002/hep.28573
发表时间：
2016-08
期刊：
Hepatology (Baltimore, Md.)
影响因子：
--
作者：
Hsu SH;Delgado ER;Otero PA;Teng KY;Kutay H;Meehan KM;Moroney JB;Monga JK;Hand NJ;Friedman JR;Ghoshal K;Duncan AW
通讯作者：
Duncan AW
影响因子：
4
作者：
Kreutz C;MacNelly S;Follo M;Wäldin A;Binninger-Lacour P;Timmer J;Bartolomé-Rodríguez MM
通讯作者：
Bartolomé-Rodríguez MM
影响因子：
5.3
作者：
Honkakoski, P;Zelko, I;Negishi, M
通讯作者：
Negishi, M
DOI：
10.1016/s0006-291x(03)00125-6
发表时间：
2003-02-28
影响因子：
3.1
作者：
Conner, EA;Lemmer, ER;Thorgeirsson, SS
通讯作者：
Thorgeirsson, SS