多倍体肝细胞的生理功能及其病理性改变的相关疾病

doi:10.16139/j.1007-9610.2023.06.015

摘要/Abstract

摘要：

成人肝脏中20%~50%的肝细胞为含2套以上染色体的多倍体细胞，是独特的多倍体器官。肝细胞多倍体化始于断奶时胰岛素信号的改变，受多种细胞周期调控因子控制，实现在多倍体细胞比例、倍性和空间分布等方面的调控，对肝脏代谢、再生和抑制肿瘤形成有重要作用。但在慢性病毒性肝炎和非酒精性脂肪肝病中，肝细胞可因细胞周期检查点抑制、氧化应激出现病理性多倍体化并参与疾病进程。区分多倍体肝细胞在生理和病理条件下的异同，有助于更好地认识慢性肝脏病与肿瘤发生的关系。

关键词: 倍性, 多倍体, 基因组不稳定性, 肝细胞, 肝细胞癌

Abstract:

Liver is a unique organ with polyploidy. About 20 to 50 percent of hepatocytes in adult human are polyploid cells, which contain more than two sets of chromosomes. Hepatocytes polyploidization is triggered by the changes in insulin signal during weaning, and regulated by various cell cycle regulator genes to ensure the polyploid cells proportion, ploidy and zonation. The regulation of polyploid hepatocytes is crucial for liver's metabolic and regenerative function, and protecting liver from tumorigenesis. However, in chronic virus hepatitis and nonalcoholic fatty liver disease, the pathological hepatocytes polyploidization can be found in disease progression because of cell cycle checkpoint inhibition and oxidative stress. Distinguishing physiological and pathological hepatocyte polyploidization will be helpful for the understanding the relationship between chronic liver disease and tumorigenesis.

Key words: Ploidy, Polyploidy, Chromosomal instability, Hepatocyte, Hepatocellular carcinoma

中图分类号:

R575
R735.7

张亦凡, 鲁逸权, 郝风节, 王俊青. 多倍体肝细胞的生理功能及其病理性改变的相关疾病[J]. 外科理论与实践, 2023, 28(06): 574-579.

ZHANG Yifan, LU Yiquan, HAO Fengjie, WANG Junqing. Physiological function of polyploid hepatocytes and pathological changes in its associated diseases[J]. Journal of Surgery Concepts & Practice, 2023, 28(06): 574-579.

参考文献 49

[1]	GJELSVIK K J, BESEN-MCNALLY R, LOSICK V P. Solving the polyploid mystery in health and disease[J]. Trends Genet, 2019, 35(1):6-14. doi: S0168-9525(18)30181-1 pmid: 30470486
[2]	SEVERIN E, WILLERS R, BETTECKEN T. Flow cytometric analysis of mouse hepatocyte ploidy. Ⅱ. The development of polyploidy pattern in four mice strains with different life spans[J]. Cell Tissue Res, 1984, 238(3):649-652. doi: 10.1007/BF00219884 URL
[3]	DUNCAN A W, HANLON NEWELL A E, SMITH L, et al. Frequent aneuploidy among normal human hepatocytes[J]. Gastroenterology, 2012, 142(1):25-28. doi: 10.1053/j.gastro.2011.10.029 pmid: 22057114
[4]	WILKINSON P D, DUNCAN A W. Differential roles for diploid and polyploid hepatocytes in acute and chronic liver injury[J]. Semin Liver Dis, 2021, 41(1):42-49. doi: 10.1055/s-0040-1719175 pmid: 33764484
[5]	MATSUMOTO T, WAKEFIELD L, TARLOW B D, et al. In vivo lineage tracing of polyploid hepatocytes reveals extensive proliferation during liver regeneration[J]. Cell Stem Cell, 2020, 26(1):34-47.e3. doi: 10.1016/j.stem.2019.11.014 URL
[6]	PANDIT S K, WESTENDORP B, NANTASANTI S, et al. E2F8 is essential for polyploidization in mammalian cells[J]. Nat Cell Biol, 2012, 14(11):1181-1191. doi: 10.1038/ncb2585 pmid: 23064264
[7]	WEI Y, WANG Y G, JIA Y, et al. Liver homeostasis is maintained by midlobular zone 2 hepatocytes[J]. Science, 2021, 371(6532):eabb1625. doi: 10.1126/science.abb1625 URL
[8]	RICHTER M L, DELIGIANNIS I K, YIN K, et al. Single-nucleus RNA-seq2 reveals functional crosstalk between liver zonation and ploidy[J]. Nat Commun, 2021, 12(1):4264. doi: 10.1038/s41467-021-24543-5 pmid: 34253736
[9]	ZHANG S, ZHOU K, LUO X, et al. The polyploid state plays a tumor-suppressive role in the liver[J]. Dev Cell, 2018, 44(4):447-459.e5. doi: S1534-5807(18)30010-8 pmid: 29429824
[10]	DUNCAN A W, TAYLOR M H, HICKEY R D, et al. The ploidy conveyor of mature hepatocytes as a source of genetic variation[J]. Nature, 2010, 467(7316):707-710. doi: 10.1038/nature09414
[11]	MATSUMOTO T, WAKEFIELD L, PETERS A, et al. Proliferative polyploid cells give rise to tumors via ploidy reduction[J]. Nat Commun, 2021, 12(1):646. doi: 10.1038/s41467-021-20916-y
[12]	DONNE R, SANGOUARD F, CELTON-MORIZUR S, et al. Hepatocyte polyploidy: driver or gatekeeper of chronic liver diseases[J]. Cancers (Basel), 2021, 13(20):5151. doi: 10.3390/cancers13205151 URL
[13]	CELTON-MORIZUR S, MERLEN G, COUTON D, et al. Polyploidy and liver proliferation: central role of insulin signaling[J]. Cell Cycle, 2010, 9(3):460-466. doi: 10.4161/cc.9.3.10542 URL
[14]	HSU S H, DELGADO E R, OTERO P A, et al. MicroRNA-122 regulates polyploidization in the murine liver[J]. Hepatology, 2016, 64(2):599-615. doi: 10.1002/hep.28573 URL
[15]	MORENO-MARíN N, MERINO J M, ALVAREZ-BARRIENTOS A, et al. Aryl hydrocarbon receptor promotes liver polyploidization and inhibits PI3K, ERK, and Wnt/β-Catenin signaling[J]. iScience, 2018, 4:44-63. doi: 10.1016/j.isci.2018.05.006 URL
[16]	TANAMI S, BEN-MOSHE S, ELKAYAM A, et al. Dynamic zonation of liver polyploidy[J]. Cell Tissue Res, 2017, 368(2):405-410. doi: 10.1007/s00441-016-2427-5 pmid: 27301446
[17]	SLADKY V C, KNAPP K, SZABO T G, et al. PIDDosome-induced p53-dependent ploidy restriction facilitates hepatocarcinogenesis[J]. EMBO reports, 2020, 21(12):e50893. doi: 10.15252/embr.202050893 URL
[18]	SLADKY V C, KNAPP K, SORATROI C, et al. E2F-family members engage the PIDDosome to limit hepatocyte ploidy in liver development and regeneration[J]. Developmental Cell, 2020, 52(3):335-349. doi: S1534-5807(19)31039-1 pmid: 31983631
[19]	FAVA L L, SCHULER F, SLADKY V, et al. The PIDDosome activates p53 in response to supernumerary centrosomes[J]. Genes Dev, 2017, 31(1):34-45. doi: 10.1101/gad.289728.116 URL
[20]	GANEM N J, CORNILS H, CHIU S Y, et al. Cytokinesis failure triggers hippo tumor suppressor pathway activation[J]. Cell, 2014, 158(4):833-848. doi: S0092-8674(14)00820-4 pmid: 25126788
[21]	SLADKY V C, AKBARI H, TAPIAS-GOMEZ D, et al. Centriole signaling restricts hepatocyte ploidy to maintain liver integrity[J]. Genes Dev, 2022, 36(13-14):843-856. doi: 10.1101/gad.349727.122 URL
[22]	LIANG C Q, ZHOU D C, PENG W T, et al. FoxO3 restricts liver regeneration by suppressing the proliferation of hepatocytes[J]. NPJ Regen Med, 2022, 7(1):33. doi: 10.1038/s41536-022-00227-6
[23]	JIN Y, ANBARCHIAN T, WU P, et al. Wnt signaling regulates hepatocyte cell division by a transcriptional repressor cascade[J]. Proc Natl Acad Sci U S A, 2022, 119(30):e2203849119. doi: 10.1073/pnas.2203849119 URL
[24]	BAHAR HALPERN K, TANAMI S, LANDEN S, et al. Bursty gene expression in the intact mammalian liver[J]. Mol Cell, 2015, 58(1):147-156. doi: 10.1016/j.molcel.2015.01.027 pmid: 25728770
[25]	ANATSKAYA O V, VINOGRADOV A E. Genome multiplication as adaptation to tissue survival: evidence from gene expression in mammalian heart and liver[J]. Genomics, 2007, 89(1):70-80. pmid: 17029690
[26]	SIGAL S H, RAJVANSHI P, GORLA G R, et al. Partial hepatectomy-induced polyploidy attenuates hepatocyte replication and activates cell aging events[J]. Am J Physiol, 1999, 276(5):G1260-G1272.
[27]	LOSICK V P. Wound-Induced polyploidy is required for tissue repair[J]. Adv Wound Care(New Rochelle), 2016, 5(6):271-278.
[28]	WILKINSON P D, ALENCASTRO F, DELGADO E R, et al. Polyploid hepatocytes facilitate adaptation and regeneration to chronic liver injury[J]. Am J Pathol, 2019, 189(6):1241-1255. doi: S0002-9440(18)30970-2 pmid: 30928253
[29]	OCHIAI T, URATA Y, YAMANO T, et al. Clonal expansion in evolution of chronic hepatitis to hepatocellular carcinoma as seen at an X-chromosome locus[J]. Hepato-logy, 2000, 31(3):615-621.
[30]	PARADIS V, DARGERE D, BONVOUST F, et al. Clonal analysis of micronodules in virus C-induced liver cirrhosis using laser capture microdissection (LCM) and HUMARA assay[J]. Lab Invest, 2000, 80(10):1553-1559. doi: 10.1038/labinvest.3780165 pmid: 11045572
[31]	VOUGIOUKALAKI M, DEMMERS J, VERMEIJ W P, et al. Different responses to DNA damage determine ageing differences between organs[J]. Aging Cell, 2022, 21(4):e13562. doi: 10.1111/acel.v21.4 URL
[32]	WANG M J, CHEN F, LI J X, et al. Reversal of hepatocyte senescence after continuous in vivo cell proliferation[J]. Hepatology, 2014, 60(1):349-361. doi: 10.1002/hep.v60.1 URL
[33]	GRAMANTIERI L, MELCHIORRI C, CHIECO P, et al. Alteration of DNA ploidy and cell nuclearity in human hepatocellular carcinoma associated with HBV infection[J]. J Hepatol, 1996, 25(6):848-853. pmid: 9007712
[34]	TOYODA H. Changes to hepatocyte ploidy and binuclearity profiles during human chronic viral hepatitis[J]. Gut, 2005, 54(2):297-302. pmid: 15647198
[35]	MEIJNIKMAN A S, VAN OLDEN C C, AYDIN Ö, et al. Hyperinsulinemia is highly associated with markers of hepatocytic senescence in two independent cohorts[J]. Diabetes, 2022, 71(9):1929-1936. doi: 10.2337/db21-1076 pmid: 35713877
[36]	BOU-NADER M, CARUSO S, DONNE R, et al. Polyploidy spectrum:a new marker in HCC classification[J]. Gut, 2020, 69(2):355-364. doi: 10.1136/gutjnl-2018-318021 URL
[37]	HERBEIN G, NEHME Z. Polyploid giant cancer cells, a hallmark of oncoviruses and a new therapeutic challenge[J]. Front Oncol, 2020, 10:567116. doi: 10.3389/fonc.2020.567116 URL
[38]	AHODANTIN J, BOU-NADER M, CORDIER C, et al. Hepatitis B virus X protein promotes DNA damage propagation through disruption of liver polyploidization and enhances hepatocellular carcinoma initiation[J]. Oncogene, 2019, 38(14):2645-2657. doi: 10.1038/s41388-018-0607-3 pmid: 30538294
[39]	SMIRNOVA I S, AKSENOV N D, KASHUBA E V, et al. Hepatitis C virus core protein transforms murine fibroblasts by promoting genomic instability[J]. Cell Oncol, 2006, 28(4):177-190.
[40]	MILEO A M, MATTAROCCI S, MATARRESE P, et al. Hepatitis C virus core protein modulates pRb2/p130 expression in human hepatocellular carcinoma cell lines through promoter methylation[J]. J Exp Clin Cancer Res, 2015, 34:140. doi: 10.1186/s13046-015-0255-1 pmid: 26576645
[41]	GENTRIC G, MAILLET V, PARADIS V, et al. Oxidative stress promotes pathologic polyploidization in nonalcoholic fatty liver disease[J]. J Clin Invest, 2015, 125(3): 981-992. doi: 10.1172/JCI73957 pmid: 25621497
[42]	LI X, LIU L, LI R, et al. Hepatic loss of Lissencephaly 1 (Lis1) induces fatty liver and accelerates liver tumorige-nesis in mice[J]. J Biol Chem, 2018, 293(14):5160-5171. doi: 10.1074/jbc.RA117.001474 URL
[43]	MORENO E, MATONDO A B, BONGIOVANNI L, et al. Inhibition of polyploidization in PTEN-deficient livers reduces steatosis[J]. Liver Int, 2022, 42(11):2442-2452. doi: 10.1111/liv.15384 pmid: 35924448
[44]	HAN Y H, KIM H J, KIM E J, et al. RORα decreases oxidative stress through the induction of SOD2 and GPx1 expression and thereby protects against nonalcoholic steatohepatitis in mice[J]. Antioxid Redox Signal, 2014, 21(15):2083-2094. doi: 10.1089/ars.2013.5655 URL
[45]	KIM J Y, YANG I S, KIM H J, et al. RORα contributes to the maintenance of genome ploidy in the liver of mice with diet-induced nonalcoholic steatohepatitis[J]. Am J Physiol Endocrinol Metab, 2022, 322(2):E118-E131. doi: 10.1152/ajpendo.00309.2021 URL
[46]	RUÀ S, COMINO A, FRUTTERO A, et al. Flow cytome-tric DNA analysis of cirrhotic liver cells in patients with hepatocellular carcinoma can provide a new prognostic factor[J]. Cancer, 1996, 78(6):1195-1202. doi: 10.1002/(ISSN)1097-0142 URL
[47]	SAETER G, SCHWARZE P E, NESLAND J M, et al. Diploid nature of hepatocellular tumours developing from transplanted preneoplastic liver cells[J]. Br J Cancer, 1989, 59(2):198-205. doi: 10.1038/bjc.1989.41
[48]	GUO L, YI X, CHEN L, et al. Single-cell DNA sequencing reveals punctuated and gradual clonal evolution in hepatocellular carcinoma[J]. Gastroenterology, 2022, 162(1):238-252. doi: 10.1053/j.gastro.2021.08.052 URL
[49]	CHAN C Y, YUEN V W, CHIU D K, et al. Polo-like kinase 4 inhibitor CFI-400945 suppresses liver cancer through cell cycle perturbation and eliciting antitumor immunity[J]. Hepatology, 2023, 77(3):729-744. doi: 10.1002/hep.32461 URL