Research progress on application of lineage tracing technology in liver regeneration_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

ZHOU Linyan ¹ , LI Yongnan ² , JIANG Xiangyan ¹ , LI Jian ¹ ,  JIAO Zuoyi ¹

1. Department of General Surgery, The Second Hospital of Lanzhou University, Lanzhou 730030, P. R. China;
2. Department of Cardiac Surgery, The Second Hospital of Lanzhou University, Lanzhou 730030, P. R. China;

Corresponding author：

JIAO Zuoyi, Email: jiaozy@lzu.edu.cn

Keywords：

lineage tracing technique; liver injury; liver regeneration; mechanism

DOI：

10.7507/1007-9424.202311044

Video：

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Abstract Full text Figures/Tables Video References Cited by

Objective To understand the latest development in lineage tracing techniques and their applications in the study of liver regeneration mechanisms. Method A review of domestic and international literature on the application of lineage tracing techniques in liver regeneration was conducted. Results A variety of more reliable and advanced lineage tracing techniques had been developed, such as single-cell RNA sequencing, DNA barcode technology, etc., providing powerful tools for a deeper understanding of the mechanisms of liver regeneration. The marked progress had been made in identifying the origins of liver regeneration cells, identifying liver regeneration areas, and studying the mechanisms of liver regeneration after injury. The lineage tracing techniques help to understand the position and function of different types of liver cells within the liver structure, revealing the regenerative potential and contribution of different subpopulations of liver cells. Moreover, these techniques had supported the phenomenon of transdifferentiation between the hepatocytes and the bile duct cells under chronic liver injury conditions, aiding in understanding the specific roles of key signaling pathways in liver regeneration, such as Wnt/β-catenin, Hippo/YAP, and Notch signaling pathways.Conclusions Although lineage tracing techniques have made marked progress in liver regeneration research, liver regeneration is a complex and important physiological process, and the technique still has limitations, such as challenges in marker specificity, longer research cycles and higher costs, potential limitations in translating from animal models to human clinical applications, inability to solve all questions about liver regeneration mechanisms, and ethical and legal issues. Therefore, more in-depth and comprehensive research is still needed to reveal more details of liver regeneration mechanism.

Citation： ZHOU Linyan, LI Yongnan, JIANG Xiangyan, LI Jian, JIAO Zuoyi. Research progress on application of lineage tracing technology in liver regeneration. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2024, 31(4): 487-494. doi: 10.7507/1007-9424.202311044 Copy

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2.	VanHorn S, Morris SA. Next-generation lineage tracing and fate mapping to interrogate development. Dev Cell, 2021, 56(1): 7-21.
3.	Conklin EG. The mutation theory from the standpoint of cytology. Science, 1905, 21(536): 525-529.
4.	Cheng H. Origin, differentiation and renewal of the four main epithelial cell types in the mouse small intestine. Ⅳ. Paneth cells. Am J Anat, 1974, 141(4): 521-535.
5.	Mio Y, Maeda K. Time-lapse cinematography of dynamic changes occurring during in vitro development of human embryos. Am J Obstet Gynecol, 2008, 199(6): 660. e1-660. e5. doi: 10.1016/j.ajog.2008.07.023.
6.	Simeonov KP, Byrns CN, Clark ML, et al. Single-cell lineage tracing of metastatic cancer reveals selection of hybrid EMT states. Cancer Cell, 2021, 39(8): 1150-1162.
7.	Wang YG, Yuan VL, Liao XH. Genetic lineage tracing in skin reveals predominant expression of HEY2 in dermal papilla during telogen and that HEY2⁺ cells contribute to the regeneration of dermal cells during wound healing. Exp Dermatol, 2023, 32(12): 2176-2179.
8.	Root SH, Vrhovac Madunic I, Kronenberg MS, et al. Lineage tracing of RGS5-CreER-labeled cells in long bones during homeostasis and injury. Stem Cells, 2023, 41(5): 493-504.
9.	Kim JS, Kolesnikov M, Peled-Hajaj S, et al. A binary Cre transgenic approach dissects microglia and CNS border-associated macrophages. Immunity, 2021, 54(1): 176-190.
10.	Wang L, Liu Y, Dai Y, et al. Single-cell RNA-seq analysis reveals BHLHE40-driven pro-tumour neutrophils with hyperactivated glycolysis in pancreatic tumour microenvironment. Gut, 2023, 72(5): 958-971.
11.	Sankaran VG, Weissman JS, Zon LI. Cellular barcoding to decipher clonal dynamics in disease. Science, 2022, 378(6616): eabm5874. doi: 10.1126/science.abm5874.
12.	Tang L. Multiomics sequencing goes spatial. Nat Methods, 2021, 18(1): 31. doi: 10.1038/s41592-020-01043-w.
13.	Casadei L, Sarchet P, de Faria FCC, et al. In situ hybridization to detect DNA amplification in extracellular vesicles. J Extracell Vesicles, 2022, 11(9): e12251. doi: 10.1002/jev2.12251.
14.	Winkler M, Staniczek T, Kürschner SW, et al. Endothelial GATA4 controls liver fibrosis and regeneration by preventing a pathogenic switch in angiocrine signaling. J Hepatol, 2021, 74(2): 380-393.
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28.	Pu W, He L, Han X, et al. Genetic targeting of organ-specific blood vessels. Circ Res, 2018, 123(1): 86-99.
29.	Kantak M, Batra P, Shende P. Integration of DNA barcoding and nanotechnology in drug delivery. Int J Biol Macromol, 2023, 230: 123262. doi: 10.1016/j.ijbiomac.2023.123262.
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40.	Furuyama K, Kawaguchi Y, Akiyama H, et al. Continuous cell supply from a Sox9-expressing progenitor zone in adult liver, exocrine pancreas and intestine. Nat Genet, 2011, 43(1): 34-41.
41.	Tarlow BD, Finegold MJ, Grompe M. Clonal tracing of Sox9⁺ liver progenitors in mouse oval cell injury. Hepatology, 2014, 60(1): 278-289.
42.	Qin D, Wang R, Ji J, et al. Hepatocyte-specific Sox9 knockout ameliorates acute liver injury by suppressing SHP signaling and improving mitochondrial function. Cell Biosci, 2023, 13(1): 159. doi: 10.1186/s13578-023-01104-5.
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44.	Martini T, Naef F, Tchorz JS. Spatiotemporal metabolic liver zonation and consequences on pathophysiology. Annu Rev Pathol, 2023, 18: 439-466.
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46.	Goel C, Monga SP, Nejak-Bowen K. Role and regulation of Wnt/β-catenin in hepatic perivenous zonation and physiological homeostasis. Am J Pathol, 2022, 192(1): 4-17.
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60.	Lin YH, Zhang S, Zhu M, et al. Mice with increased numbers of polyploid hepatocytes maintain regenerative capacity but develop fewer hepatocellular carcinomas following chronic liver injury. Gastroenterology, 2020, 158(6): 1698-1712.
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1. Goikoetxea-Usandizaga N, Serrano-Maciá M, Delgado TC, et al. Mitochondrial bioenergetics boost macrophage activation, promoting liver regeneration in metabolically compromised animals. Hepatology, 2022, 75(3): 550-566.
2. VanHorn S, Morris SA. Next-generation lineage tracing and fate mapping to interrogate development. Dev Cell, 2021, 56(1): 7-21.
3. Conklin EG. The mutation theory from the standpoint of cytology. Science, 1905, 21(536): 525-529.
4. Cheng H. Origin, differentiation and renewal of the four main epithelial cell types in the mouse small intestine. Ⅳ. Paneth cells. Am J Anat, 1974, 141(4): 521-535.
5. Mio Y, Maeda K. Time-lapse cinematography of dynamic changes occurring during in vitro development of human embryos. Am J Obstet Gynecol, 2008, 199(6): 660. e1-660. e5. doi: 10.1016/j.ajog.2008.07.023.
6. Simeonov KP, Byrns CN, Clark ML, et al. Single-cell lineage tracing of metastatic cancer reveals selection of hybrid EMT states. Cancer Cell, 2021, 39(8): 1150-1162.
7. Wang YG, Yuan VL, Liao XH. Genetic lineage tracing in skin reveals predominant expression of HEY2 in dermal papilla during telogen and that HEY2⁺ cells contribute to the regeneration of dermal cells during wound healing. Exp Dermatol, 2023, 32(12): 2176-2179.
8. Root SH, Vrhovac Madunic I, Kronenberg MS, et al. Lineage tracing of RGS5-CreER-labeled cells in long bones during homeostasis and injury. Stem Cells, 2023, 41(5): 493-504.
9. Kim JS, Kolesnikov M, Peled-Hajaj S, et al. A binary Cre transgenic approach dissects microglia and CNS border-associated macrophages. Immunity, 2021, 54(1): 176-190.
10. Wang L, Liu Y, Dai Y, et al. Single-cell RNA-seq analysis reveals BHLHE40-driven pro-tumour neutrophils with hyperactivated glycolysis in pancreatic tumour microenvironment. Gut, 2023, 72(5): 958-971.
11. Sankaran VG, Weissman JS, Zon LI. Cellular barcoding to decipher clonal dynamics in disease. Science, 2022, 378(6616): eabm5874. doi: 10.1126/science.abm5874.
12. Tang L. Multiomics sequencing goes spatial. Nat Methods, 2021, 18(1): 31. doi: 10.1038/s41592-020-01043-w.
13. Casadei L, Sarchet P, de Faria FCC, et al. In situ hybridization to detect DNA amplification in extracellular vesicles. J Extracell Vesicles, 2022, 11(9): e12251. doi: 10.1002/jev2.12251.
14. Winkler M, Staniczek T, Kürschner SW, et al. Endothelial GATA4 controls liver fibrosis and regeneration by preventing a pathogenic switch in angiocrine signaling. J Hepatol, 2021, 74(2): 380-393.
15. Funk L, Su KC, Ly J, et al. The phenotypic landscape of essential human genes. Cell, 2022, 185(24): 4634-4653.
16. Han X, Zhang Z, He L, et al. A suite of new Dre recombinase drivers markedly expands the ability to perform intersectional genetic targeting. Cell Stem Cell, 2021, 28(6): 1160-1176.
17. Bittel M, Reichert P, Sarfati I, et al. Visualizing transfer of microbial biomolecules by outer membrane vesicles in microbe-host-communication in vivo. J Extracell Vesicles, 2021, 10(12): e12159. doi: 10.1002/jev2.12159.
18. Wu X, Liu H, Brooks A, et al. SIRT6 mitigates heart failure with preserved ejection fraction in diabetes. Circ Res, 2022, 131(11): 926-943.
19. Liu B, Jing Z, Zhang X, et al. Large-scale multiplexed mosaic CRISPR perturbation in the whole organism. Cell, 2022, 185(16): 3008-3024.
20. Chan LY, Chang CC, Lai PL, et al. Cre/LoxP genetic recombination sustains cartilage anabolic factor expression in hyaluronan encapsulated MSCs alleviates intervertebral Disc degeneration. Biomedicines, 2022, 10(3): 555. doi: 10.3390/biomedicines10030555.
21. Bao Y, Kim D, Cho YH, et al. Cre-loxP system-based mouse model for investigating Graves’ disease and associated orbitopathy. Thyroid, 2023, 33(11): 1358-1367.
22. Chen MY, Zhao FL, Chu WL, et al. A review of tamoxifen administration regimen optimization for Cre/loxp system in mouse bone study. Biomed Pharmacother, 2023, 165: 115045. doi: 10.1016/j.biopha.2023.115045.
23. Wang JF, Wang YP, Xie J, et al. Upregulated PD-L1 delays human neutrophil apoptosis and promotes lung injury in an experimental mouse model of sepsis. Blood, 2021, 138(9): 806-810.
24. Liu K, Liu J, Zou B, et al. Trypsin-mediated sensitization to ferroptosis increases the severity of pancreatitis in mice. Cell Mol Gastroenterol Hepatol, 2022, 13(2): 483-500.
25. Chen Q, Weng K, Lin M, et al. SOX9 modulates the transformation of gastric stem cells through biased symmetric cell division. Gastroenterology, 2023, 164(7): 1119-1136.
26. Takao T, Hiraoka Y, Kawabe K, et al. Establishment of a tTA-dependent photoactivatable Cre recombinase knock-in mouse model for optogenetic genome engineering. Biochem Biophys Res Commun, 2020, 526(1): 213-217.
27. Weng W, Liu X, Lui KO, et al. Harnessing orthogonal recombinases to decipher cell fate with enhanced precision. Trends Cell Biol, 2022, 32(4): 324-337.
28. Pu W, He L, Han X, et al. Genetic targeting of organ-specific blood vessels. Circ Res, 2018, 123(1): 86-99.
29. Kantak M, Batra P, Shende P. Integration of DNA barcoding and nanotechnology in drug delivery. Int J Biol Macromol, 2023, 230: 123262. doi: 10.1016/j.ijbiomac.2023.123262.
30. Xie L, Liu H, You Z, et al. Comprehensive spatiotemporal mapping of single-cell lineages in developing mouse brain by CRISPR-based barcoding. Nat Methods, 2023, 20(8): 1244-1255.
31. Ben-Moshe S, Veg T, Manco R, et al. The spatiotemporal program of zonal liver regeneration following acute injury. Cell Stem Cell, 2022, 29(6): 973-989. e10. doi: 10.1016/j.stem.2022.04.008.
32. Qing J, Ren Y, Zhang Y, et al. Dopamine receptor D2 antagonism normalizes profibrotic macrophage-endothelial crosstalk in non-alcoholic steatohepatitis. J Hepatol, 2022, 76(2): 394-406.
33. Fu X, He Q, Tao Y, et al. Recent advances in tissue stem cells. Sci China Life Sci, 2021, 64(12): 1998-2029.
34. Fausto N, Campbell JS. The role of hepatocytes and oval cells in liver regeneration and repopulation. Mech Dev, 2003, 120(1): 117-130.
35. Ock SA, Kim SY, Ju WS, et al. Adipose tissue-derived mesenchymal stem cells extend the lifespan and enhance liver function in hepatocyte organoids. Int J Mol Sci, 2023, 24(20): 15429. doi: 10.3390/ijms242015429.
36. Hou X, Liu W, Yang X, et al. Extracellular microparticles derived from hepatic progenitor cells deliver a death signal to hepatoma-initiating cells. J Nanobiotechnology, 2022, 20(1): 79. doi: 10.1186/s12951-022-01280-5.
37. He Y, Pei Y, Liu K, et al. GITR/GITRL reverse signalling modulates the proliferation of hepatic progenitor cells by recruiting ANXA2 to phosphorylate ERK1/2 and Akt. Cell Death Dis, 2022, 13(4): 297. doi: 10.1038/s41419-022-04759-z.
38. Lu WY, Bird TG, Boulter L, et al. Hepatic progenitor cells of biliary origin with liver repopulation capacity. Nat Cell Biol, 2015, 17(8): 971-983.
39. Aizarani N, Saviano A, Sagar None, et al. A human liver cell atlas reveals heterogeneity and epithelial progenitors. Nature, 2019, 572(7768): 199-204.
40. Furuyama K, Kawaguchi Y, Akiyama H, et al. Continuous cell supply from a Sox9-expressing progenitor zone in adult liver, exocrine pancreas and intestine. Nat Genet, 2011, 43(1): 34-41.
41. Tarlow BD, Finegold MJ, Grompe M. Clonal tracing of Sox9⁺ liver progenitors in mouse oval cell injury. Hepatology, 2014, 60(1): 278-289.
42. Qin D, Wang R, Ji J, et al. Hepatocyte-specific Sox9 knockout ameliorates acute liver injury by suppressing SHP signaling and improving mitochondrial function. Cell Biosci, 2023, 13(1): 159. doi: 10.1186/s13578-023-01104-5.
43. Lin T, Feng R, Liebe R, et al. Liver progenitor cells in massive hepatic necrosis-how can a patient survive acute liver failure?. Biomolecules, 2022, 12(1): 66. doi: 10.3390/biom12010066.
44. Martini T, Naef F, Tchorz JS. Spatiotemporal metabolic liver zonation and consequences on pathophysiology. Annu Rev Pathol, 2023, 18: 439-466.
45. Huang R, Zhang X, Gracia-Sancho J, et al. Liver regeneration: cellular origin and molecular mechanisms. Liver Int, 2022, 42(7): 1486-1495.
46. Goel C, Monga SP, Nejak-Bowen K. Role and regulation of Wnt/β-catenin in hepatic perivenous zonation and physiological homeostasis. Am J Pathol, 2022, 192(1): 4-17.
47. Hu S, Liu S, Bian Y, et al. Single-cell spatial transcriptomics reveals a dynamic control of metabolic zonation and liver regeneration by endothelial cell Wnt2 and Wnt9b. Cell Rep Med, 2022, 3(10): 100754. doi: 10.1016/j.xcrm.2022.100754.
48. Xu C, Xu Z, Zhang Y, et al. β-catenin signaling in hepatocellular carcinoma. J Clin Invest, 2022, 132(4): e154515. doi: 10.1172/JCI154515.
49. Wang B, Zhao L, Fish M, et al. Self-renewing diploid Axin2⁺ cells fuel homeostatic renewal of the liver. Nature, 2015, 524(7564): 180-185.
50. Sun T, Pikiolek M, Orsini V, et al. AXIN2⁺ pericentral hepatocytes have limited contributions to liver homeostasis and regeneration. Cell Stem Cell, 2020, 26(1): 97-107.
51. Font-Burgada J, Shalapour S, Ramaswamy S, et al. Hybrid periportal hepatocytes regenerate the injured liver without giving rise to cancer. Cell, 2015, 162(4): 766-779.
52. Pu W, Zhang H, Huang X, et al. Mfsd2a⁺ hepatocytes repopulate the liver during injury and regeneration. Nat Commun, 2016, 7: 13369. doi: 10.1038/ncomms13369.
53. Lin S, Nascimento EM, Gajera CR, et al. Distributed hepatocytes expressing telomerase repopulate the liver in homeostasis and injury. Nature, 2018, 556(7700): 244-248.
54. He L, Pu W, Liu X, et al. Proliferation tracing reveals regional hepatocyte generation in liver homeostasis and repair. Science, 2021, 371(6532): eabc4346. doi: 10.1126/science.abc4346.
55. Wei Y, Wang YG, Jia Y, et al. Liver homeostasis is maintained by midlobular zone 2 hepatocytes. Science, 2021, 371(6532): eabb1625. doi: 10.1126/science.abb1625.
56. Michalopoulos GK, Bhushan B. Liver regeneration: biological and pathological mechanisms and implications. Nat Rev Gastroenterol Hepatol, 2021, 18(1): 40-55.
57. Chen F, Jimenez RJ, Sharma K, et al. Broad distribution of hepatocyte proliferation in liver homeostasis and regeneration. Cell Stem Cell, 2020, 26(1): 27-33.
58. Yagi S, Hirata M, Miyachi Y, et al. Liver regeneration after hepatectomy and partial liver transplantation. Int J Mol Sci, 2020, 21(21): 8414. doi: 10.3390/ijms21218414.
59. Wen Y, Emontzpohl C, Xu L, et al. Interleukin-33 facilitates liver regeneration through serotonin-involved gut-liver axis. Hepatology, 2023, 77(5): 1580-1592.
60. Lin YH, Zhang S, Zhu M, et al. Mice with increased numbers of polyploid hepatocytes maintain regenerative capacity but develop fewer hepatocellular carcinomas following chronic liver injury. Gastroenterology, 2020, 158(6): 1698-1712.
61. Matsumoto T, Wakefield L, Tarlow BD, et al. In vivo lineage tracing of polyploid hepatocytes reveals extensive proliferation during liver regeneration. Cell Stem Cell, 2020, 26(1): 34-47.
62. Rodrigo-Torres D, Affò S, Coll M, et al. The biliary epithelium gives rise to liver progenitor cells. Hepatology, 2014, 60(4): 1367-1377.
63. Gadd VL, Aleksieva N, Forbes SJ. Epithelial plasticity during liver injury and regeneration. Cell Stem Cell, 2020, 27(4): 557-573.
64. Choi TY, Ninov N, Stainier DY, et al. Extensive conversion of hepatic biliary epithelial cells to hepatocytes after near total loss of hepatocytes in zebrafish. Gastroenterology, 2014, 146(3): 776-788.
65. Pu W, Zhu H, Zhang M, et al. Bipotent transitional liver progenitor cells contribute to liver regeneration. Nat Genet, 2023, 55(4): 651-664.
66. Ho DWH, Chan LK, Chiu YT, et al. TSC1/2 mutations define a molecular subset of HCC with aggressive behaviour and treatment implication. Gut, 2017, 66(8): 1496-1506.
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