CoChat
Sign Up
Cited by 49Liver physiology and pathologyTissue Engineering and Regenerative MedicineOrgan Transplantation Techniques and Outcomes

Liver regeneration after injury: Mechanisms, cellular interactions and therapeutic innovations

Open access
Liu, Qi, Wang, Senyan, Fu, Jing, Chen, Yao, Xu, Jing, Wei, Wenjuan, Song, Hao, Zhao, Xiaofang +1 more·2024·Clinical and Translational Medicine
DOI 10.1002/ctm2.1812PMC PMC11329751
Open this paper in CoChat — free accountOpen PDF

Abstract

The liver possesses a distinctive capacity for regeneration within the human body. Under normal circumstances, liver cells replicate themselves to maintain liver function. Compensatory replication of healthy hepatocytes is sufficient for the regeneration after acute liver injuries. In the late stage of chronic liver damage, a large number of hepatocytes die and hepatocyte replication is blocked. Liver regeneration has more complex mechanisms, such as the transdifferentiation between cell types or hepatic progenitor cells mediated. Dysregulation of liver regeneration causes severe chronic liver disease. Gaining a more comprehensive understanding of liver regeneration mechanisms would facilitate the advancement of efficient therapeutic approaches. This review provides an overview of the signalling pathways linked to different aspects of liver regeneration in various liver diseases. Moreover, new knowledge on cellular interactions during the regenerative process is also presented. Finally, this paper explores the potential applications of new technologies, such as nanotechnology, stem cell transplantation and organoids, in liver regeneration after injury, offering fresh perspectives on treating liver disease.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1002/ctm2.1812

Cites

23 of 23 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Meloxicam, a selective cyclooxygenase-2 inhibitor, enhances liver regeneration by increasing EGFR expression, leading to a 70% improvement in liver regeneration following resection.

    “For instance, Meloxicam - a selective cyclooxygenase-2 inhibitor, was identified as a pharmacological agent capable of enhancing LR, demonstrating the increase of EGFR expression, leading to a 70% improvement in LR following resection[67].”

    From Liver regeneration after partial hepatectomy: Triggers and mechanisms (2025) · cites this paper as [67]

    The “Liver regeneration after resection” section (page not provided) reports increased hepatocyte EGFR expression and 70% greater liver-mass regeneration after hepatectomy with meloxicam. That result is specifically in diet-induced obese mice, whereas the claim leaves the population unrestricted. Our copy also does not identify meloxicam as a selective cyclooxygenase-2 inhibitor or establish that increased EGFR expression caused the improvement. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 131

  1. [1]Trefts E, Gannon M, Wasserman DH. The liver. Curr Biol. 2017; 27: R1147‐ r1151. doi: 10.1016/j.cub.2017.09.019 29112863 PMC5897118 · DOI · Paper page
  2. [4]Hu Y, Wang R, An Ni, et al. Unveiling the power of microenvironment in liver regeneration: an in‐depth overview. Front Genet. 2023; 14: 1332190. doi: 10.3389/fgene.2023.1332190 38152656 PMC10751322 · DOI
  3. [5]Paris J, Henderson NC. Liver zonation, revisited. Hepatology. 2022; 76: 1219‐ 1230. doi: 10.1002/hep.32408 35175659 PMC9790419 · DOI
  4. [7]Li W, Li Lu, Hui L. Cell plasticity in liver regeneration. Trends Cell Biol. 2020; 30: 329‐ 338. doi: 10.1016/j.tcb.2020.01.007 32200807 · DOI · Paper page
  5. [8]Rizvi F, Lee Yu‐Ri, Diaz‐Aragon R, et al. VEGFA mRNA‐LNP promotes biliary epithelial cell‐to‐hepatocyte conversion in acute and chronic liver diseases and reverses steatosis and fibrosis. Cell Stem Cell. 2023; 30: 1640‐ 1657.e1648. doi: 10.1016/j.stem.2023.10.008 38029740 PMC10843608 · DOI
  6. [9]Wang B, Shen H, Wei Y, et al. Balance of Gata3 and Ramp2 in hepatocytes regulates hepatic vascular reconstitution in postoperative liver regeneration. J Hepatol. 2024; 80: 309‐ 321. doi: 10.1016/j.jhep.2023.10.016 37918568 · DOI
  7. [10]Nicolas CT, Hickey RD, Chen HS, et al. Concise review: liver regenerative medicine: from hepatocyte transplantation to bioartificial livers and bioengineered grafts. Stem Cells. 2017; 35: 42‐ 50. doi: 10.1002/stem.2500 27641427 PMC5529050 · DOI
  8. [11]Gao Ce, Peng J. All routes lead to Rome: multifaceted origin of hepatocytes during liver regeneration. Cell Regen. 2021; 10: 2. doi: 10.1186/s13619-020-00063-3 33403526 PMC7785766 · DOI
  9. [12]Yagi S, Hirata M, Miyachi Y, Uemoto S. Liver regeneration after hepatectomy and partial liver transplantation. Int J Mol Sci. 2020; 21. doi: 10.3390/ijms21218414 PMC7665117 33182515 · DOI · Paper page
  10. [13]Wu Yi, Li N, Shu X, et al. Biomechanics in liver regeneration after partial hepatectomy. Front Bioeng Biotechnol. 2023; 11: 1165651. doi: 10.3389/fbioe.2023.1165651 37214300 PMC10196191 · DOI
  11. [14]Taub R. Liver regeneration: from myth to mechanism. Nat Rev Mol Cell Biol. 2004; 5: 836‐ 847. doi: 10.1038/nrm1489 15459664 · DOI · Paper page
  12. [15]Higgins GM. Experimental pathology of the liver. 12. Effect of feeding desiccated thyroid gland on restoration of the liver. Arch Pathol. 1933;16:226‐231.
  13. [16]Van Haele M, Snoeck J, Roskams T. Human liver regeneration: an etiology dependent process. Int J Mol Sci. 2019; 20. doi: 10.3390/ijms20092332 PMC6539121 31083462 · DOI
  14. [19]Kawasaki S, Makuuchi M, Ishizone S, Matsunami H, Terada M, Kawarazaki H. Liver regeneration in recipients and donors after transplantation. Lancet. 1992; 339: 580‐ 581. doi: 10.1016/0140-6736(92)90867-3 1347095 · DOI
  15. [20]Alison MR. Regulation of hepatic growth. Physiol Rev. 1986; 66: 499‐ 541. doi: 10.1152/physrev.1986.66.3.499 2426724 · DOI
  16. [21]Kwon YJ, Lee KG, Choi D. Clinical implications of advances in liver regeneration. Clin Mol Hepatol. 2015; 21: 7‐ 13. doi: 10.3350/cmh.2015.21.1.7 25834796 PMC4379199 · DOI
  17. [22]Jaeschke H, Akakpo JY, Umbaugh DS, Ramachandran A. Novel therapeutic approaches against acetaminophen‐induced liver injury and acute liver failure. Toxicol Sci. 2020; 174: 159‐ 167. doi: 10.1093/toxsci/kfaa002 31926003 PMC7098369 · DOI
  18. [23]Chao X, Wang H, Jaeschke H, Ding W‐X. Role and mechanisms of autophagy in acetaminophen‐induced liver injury. Liver Int. 2018; 38: 1363‐ 1374. doi: 10.1111/liv.13866 29682868 PMC6105454 · DOI
  19. [24]Lukacs‐Kornek V, Lammert F. The progenitor cell dilemma: cellular and functional heterogeneity in assistance or escalation of liver injury. J Hepatol. 2017; 66: 619‐ 630. doi: 10.1016/j.jhep.2016.10.033 27826058 · DOI
  20. [25]Faccioli LAP, Dias ML, Paranhos BA, Dos Santos Goldenberg RC. Liver cirrhosis: an overview of experimental models in rodents. Life Sci. 2022; 301: 120615. doi: 10.1016/j.lfs.2022.120615 35526595 · DOI · Paper page
  21. [27]Tacke F, Zimmermann HW. Macrophage heterogeneity in liver injury and fibrosis. J Hepatol. 2014; 60: 1090‐ 1096. doi: 10.1016/j.jhep.2013.12.025 24412603 · DOI · Paper page
  22. [28]Ko S, Russell JO, Tian J, et al. Hdac1 Regulates differentiation of bipotent liver progenitor cells during regeneration via Sox9b and Cdk8. Gastroenterology. 2019; 156: 187‐ 202. doi: 10.1053/j.gastro.2018.09.039 e114 30267710 PMC6309465 · DOI
  23. [29]Russell JO, Lu W‐Yu, Okabe H, et al. Hepatocyte‐specific β‐catenin deletion during severe liver injury provokes cholangiocytes to differentiate into hepatocytes. Hepatology. 2019; 69: 742‐ 759. doi: 10.1002/hep.30270 30215850 PMC6351199 · DOI
  24. [30]Gu CY, Lee TKW. Preclinical mouse models of hepatocellular carcinoma: an overview and update. Exp Cell Res. 2022; 412: 113042. doi: 10.1016/j.yexcr.2022.113042 35101391 · DOI
  25. [31]Tao Y, Wang M, Chen E, Tang H. Liver regeneration: analysis of the main relevant signaling molecules. Mediators Inflamm. 2017; 2017: 4256352. doi: 10.1155/2017/4256352 28947857 PMC5602614 · DOI
  26. [32]Tsagianni A, Mars WM, Bhushan B, et al. Combined systemic disruption of MET and epidermal growth factor receptor signaling causes liver failure in normal mice. Am J Pathol. 2018; 188: 2223‐ 2235. doi: 10.1016/j.ajpath.2018.06.009 30031724 PMC6168971 · DOI · Paper page
  27. [33]Kaminsky‐Kolesnikov Y, Rauchbach E, Abu‐Halaka D, et al. Cholesterol induces Nrf‐2‐ and HIF‐1α‐dependent hepatocyte proliferation and liver regeneration to ameliorate bile acid toxicity in mouse models of NASH and fibrosis. Oxid Med Cell Longev. 2020; 2020: 5393761. doi: 10.1155/2020/5393761 32566088 PMC7271232 · DOI · Paper page
  28. [34]Apte U, Thompson MD, Cui S, Liu B, Cieply B, Monga SPS. Wnt/beta‐catenin signaling mediates oval cell response in rodents. Hepatology. 2008; 47: 288‐ 295. doi: 10.1002/hep.21973 17929301 · DOI
  29. [35]Jin X, Zimmers TA, Jiang Y, Milgrom DP, Zhang Z, Koniaris LG. Meloxicam increases epidermal growth factor receptor expression improving survival after hepatic resection in diet‐induced obese mice. Surgery. 2018; 163: 1264‐ 1271. doi: 10.1016/j.surg.2017.11.029 29361369 PMC5985213 · DOI
  30. [37]Nejak‐Bowen KN, Monga SPS. Beta‐catenin signaling, liver regeneration and hepatocellular cancer: sorting the good from the bad. Semin Cancer Biol. 2011; 21: 44‐ 58. doi: 10.1016/j.semcancer.2010.12.010 21182948 PMC3050081 · DOI · Paper page
  31. [38]Yang W, Yan He‐X, Chen L, et al. Wnt/beta‐catenin signaling contributes to activation of normal and tumorigenic liver progenitor cells. Cancer Res. 2008; 68: 4287‐ 4295. doi: 10.1158/0008-5472.Can-07-6691 18519688 · DOI
  32. [39]Li N, Kong M, Zeng S, et al. Brahma related gene 1 (Brg1) contributes to liver regeneration by epigenetically activating the Wnt/β‐catenin pathway in mice. Faseb J. 2019; 33: 327‐ 338. doi: 10.1096/fj.201800197R 30001167 · DOI
  33. [40]Zhu Y, Qiu Z, Zhang Y, Li B, Jiang X. Partial hepatectomy‑induced upregulation of SNHG12 promotes hepatocyte proliferation and liver regeneration. Mol Med Rep. 2020; 21: 1089‐ 1096. doi: 10.3892/mmr.2019.10904 31894329 PMC7003022 · DOI
  34. [41]Yang J, Mowry LE, Nejak‐Bowen KN, et al. β‐catenin signaling in murine liver zonation and regeneration: a Wnt‐Wnt situation!. Hepatology. 2014; 60: 964‐ 976. doi: 10.1002/hep.27082 24700412 PMC4139486 · DOI
  35. [42]Russell JO, Monga SP. Wnt/β‐catenin signaling in liver development, homeostasis, and pathobiology. Annu Rev Pathol. 2018; 13: 351‐ 378. doi: 10.1146/annurev-pathol-020117-044010 29125798 PMC5927358 · DOI · Paper page
  36. [43]Aldeguer X, Debonera F, Shaked A, et al. Interleukin‐6 from intrahepatic cells of bone marrow origin is required for normal murine liver regeneration. Hepatology. 2002; 35: 40‐ 48. doi: 10.1053/jhep.2002.30081 11786958 · DOI · Paper page
  37. [45]Sun J‐Y, Du L‐J, Shi X‐R, et al. An IL‐6/STAT3/MR/FGF21 axis mediates heart‐liver cross‐talk after myocardial infarction. Sci Adv. 2023; 9: eade4110. doi: 10.1126/sciadv.ade4110 37018396 PMC10075967 · DOI
  38. [46]Johnson DE, O'keefe RA, Grandis JR. Targeting the IL‐6/JAK/STAT3 signalling axis in cancer. Nat Rev Clin Oncol. 2018; 15: 234‐ 248. doi: 10.1038/nrclinonc.2018.8 29405201 PMC5858971 · DOI · Paper page
  39. [47]Park J, Zhao Y, Zhang F, et al. IL‐6/STAT3 axis dictates the PNPLA3‐mediated susceptibility to non‐alcoholic fatty liver disease. J Hepatol. 2023; 78: 45‐ 56. doi: 10.1016/j.jhep.2022.08.022 36049612 PMC9772150 · DOI · Paper page
  40. [48]Hunter CA, Jones SA. IL‐6 as a keystone cytokine in health and disease. Nat Immunol. 2015; 16: 448‐ 457. doi: 10.1038/ni.3153 25898198 · DOI · Paper page
  41. [49]Roxburgh CSD, Mcmillan DC. Therapeutics targeting innate immune/inflammatory responses through the interleukin‐6/JAK/STAT signal transduction pathway in patients with cancer. Transl Res. 2016; 167: 61‐ 66. doi: 10.1016/j.trsl.2015.08.013 26432924 · DOI
  42. [50]Van Snick J. Interleukin‐6: an overview. Annu Rev Immunol. 1990; 8: 253‐ 278. doi: 10.1146/annurev.iy.08.040190.001345 2188664 · DOI · Paper page
  43. [51]Wen Y, Emontzpohl C, Xu L, et al. Interleukin‐33 facilitates liver regeneration through serotonin‐involved gut‐liver axis. Hepatology. 2023; 77: 1580‐ 1592. doi: 10.1002/hep.32744 36129070 PMC10758291 · DOI · Paper page
  44. [52]Huang M, Jiao J, Cai H, et al. C‐C motif chemokine ligand 5 confines liver regeneration by down‐regulating reparative macrophage‐derived hepatocyte growth factor in a forkhead box O 3a‐dependent manner. Hepatology. 2022; 76: 1706‐ 1722. doi: 10.1002/hep.32458 35288960 PMC9790589 · DOI
  45. [53]Ishikawa T, Factor VM, Marquardt JU, et al. Hepatocyte growth factor/c‐met signaling is required for stem‐cell‐mediated liver regeneration in mice. Hepatology. 2012; 55: 1215‐ 1226. doi: 10.1002/hep.24796 22095660 PMC3299882 · DOI
  46. [55]Doignon I, Julien B, Serrière‐Lanneau V, et al. Immediate neuroendocrine signaling after partial hepatectomy through acute portal hyperpressure and cholestasis. J Hepatol. 2011; 54: 481‐ 488. doi: 10.1016/j.jhep.2010.07.012 21163545 · DOI · Paper page
  47. [56]Wang Y‐D, Chen W‐D, Moore DD, Huang W. FXR: a metabolic regulator and cell protector. Cell Res. 2008; 18: 1087‐ 1095. doi: 10.1038/cr.2008.289 18825165 · DOI · Paper page
  48. [57]Huang W, Ma Ke, Zhang J, et al. Nuclear receptor‐dependent bile acid signaling is required for normal liver regeneration. Science. 2006; 312: 233‐ 236. doi: 10.1126/science.1121435 16614213 · DOI · Paper page
  49. [58]Frampton G, Reddy P, Jefferson B, Ali M, Khan D, Mcmillin M. Inhibition of thrombospondin‐1 reduces glutathione activity and worsens acute liver injury during acetaminophen hepatotoxicity in mice. Toxicol Appl Pharmacol. 2020; 409: 115323. doi: 10.1016/j.taap.2020.115323 33176120 PMC8364670 · DOI
  50. [59]Sivilotti MLA, Yarema MC, Juurlink DN. Treating acetaminophen overdose. Cmaj. 2022; 194: E554. doi: 10.1503/cmaj.210703 35440504 PMC9035297 · DOI
  51. [60]Chidiac AS, Buckley NA, Noghrehchi F, Cairns R. Paracetamol (acetaminophen) overdose and hepatotoxicity: mechanism, treatment, prevention measures, and estimates of burden of disease. Expert Opin Drug Metab Toxicol. 2023; 19: 297‐ 317. doi: 10.1080/17425255.2023.2223959 37436926 · DOI · Paper page
  52. [62]Viswanathan P, Sharma Y, Gupta P, Gupta S. Replicative stress and alterations in cell cycle checkpoint controls following acetaminophen hepatotoxicity restrict liver regeneration. Cell Prolif. 2018; 51: e12445. doi: 10.1111/cpr.12445 29504225 PMC6500460 · DOI
  53. [63]Borude P, Bhushan B, Gunewardena S, Akakpo J, Jaeschke H, Apte U. Pleiotropic role of p53 in injury and liver regeneration after acetaminophen overdose. Am J Pathol. 2018; 188: 1406‐ 1418. doi: 10.1016/j.ajpath.2018.03.006 29654721 PMC5971235 · DOI
  54. [64]Xu P, Xi Y, Wang P, et al. Inhibition of p53 sulfoconjugation prevents oxidative hepatotoxicity and acute liver failure. Gastroenterology. 2022; 162: 1226‐ 1241. doi: 10.1053/j.gastro.2021.12.260 34954226 PMC8934304 · DOI
  55. [65]Dong S, Ji J, Hu L, Wang H. Dihydromyricetin alleviates acetaminophen‐induced liver injury via the regulation of transformation, lipid homeostasis, cell death and regeneration. Life Sci. 2019; 227: 20‐ 29. doi: 10.1016/j.lfs.2019.04.019 30974116 · DOI
  56. [66]Wen Y, Wang C, Gu J, et al. Metabolic modulation of acetaminophen‐induced hepatotoxicity by osteopontin. Cell Mol Immunol. 2019; 16: 483‐ 494. doi: 10.1038/s41423-018-0033-z 29735980 PMC6474212 · DOI
  57. [67]Kotulkar M, Paine‐Cabrera D, Abernathy S, et al. Role of HNF4alpha‐cMyc interaction in liver regeneration and recovery after acetaminophen‐induced acute liver injury. Hepatology. 2023; 78: 1106‐ 1117. doi: 10.1097/hep.0000000000000367 37021787 PMC10523339 · DOI
  58. [69]Lucey MR, Mathurin P, Morgan TR. Alcoholic hepatitis. N Engl J Med. 2009; 360: 2758‐ 2769. doi: 10.1056/NEJMra0805786 19553649 · DOI
  59. [70]Sehrawat TS, Liu M, Shah VH. The knowns and unknowns of treatment for alcoholic hepatitis. Lancet Gastroenterol Hepatol. 2020; 5: 494‐ 506. doi: 10.1016/s2468-1253(19)30326-7 32277902 PMC7238289 · DOI
  60. [71]Kwo PY. Alcoholic hepatitis and its many facets. Clin Liver Dis. 2021; 25: xiii‐ xiv. doi: 10.1016/j.cld.2021.04.003 34229847 · DOI
  61. [72]Hosseini N, Shor J, Szabo G. Alcoholic hepatitis: a review. Alcohol. 2019; 54: 408‐ 416. doi: 10.1093/alcalc/agz036 PMC6671387 31219169 · DOI
  62. [73]Buzzetti E, Pinzani M, Tsochatzis EA. The multiple‐hit pathogenesis of non‐alcoholic fatty liver disease (NAFLD). Metabolism. 2016; 65: 1038‐ 1048. doi: 10.1016/j.metabol.2015.12.012 26823198 · DOI · Paper page
  63. [75]Seeger C, Mason WS. Hepatitis B virus biology. Microbiol Mol Biol Rev. 2000; 64: 51‐ 68. doi: 10.1128/mmbr.64.1.51-68.2000 10704474 PMC98986 · DOI
  64. [76]Rehermann B. Hepatitis C virus versus innate and adaptive immune responses: a tale of coevolution and coexistence. J Clin Invest. 2009; 119: 1745‐ 1754. doi: 10.1172/jci39133 19587449 PMC2701885 · DOI
  65. [77]Mahmood A, Seetharaman R, Kshatriya P, Patel D, Srivastava AS. Stem cell transplant for advanced stage liver disorders: current scenario and future prospects. Curr Med Chem. 2020; 27: 6276‐ 6293. doi: 10.2174/0929867326666191004161802 31584360 · DOI
  66. [78]Gribben C, Galanakis V, Calderwood A, et al. Acquisition of epithelial plasticity in human chronic liver disease. Nature. 2024; 630: 166‐ 173. doi: 10.1038/s41586-024-07465-2 38778114 PMC11153150 · DOI · Paper page
  67. [80]Pu W, Zhu H, Zhang M, et al. Bipotent transitional liver progenitor cells contribute to liver regeneration. Nat Genet. 2023; 55: 651‐ 664. doi: 10.1038/s41588-023-01335-9 36914834 PMC10101857 · DOI · Paper page
  68. [81]Wu H, Zhou Xu, Fu G‐Bo, et al. Reversible transition between hepatocytes and liver progenitors for in vitro hepatocyte expansion. Cell Res. 2017; 27: 709‐ 712. doi: 10.1038/cr.2017.47 28374751 PMC5520858 · DOI
  69. [83]Huang W‐J, Zhou Xu, Fu G‐Bo, et al. The combined induction of liver progenitor cells and the suppression of stellate cells by small molecules reverts chronic hepatic dysfunction. Theranostics. 2021; 11: 5539‐ 5552. doi: 10.7150/thno.54457 33859762 PMC8039967 · DOI
  70. [84]Fu G‐Bo, Huang W‐J, Zeng M, et al. Expansion and differentiation of human hepatocyte‐derived liver progenitor‐like cells and their use for the study of hepatotropic pathogens. Cell Res. 2019; 29: 8‐ 22. doi: 10.1038/s41422-018-0103-x 30361550 PMC6318298 · DOI · Paper page
  71. [85]Liu W‐M, Zhou Xu, Chen C‐Y, et al. Establishment of functional liver spheroids from human hepatocyte‐derived liver progenitor‐like cells for cell therapy. Front Bioeng Biotechnol. 2021; 9: 738081. doi: 10.3389/fbioe.2021.738081 34858956 PMC8630579 · DOI
  72. [86]Segal JM, Kent D, Wesche DJ, et al. Single cell analysis of human foetal liver captures the transcriptional profile of hepatobiliary hybrid progenitors. Nat Commun. 2019; 10: 3350. doi: 10.1038/s41467-019-11266-x 31350390 PMC6659636 · DOI
  73. [87]So J, Khaliq M, Evason K, et al. Wnt/β‐catenin signaling controls intrahepatic biliary network formation in zebrafish by regulating notch activity. Hepatology. 2018; 67: 2352‐ 2366. doi: 10.1002/hep.29752 29266316 PMC5991997 · DOI
  74. [88]Martinez Lyons A, Boulter L. NOTCH signalling—a core regulator of bile duct disease? Dis Model Mech. 2023; 16. doi: 10.1242/dmm.050231 PMC10461466 37605966 · DOI
  75. [89]Boulter L, Govaere O, Bird TG, et al. Macrophage‐derived Wnt opposes Notch signaling to specify hepatic progenitor cell fate in chronic liver disease. Nat Med. 2012; 18: 572‐ 579. doi: 10.1038/nm.2667 22388089 PMC3364717 · DOI · Paper page
  76. [90]Lu J, Zhou Y, Hu T, et al. Notch signaling coordinates progenitor cell‐mediated biliary regeneration following partial hepatectomy. Sci Rep. 2016; 6: 22754. doi: 10.1038/srep22754 26951801 PMC4782135 · DOI
  77. [91]Tang D, Chen Yi, Fu G‐Bo, et al. EpCAM inhibits differentiation of human liver progenitor cells into hepatocytes in vitro by activating Notch1 signaling. Biochem Biophys Res Commun. 2020. doi: 10.1016/j.bbrc.2020.02.041 32087972 · DOI
  78. [92]Lee S‐H, So J, Shin D. Hepatocyte‐to‐cholangiocyte conversion occurs through transdifferentiation independently of proliferation in zebrafish. Hepatology. 2023; 77: 1198‐ 1210. doi: 10.1097/hep.0000000000000016 36626626 PMC10023500 · DOI
  79. [93]Kitade M, Factor VM, Andersen JB, et al. Specific fate decisions in adult hepatic progenitor cells driven by MET and EGFR signaling. Genes Dev. 2013; 27: 1706‐ 1717. doi: 10.1101/gad.214601.113 23913923 PMC3744728 · DOI
  80. [95]Anakk S, Bhosale M, Schmidt VA, Johnson RL, Finegold MJ, Moore DD. Bile acids activate YAP to promote liver carcinogenesis. Cell Rep. 2013; 5: 1060‐ 1069. doi: 10.1016/j.celrep.2013.10.030 24268772 PMC3961013 · DOI · Paper page
  81. [96]Zhao B, Wei X, Li W, et al. Inactivation of YAP oncoprotein by the Hippo pathway is involved in cell contact inhibition and tissue growth control. Genes Dev. 2007; 21: 2747‐ 2761. doi: 10.1101/gad.1602907 17974916 PMC2045129 · DOI · Paper page
  82. [97]Moya IM, Halder G. Hippo‐YAP/TAZ signalling in organ regeneration and regenerative medicine. Nat Rev Mol Cell Biol. 2019; 20: 211‐ 226. doi: 10.1038/s41580-018-0086-y 30546055 · DOI · Paper page
  83. [98]Cook D, Ogunnaike BA, Vadigepalli R. Systems analysis of non‐parenchymal cell modulation of liver repair across multiple regeneration modes. BMC Syst Biol. 2015; 9: 71. doi: 10.1186/s12918-015-0220-9 26493454 PMC4618752 · DOI
  84. [99]Fujiyoshi M, Ozaki M. Molecular mechanisms of liver regeneration and protection for treatment of liver dysfunction and diseases. J Hepatobiliary Pancreat Sci. 2011; 18: 13‐ 22. doi: 10.1007/s00534-010-0304-2 20607568 · DOI
  85. [100]Hammoutene A, Rautou P‐E. Role of liver sinusoidal endothelial cells in non‐alcoholic fatty liver disease. J Hepatol. 2019; 70: 1278‐ 1291. doi: 10.1016/j.jhep.2019.02.012 30797053 · DOI · Paper page
  86. [102]Ito Y, Hosono K, Amano H. Responses of hepatic sinusoidal cells to liver ischemia‐reperfusion injury. Front Cell Dev Biol. 2023; 11: 1171317. doi: 10.3389/fcell.2023.1171317 37082623 PMC10112669 · DOI
  87. [103]Schoen JM, Wang HH, Minuk GY, Lautt WW. Shear stress‐induced nitric oxide release triggers the liver regeneration cascade. Nitric Oxide. 2001; 5: 453‐ 464. doi: 10.1006/niox.2001.0373 11587560 · DOI · Paper page
  88. [105]Duan J‐Li, Zhou Zi‐Yi, Ruan B, et al. Notch‐regulated c‐kit‐positive liver sinusoidal endothelial cells contribute to liver zonation and regeneration. Cell Mol Gastroenterol Hepatol. 2022; 13: 1741‐ 1756. doi: 10.1016/j.jcmgh.2022.01.019 35114417 PMC9046233 · DOI
  89. [106]Saviano A, Henderson NC, Baumert TF. Single‐cell genomics and spatial transcriptomics: discovery of novel cell states and cellular interactions in liver physiology and disease biology. J Hepatol. 2020; 73: 1219‐ 1230. doi: 10.1016/j.jhep.2020.06.004 32534107 PMC7116221 · DOI
  90. [107]Michalopoulos G. HGF and liver regeneration. Gastroenterol Jpn. 1993; 28(4): 36‐ 39. doi: 10.1007/bf02782887. Suppl. discussion 53‐36. 7683618 · DOI
  91. [108]Yin C, Evason KJ, Asahina K, Stainier DYR. Hepatic stellate cells in liver development, regeneration, and cancer. J Clin Invest. 2013; 123: 1902‐ 1910. doi: 10.1172/jci66369 23635788 PMC3635734 · DOI · Paper page
  92. [109]Kitade M, Kaji K, Yoshiji H. Relationship between hepatic progenitor cell‐mediated liver regeneration and non‐parenchymal cells. Hepatol Res. 2016; 46: 1187‐ 1193. doi: 10.1111/hepr.12682 26895456 · DOI
  93. [110]Houck KA, Cruise JL, Michalopoulos G. Norepinephrine modulates the growth‐inhibitory effect of transforming growth factor‐beta in primary rat hepatocyte cultures. J Cell Physiol. 1988; 135: 551‐ 555. doi: 10.1002/jcp.1041350327 3165094 · DOI
  94. [111]Olsen PS, Poulsen SS, Kirkegaard P. Adrenergic effects on secretion of epidermal growth factor from Brunner's glands. Gut. 1985; 26: 920‐ 927. doi: 10.1136/gut.26.9.920 2863199 PMC1432851 · DOI
  95. [112]Liu W‐H, Ren Li‐Na, Wang T, Navarro‐Alvarez N, Tang Li‐J. The involving roles of intrahepatic and extrahepatic stem/progenitor cells (SPCs) to liver regeneration. Int J Biol Sci. 2016; 12: 954‐ 963. doi: 10.7150/ijbs.15715 27489499 PMC4971734 · DOI
  96. [113]Shang H, Wang Z, Song Y. Liver progenitor cells‐mediated liver regeneration in liver cirrhosis. Hepatol Int. 2016; 10: 440‐ 447. doi: 10.1007/s12072-015-9693-2 26742763 · DOI
  97. [114]Lee UE, Friedman SL. Mechanisms of hepatic fibrogenesis. Best Pract Res Clin Gastroenterol. 2011; 25: 195‐ 206. doi: 10.1016/j.bpg.2011.02.005 21497738 PMC3079877 · DOI · Paper page
  98. [115]Dedhar S, Williams B, Hannigan G. Integrin‐linked kinase (ILK): a regulator of integrin and growth‐factor signalling. Trends Cell Biol. 1999; 9: 319‐ 323. doi: 10.1016/s0962-8924(99)01612-8 10407411 · DOI
  99. [116]Martucci N, Michalopoulos GK, Mars WM. Integrin linked kinase (ILK) and its role in liver pathobiology. Gene Expr. 2021; 20: 201‐ 207. 33482930 PMC8201652
  100. [117]Hynes RO. Integrins: bidirectional, allosteric signaling machines. Cell. 2002; 110: 673‐ 687. doi: 10.1016/s0092-8674(02)00971-6 12297042 · DOI
  101. [120]Sousa Da Silva RX, Weber A, Dutkowski P, Clavien P‐A. Machine perfusion in liver transplantation. Hepatology. 2022; 76: 1531‐ 1549. doi: 10.1002/hep.32546 35488496 · DOI
  102. [121]Martins PN, Buchwald JE, Mergental H, Vargas L, Quintini C. The role of normothermic machine perfusion in liver transplantation. Int J Surg. 2020; 82s: 52‐ 60. doi: 10.1016/j.ijsu.2020.05.026 32417462 · DOI
  103. [122]Lascaris B, De Meijer VE, Porte RJ. Normothermic liver machine perfusion as a dynamic platform for regenerative purposes: what does the future have in store for us? J Hepatol. 2022; 77: 825‐ 836. doi: 10.1016/j.jhep.2022.04.033 35533801 · DOI
  104. [123]Hann A, Nutu A, Clarke G, et al. Normothermic machine perfusion‐improving the supply of transplantable livers for high‐risk recipients. Transpl Int. 2022; 35: 10460. doi: 10.3389/ti.2022.10460 35711320 PMC9192954 · DOI
  105. [124]Li M, Fang F, Sun M, Zhang Y, Hu M, Zhang J. Extracellular vesicles as bioactive nanotherapeutics: an emerging paradigm for regenerative medicine. Theranostics. 2022; 12: 4879‐ 4903. doi: 10.7150/thno.72812 35836815 PMC9274746 · DOI
  106. [125]Córdoba‐Jover B, Arce‐Cerezo A, Ribera J, et al. Cerium oxide nanoparticles improve liver regeneration after acetaminophen‐induced liver injury and partial hepatectomy in rats. J Nanobiotechnol. 2019; 17: 112. doi: 10.1186/s12951-019-0544-5 PMC6822381 31672158 · DOI
  107. [126]Chen Y, Shi S, Li Bo, et al. Therapeutic effects of self‐assembled tetrahedral framework nucleic acids on liver regeneration in acute liver failure. ACS Appl Mater Interfaces. 2022; 14: 13136‐ 13146. doi: 10.1021/acsami.2c02523 35285610 · DOI
  108. [127]Barreto Da Silva T, Dias EA, Cardoso LMDaF, Gama JFG, Alves LA, Henriques‐Pons A. Magnetic nanostructures and stem cells for regenerative medicine, application in liver diseases. Int J Mol Sci. 2023; 24. doi: 10.3390/ijms24119293 PMC10253131 37298243 · DOI
  109. [128]El Baz H, Demerdash Z, Kamel M, et al. Potentials of differentiated human cord blood‐derived unrestricted somatic stem cells in treatment of liver cirrhosis. Exp Clin Transplant. 2019; 17: 251‐ 258. doi: 10.6002/ect.2017.0249 30346265 · DOI
  110. [129]Zhang J, Lu T, Xiao J, et al. MSC‐derived extracellular vesicles as nanotherapeutics for promoting aged liver regeneration. J Control Release. 2023; 356: 402‐ 415. doi: 10.1016/j.jconrel.2023.02.032 36858264 · DOI · Paper page
  111. [130]Zhang J, Gao J, Li X, et al. Bone marrow mesenchymal stem cell‐derived small extracellular vesicles promote liver regeneration via miR‐20a‐5p/PTEN. Front Pharmacol. 2023; 14: 1168545. doi: 10.3389/fphar.2023.1168545 37305542 PMC10248071 · DOI
  112. [131]Zhu L, Wang Q, Guo M, et al. Mesenchymal stem cell‐derived exosomes in various chronic liver diseases: hype or hope? J Inflamm Res. 2024; 17: 171‐ 189. doi: 10.2147/jir.S439974 38223423 PMC10788055 · DOI · Paper page
  113. [132]Driscoll J, Wehrkamp C, Ota Yu, Thomas JN, Yan IK, Patel T. Biological nanotherapeutics for liver disease. Hepatology. 2021; 74: 2863‐ 2875. doi: 10.1002/hep.31847 33825210 · DOI
  114. [133]Miyoshi T, Hiratsuka K, Garcia Saiz E, Morizane R. Kidney organoids in translational medicine: disease modeling and regenerative medicine. Dev Dyn. 2019;249(1):34‐45. PMC6731163 30843293
  115. [134]Kuse Y, Taniguchi H. Present and future perspectives of using human‐induced pluripotent stem cells and organoid against liver failure. Cell Transplant. 2019; 28: 160s‐ 165s. doi: 10.1177/0963689719888459 31838891 PMC7016460 · DOI
  116. [135]Nie Y‐Z, Zheng Y‐W, Ogawa M, Miyagi E, Taniguchi H. Human liver organoids generated with single donor‐derived multiple cells rescue mice from acute liver failure. Stem Cell Res Ther. 2018; 9: 5. doi: 10.1186/s13287-017-0749-1 29321049 PMC5763644 · DOI
  117. [137]Katsuda T, Kawamata M, Hagiwara K, et al. Conversion of terminally committed hepatocytes to culturable bipotent progenitor cells with regenerative capacity. Cell Stem Cell. 2017; 20: 41‐ 55. doi: 10.1016/j.stem.2016.10.007 27840021 · DOI · Paper page
  118. [138]He J, Cui H, Shi X, et al. Functional hepatobiliary organoids recapitulate liver development and reveal essential drivers of hepatobiliary cell fate determination. Life Medicine. 2022; 1: 345‐ 358. doi: 10.1093/lifemedi/lnac055 PMC11749142 39872746 · DOI
  119. [139]Sun L, Hui L. Progress in human liver organoids. J Mol Cell Biol. 2020; 12: 607‐ 617. doi: 10.1093/jmcb/mjaa013 32236564 PMC7683012 · DOI
  120. [141]Feng S, Wu J, Qiu W‐L, et al. Large‐scale generation of functional and transplantable hepatocytes and cholangiocytes from human endoderm stem cells. Cell Rep. 2020; 33: 108455. doi: 10.1016/j.celrep.2020.108455 33296648 · DOI
  121. [142]Masuda Y, Yoshizawa K, Ohno Y, Mita A, Shimizu A, Soejima Y. Small‐for‐size syndrome in liver transplantation: definition, pathophysiology and management. Hepatobiliary Pancreat Dis Int. 2020; 19: 334‐ 341. doi: 10.1016/j.hbpd.2020.06.015 32646775 · DOI
  122. [143]Søreide JA, Deshpande R. Post hepatectomy liver failure (PHLF)—Recent advances in prevention and clinical management. Eur J Surg Oncol. 2021; 47: 216‐ 224. doi: 10.1016/j.ejso.2020.09.001 32943278 · DOI
  123. [144]Yuan X, Wu J, Sun Z, et al. Preclinical efficacy and safety of encapsulated proliferating human hepatocyte organoids in treating liver failure. Cell Stem Cell. 2024. doi: 10.1016/j.stem.2024.02.005 38458193 · DOI
  124. [145]Sampaziotis F, Justin AW, Tysoe OC, et al. Reconstruction of the mouse extrahepatic biliary tree using primary human extrahepatic cholangiocyte organoids. Nat Med. 2017; 23: 954‐ 963. doi: 10.1038/nm.4360 28671689 · DOI · Paper page
  125. [146]Tysoe OC, Justin AW, Brevini T, et al. Isolation and propagation of primary human cholangiocyte organoids for the generation of bioengineered biliary tissue. Nat Protoc. 2019; 14: 1884‐ 1925. doi: 10.1038/s41596-019-0168-0 31110298 · DOI
  126. [147]Sampaziotis F, Muraro D, Tysoe OC, et al. Cholangiocyte organoids can repair bile ducts after transplantation in the human liver. Science. 2021; 371: 839‐ 846. doi: 10.1126/science.aaz6964 33602855 PMC7610478 · DOI · Paper page
  127. [148]Tandon R, Froghi S. Artificial liver support systems. J Gastroenterol Hepatol. 2021; 36: 1164‐ 1179. doi: 10.1111/jgh.15255 32918840 · DOI
  128. [149]Saliba F, Bañares R, Larsen FS, et al. Artificial liver support in patients with liver failure: a modified DELPHI consensus of international experts. Intensive Care Med. 2022; 48: 1352‐ 1367. doi: 10.1007/s00134-022-06802-1 36066598 · DOI
  129. [150]Starokozhko V, Groothuis GMM. Challenges on the road to a multicellular bioartificial liver. J Tissue Eng Regen Med. 2018; 12: e227‐ e236. doi: 10.1002/term.2385 27943623 · DOI
  130. [151]Larsen FS. Artificial liver support in acute and acute‐on‐chronic liver failure. Curr Opin Crit Care. 2019; 25: 187‐ 191. doi: 10.1097/mcc.0000000000000584 30672818 · DOI
  131. [153]Shi X‐L, Gao Y, Yan Y, et al. Improved survival of porcine acute liver failure by a bioartificial liver device implanted with induced human functional hepatocytes. Cell Res. 2016; 26: 206‐ 216. doi: 10.1038/cr.2016.6 26768767 PMC4746613 · DOI

Cited by

Sorted by citations

Authors
Liu, Q., Wang, S., Fu, J., Chen, Y., Xu, J., Wei, W., Song, H., Zhao, X., & Wang, H.
Affiliations
  • First Affiliated Hospital of Zhengzhou University (CN)
  • Second Military Medical University (CN)
  • Translational Medicine Centre The First Affiliated Hospital of Zhengzhou University Zhengzhou Henan Province China
Corresponding author
  • Zhao, Xiaofang
  • Wang, Hongyang
ORCID
Venue
Clinical and Translational Medicine
Publisher
Wiley
Published
2024-08
Volume
14
Issue
8
Pages
e1812-e1812
ISSN
2001-1326 (ISSN-L)
DOI
10.1002/ctm2.1812
PMC
PMC11329751
OpenAlex
W4401667588
Cited by
49
References
23
Citations by year
2026: 23 · 2025: 25 · 2024: 1
FWCI
3.54
Type
journal article
Language
en
Open access
Licence
Locations
  • Clinical and Translational Medicine (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Natural Science Foundation of Henan Province (242300420070)
  • National Key Research and Development Program of China (2022YFC3400902)
  • National Natural Science Foundation of China (82073411)
Topics
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Health Sciences › Medicine › Surgery › Tissue Engineering and Regenerative Medicine
  • Health Sciences › Medicine › Surgery › Organ Transplantation Techniques and Outcomes
Keywords
liver regeneration, hepatocyte proliferation, hepatocyte transdifferentiation, hepatic progenitor cells, chronic liver disease, signaling pathways, cellular interactions, nanotechnology, stem cell transplantation, organoids, liver injury
MeSH terms
Animals, Cell Communication, Humans, Liver, Liver Diseases, Liver Regeneration, Signal Transduction, Hepatocytes

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review