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Cited by 444Liver physiology and pathologyTissue Engineering and Regenerative MedicineOrgan Transplantation Techniques and Outcomes

Hepatostat: Liver regeneration and normal liver tissue maintenance

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Michalopoulos, George K.·2017·Hepatology
DOI 10.1002/hep.28988
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Abstract

In contrast to all other organs, liver‐to‐body‐weight ratio needs to be maintained always at 100% of what is required for body homeostasis. Adjustment of liver size to 100% of what is required for homeostasis has been called “hepatostat.” Removal of a portion of any other organ is followed with local regeneration of a limited degree, but it never attempts to reach 100% of the original size. The complex mechanisms involved in this uniquely hepatic process encompass a variety of regenerative pathways that are specific to different types of injury. The most studied form of liver regeneration (LR) is that occurring after loss of hepatocytes in a single acute injury, such as rodent LR after two‐thirds partial hepatectomy or administration of damaging chemicals (CCl 4 , acetaminophen, etc.). Alternative regenerative pathways become activated when normal regeneration is thwarted and trigger the appearance of “progenitor” cells. Chronic loss of hepatocytes is associated with regenerative efforts characterized by continual hepatocyte proliferation and often has adverse consequences (development of cirrhosis or liver cancer). Even though a very few hepatocytes proliferate at any given time in normal liver, the mechanisms involved in the maintenance of liver weight by this slow process in the absence of liver injury are not as well understood. (H epatology 2017;65:1384‐1392)

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  • After partial hepatectomy or injury, hepatocytes can re-enter the cell cycle and proliferate extensively in vivo, but this regenerative response requires a tightly controlled interplay of mitogenic growth factors, cytokines, metabolic cues, and mechanical stimuli that are difficult to recapitulate ex vivo.

    “After partial hepatectomy or injury, hepatocytes can re-enter the cell cycle and proliferate extensively in vivo, but this regenerative response requires a tightly controlled interplay of mitogenic growth factors, cytokines, metabolic cues, and mechanical stimuli that are difficult to recapitulate ex vivo [12].”

    From The Hepatocyte Expansion Paradox: A Review of In Vitro Challenges and Advances (2026) · cites this paper as [12]

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  • The hepatostat is set such that the liver regenerates back to 100% of what is required for homeostasis, unlike other solid organs with more limited regenerative potential.

    “This is necessary to adapt the size of the liver and number of hepatocytes to the body`s needs, and the “hepatostat” is set such that the liver regenerates back to 100% of what is required for homeostasis, unlike other solid organs with more limited regenerative potential.73,74”

    From Distinct hepatocyte identities in liver homeostasis and regeneration (2023) · cites this paper as [73]

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  1. Michalopoulos GK. Principles of liver regeneration and growth homeostasis. Compr Physiol 2013;3:485-513.
  2. Michalopoulos GK. Liver regeneration after partial hepatectomy: crit- ical analysis of mechanistic dilemmas. Am J Pathol 2010;176:2-13.
  3. Michalopoulos GK, DeFrances MC. Liver regeneration. Science 1997;276:60-66.
  4. Fausto N, Campbell JS, Riehle KJ. Liver regeneration. HEPATOL- OGY 2006;43:S45-53.
  5. Taub R. Liver regeneration: from myth to mechanism. Nat Rev Mol Cell Biol 2004;5:836-847.
  6. Taub R. Liver regeneration 4: transcriptional control of liver regeneration. FASEB J 1996;10:413-427.
  7. Naugler WE, Tarlow BD, Fedorov LM, Taylor M, Pelz C, Li B, et al. Fibroblast growth factor signaling controls liver size in mice with humanized livers. Gastroenterology 2015;149:728- 740.e15. FIG.
  8. Different results driven by acute versus chronic LR. Whereas acute injury leads to restoration of the previous hepatic structure and size, chronic liver injury leads to regenerative events, which generate diploid/aneuploid hepatocytes with genomic alterations that can lead to development of HCC. Abbreviation: ROS, reactive oxygen species. 9) Sauter KA, Waddell LA, Lisowski ZM, Young R, Lefevre L, Davis GM, et al. Macrophage colony-stimulating factor (CSF1) controls monocyte production and maturation and the steady- state size of the liver in pigs. Am J Physiol Gastrointest Liver Physiol 2016;311:G533-G547.
  9. Avila MA, Moschetta A. The FXR-FGF19 gut-liver axis as a novel "hepatostat". Gastroenterology 2015;149:537-540.
  10. Huch M, Dolle L. The plastic cellular states of liver cells: are EpCAM and Lgr5 fit for purpose? HEPATOLOGY 2016;64: 652-662.
  11. Mohn KL, Laz TM, Hsu JC, Melby AE, Bravo R, Taub R. The immediate-early growth response in regenerating liver and insulin-stimulated H-35 cells: comparison with serum- stimulated 3T3 cells and identification of 41 novel immediate- early genes. Mol Cell Biol 1991;11:381-390.
  12. Marubashi S, Sakon M, Nagano H, Gotoh K, Hashimoto K, Kubota M, et al. Effect of portal hemodynamics on liver regener- ation studied in a novel portohepatic shunt rat model. Surgery 2004;136:1028-1037.
  13. Leffert HL, Koch KS, Moran T, Rubalcava B. Hormonal control of rat liver regeneration. Gastroenterology 1979;76:1470-1482.
  14. Stolz DB, Mars WM, Petersen BE, Kim TH, Michalopoulos GK. Growth factor signal transduction immediately after two-thirds par- tial hepatectomy in the rat. Cancer Res 1999;59:3954-3960.
  15. Mullany LK, White P, Hanse EA, Nelsen CJ, Goggin MM, Mullany JE, et al. Distinct proliferative and transcriptional effects of the D-type cyclins in vivo. Cell Cycle 2008;7:2215-2224.
  16. Bhave VS, Paranjpe S, Bowen WC, Donthamsetty S, Bell AW, Khillan JS, Michalopoulos GK. Genes inducing iPS phenotype play a role in hepatocyte survival and proliferation in vitro and liver regeneration in vivo. HEPATOLOGY 2011;54:1360-1370.
  17. Song G, Sharma AD, Roll GR, Ng R, Lee AY, Blelloch RH, et al. MicroRNAs control hepatocyte proliferation during liver regeneration. HEPATOLOGY 2010;51:1735-1743.
  18. Ng R, Song G, Roll GR, Frandsen NM, Willenbring H. A microRNA-21 surge facilitates rapid cyclin D1 translation and cell cycle progression in mouse liver regeneration. J Clin Invest 2012;122:1097-1108.
  19. Miyaoka Y, Ebato K, Kato H, Arakawa S, Shimizu S, Miyajima A. Hypertrophy and unconventional cell division of hepatocytes underlie liver regeneration. Curr Biol 2012;22:1166-1175.
  20. Miyaoka Y, Miyajima A. To divide or not to divide: revisiting liver regeneration. Cell Div 2013;8:8.
  21. Wang L, Wang X, Xie G, Wang L, Hill CK, DeLeve LD. Liv- er sinusoidal endothelial cell progenitor cells promote liver regen- eration in rats. J Clin Invest 2012;122:1567-1573.
  22. Block GD, Locker J, Bowen WC, Petersen BE, Katyal S, Strom SC, et al. Population expansion, clonal growth, and specific dif- ferentiation patterns in primary cultures of hepatocytes induced by HGF/SF, EGF and TGF alpha in a chemically defined (HGM) medium. J Cell Biol 1996;132:1133-1149.
  23. Limaye PB, Bowen WC, Orr AV, Luo J, Tseng GC, Michalopoulos GK. Mechanisms of hepatocyte growth factor- mediated and epidermal growth factor-mediated signaling in transdifferentiation of rat hepatocytes to biliary epithelium. HEPATOLOGY 2008;47:1702-1713.
  24. Fafalios A, Ma J, Tan X, Stoops J, Luo J, Defrances MC, Zarnegar R. A hepatocyte growth factor receptor (Met)-insulin receptor hybrid governs hepatic glucose metabolism. Nat Med 2011;17:1577-1584.
  25. Wang X, DeFrances MC, Dai Y, Pediaditakis P, Johnson C, Bell A, et al. A mechanism of cell survival: sequestration of Fas by the HGF receptor Met. Mol Cell 2002;9:411-421.
  26. Gomes DA, Rodrigues MA, Leite MF, Gomez MV, Varnai P, Balla T, et al. c-Met must translocate to the nucleus to initiate calcium signals. J Biol Chem 2008;283:4344-4351.
  27. Nejak-Bowen K, Orr A, Bowen WC, Jr., Michalopoulos GK. Conditional genetic elimination of hepatocyte growth factor in mice compromises liver regeneration after partial hepatectomy. PLoS One 2013;8:e59836.
  28. Skov Olsen P, Boesby S, Kirkegaard P, Therkelsen K, Almdal T, Poulsen SS, Nexo E. Influence of epidermal growth factor on liver regeneration after partial hepatectomy in rats. HEPATOLOGY 1988;8:992-996.
  29. Paranjpe S, Bowen WC, Mars WM, Orr A, Haynes MM, DeFrances MC, et al. Combined systemic elimination of MET and EGFR signaling completely abolishes liver regeneration and leads to liver decompensation. HEPATOLOGY 2016;64:1711-1724.
  30. Hou JZ, Kan MK, McKeehan K, McBride G, Adams P, McKeehan WL. Fibroblast growth factor receptors from liver vary in three structural domains. Science 1991;251:665-668.
  31. Kan M, Huang JS, Mansson PE, Yasumitsu H, Carr B, McKeehan WL. Heparin-binding growth factor type 1 (acidic fibroblast growth factor): a potential biphasic autocrine and para- crine regulator of hepatocyte regeneration. Proc Natl Acad Sci U S A 1989;86:7432-7436.
  32. Padrissa-Altes S, Bachofner M, Bogorad RL, Pohlmeier L, Rossolini T, Bohm F, et al. Control of hepatocyte proliferation and survival by Fgf receptors is essential for liver regeneration in mice. Gut 2015;64:1444-1453.
  33. Mukhopadhyay B, Cinar R, Yin S, Liu J, Tam J, Godlewski G, et al. Hyperactivation of anandamide synthesis and regulation of cell-cycle progression via cannabinoid type 1 (CB1) receptors in the regenerating liver. Proc Natl Acad Sci USA 2011;108:6323-6328.
  34. Lesurtel M, Graf R, Aleil B, Walther B, Tian Y, Jochum W, et al. Platelet-derived serotonin mediates liver regeneration. Sci- ence 2006;312:104-107.
  35. Huang W, Ma K, Zhang J, Qatanani M, Cuvillier J, Liu J, Dong B, et al. Nuclear receptor-dependent bile acid signaling is required for normal liver regeneration. Science 2006;312:233-236.
  36. Keitel V, Haussinger D. TGR5 in cholangiocytes. Curr Opin Gastroenterol 2013;29:299-304.
  37. Francavilla A, Starzl TE, Porter K, Foglieni CS, Michalopoulos GK, Carrieri G, et al. Screening for candidate hepatic growth factors by selective portal infusion after canine Eck's fistula. HEPATOLOGY 1991;14:665-670.
  38. Bowen WC, Michalopoulos AW, Orr A, Ding MQ, Stolz DB, Michalopoulos GK. Development of a chemically defined medi- um and discovery of new mitogenic growth factors for mouse hepatocytes: mitogenic effects of FGF1/2 and PDGF. PLoS One 2014;9:e95487.
  39. Ochoa B, Syn WK, Delgado I, Karaca GF, Jung Y, Wang J, et al. Hedgehog signaling is critical for normal liver regeneration after partial hepatectomy in mice. HEPATOLOGY 2010;51:1712-1723.
  40. Bhave VS, Mars W, Donthamsetty S, Zhang X, Tan L, Luo J, et al. Regulation of liver growth by glypican 3, CD81, hedgehog, and Hhex. Am J Pathol 2013;183:153-159.
  41. Omenetti A, Diehl AM. Hedgehog signaling in cholangiocytes. Curr Opin Gastroenterol 2011;27:268-275.
  42. Zeng G, Awan F, Otruba W, Muller P, Apte U, Tan X, et al. Wnt'er in liver: expression of Wnt and frizzled genes in mouse. HEPATOLOGY 2007;45:195-204.
  43. Tan X, Apte U, Micsenyi A, Kotsagrelos E, Luo JH, Ranganathan S, et al. Epidermal growth factor receptor: a novel target of the Wnt/beta-catenin pathway in liver. Gastroenterology 2005;129:285-302.
  44. Tao J, Calvisi DF, Ranganathan S, Cigliano A, Zhou L, Singh S, et al. Activation of beta-catenin and Yap1 in human hepato- blastoma and induction of hepatocarcinogenesis in mice. Gastro- enterology 2014;147:690-701.
  45. Thompson MD, Monga SP. WNT/beta-catenin signaling in liv- er health and disease. HEPATOLOGY 2007;45:1298-1305.
  46. Monga SP, Pediaditakis P, Mule K, Stolz DB, Michalopoulos GK. Changes in WNT/beta-catenin pathway during regulated growth in rat liver regeneration. HEPATOLOGY 2001;33:1098- 1109.
  47. Chari RS, Price DT, Sue SR, Meyers WC, Jirtle RL. Down- regulation of transforming growth factor beta receptor type I, II, and III during liver regeneration. Am J Surg 1995;169:126-131; discussion, 131-122.
  48. Thenappan A, Shukla V, Abdul Khalek FJ, Li Y, Shetty K, Liu P, et al. Loss of transforming growth factor beta adaptor protein beta- 2 spectrin leads to delayed liver regeneration in mice. HEPATOLOGY 2011;53:1641-1650.
  49. Jirtle RL, Carr BI, Scott CD. Modulation of insulin-like growth factor-II/mannose 6-phosphate receptors and transforming growth factor-beta 1 during liver regeneration [published erratum appears in: J Biol Chem 1991;266:24860]. J Biol Chem 1991; 266:22444-22450.
  50. Apte U, Gkretsi V, Bowen WC, Mars WM, Luo JH, Donthamsetty S, et al. Enhanced liver regeneration following changes induced by hepatocyte-specific genetic ablation of integrin-linked kinase. HEPATOLOGY 2009;50:844-851.
  51. Jin J, Hong IH, Lewis K, Iakova P, Breaux M, Jiang Y, et al. Cooperation of C/EBP family proteins and chromatin remodel- ing proteins is essential for termination of liver regeneration. HEPATOLOGY 2015;61:315-325.
  52. Liu B, Paranjpe S, Bowen WC, Bell AW, Luo JH, Yu YP, et al. Investigation of the role of glypican 3 in liver regeneration and hepatocyte proliferation. Am J Pathol 2009;175:717-724.
  53. Koral K, Paranjpe S, Bowen WC, Mars W, Luo J, Michalopoulos GK. Leukocyte-specific protein 1: a novel regu- lator of hepatocellular proliferation and migration deleted in human hepatocellular carcinoma. HEPATOLOGY 2015;61:537- 547.
  54. Li JW, Wang GP, Fan JY, Chang CF, Xu CS. Eight paths of ERK1/2 signalling pathway regulating hepatocyte proliferation in rat liver regeneration. J Genet 2011;90:435-442.
  55. Avruch J, Zhou D, Fitamant J, Bardeesy N. Mst1/2 signalling to Yap: gatekeeper for liver size and tumour development. Br J Cancer 2011;104:24-32.
  56. Wang C, Zhang L, He Q, Feng X, Zhu J, Xu Z, et al. Differ- ences in Yes-associated protein and mRNA levels in regenerating liver and hepatocellular carcinoma. Mol Med Rep 2012;5:410-414.
  57. George NM, Boerner BP, Mir SU, Guinn Z, Sarvetnick NE. Exploiting expression of Hippo effector, Yap, for expansion of functional islet mass. Mol Endocrinol 2015;29:1594-1607.
  58. Elbediwy A, Vincent-Mistiaen ZI, Thompson BJ. YAP and TAZ in epithelial stem cells: a sensor for cell polarity, mechanical forces and tissue damage. Bioessays 2016;38:644-653.
  59. Zhou D, Conrad C, Xia F, Park JS, Payer B, Yin Y, et al. Mst1 and Mst2 maintain hepatocyte quiescence and suppress hepato- cellular carcinoma development through inactivation of the Yap1 oncogene. Cancer Cell 2009;16:425-438.
  60. Halder G, Johnson RL. Hippo signaling: growth control and beyond. Development 2011;138:9-22.
  61. Moleirinho S, Chang N, Sims AH, Tilston-Lunel AM, Angus L, Steele A, Boswell V, et al. KIBRA exhibits MST- independent functional regulation of the Hippo signaling path- way in mammals. Oncogene 2013;32:1821-1830.
  62. Bodewes FA, Bijvelds MJ, de Vries W, Baller JF, Gouw AS, de Jonge HR, Verkade HJ. Cholic acid induces a Cftr dependent biliary secretion and liver growth response in mice. PLoS One 2015;10:e0117599.
  63. Eriksson S, Prigge JR, Talago EA, Arner ES, Schmidt EE. Die- tary methionine can sustain cytosolic redox homeostasis in the mouse liver. Nat Commun 2015;6:6479.
  64. Truong TH, Ung PM, Palde PB, Paulsen CE, Schlessinger A, Carroll KS. Molecular basis for redox activation of epidermal growth factor receptor kinase. Cell Chem Biol 2016;23:837-848.
  65. Ponder KP. Analysis of liver development, regeneration, and carci- nogenesis by genetic marking studies. FASEB J 1996;10:673-682.
  66. Carpentier R, Suñer RE, van Hul N, Kopp JL, Beaudry JB, Cordi S, et al. Embryonic ductal plate cells give rise to cholan- giocytes, periportal hepatocytes, and adult liver progenitor cells. Gastroenterology 2011;141:1432-1438, 1438.e1-4.
  67. Font-Burgada J, Shalapour S, Ramaswamy S, Hsueh B, Rossell D, Umemura A, et al. Hybrid periportal hepatocytes regenerate the injured liver without giving rise to cancer. Cell 2015;162:766-779.
  68. Melchiorri C, Chieco P, Zedda AI, Coni P, Ledda-Columbano GM, Columbano A. Ploidy and nuclearity of rat hepatocytes after compensatory regeneration or mitogen-induced liver growth. Carcinogenesis 1993;14:1825-1830.
  69. Duncan AW, Hanlon Newell AE, Smith L, Wilson EM, Olson SB, Thayer MJ, et al. Frequent aneuploidy among normal human hepatocytes. Gastroenterology 2012;142:25-28.
  70. Duncan AW, Taylor MH, Hickey RD, Hanlon Newell AE, Lenzi ML, Olson SB, et al. The ploidy conveyor of mature hepatocytes as a source of genetic variation. Nature 2010;467:707-710.
  71. Anti M, Marra G, Rapaccini GL, Rumi C, Bussa S, Fadda G, et al. DNA ploidy pattern in human chronic liver diseases and hepatic nodular lesions. Flow cytometric analysis on echo-guided needle liver biopsy. Cancer 1994;73:281-288.

Cited by

Sorted by citations

Authors
Michalopoulos, G. K.
Affiliations
University of Pittsburgh (US)
Corresponding author
Michalopoulos, George K.
ORCID
Michalopoulos, George K.
Venue
Hepatology
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2017-03-06
Volume
65
Issue
4
Pages
1384-1392
ISSN
  • 0270-9139 (ISSN-L)
  • 1527-3350
DOI
10.1002/hep.28988
OpenAlex
W2563604790
Cited by
444
References
11
Citations by year
2026: 25 · 2025: 34 · 2024: 45 · 2023: 64 · 2022: 57 · 2021: 54 · 2020: 57 · 2019: 46 · 2018: 46 · 2017: 16
FWCI
4.49
Type
journal article
Language
en
Open access
Licence
Locations
  • Hepatology (publishedVersion)
  • PubMed (publishedVersion)
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, liver homeostasis, hepatocyte proliferation, partial hepatectomy, liver injury, hepatic progenitor cells, liver cirrhosis, liver cancer
MeSH terms
Animals, Body Weight, Hepatectomy, Homeostasis, Humans, Liver, Liver Regeneration, Organ Size, Prognosis, Reference Standards, Risk Assessment

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