CoChat
Sign Up
Cited by 9Liver physiology and pathologyWnt/β-catenin signaling in development and cancerTissue Engineering and Regenerative Medicine

MANF serves as a novel hepatocyte factor to promote liver regeneration after 2/3 partial hepatectomy via doubly targeting Wnt/β-catenin signaling

Open access
Liang, Yanyan, Mei, Qiong, He, Enguang, Ballar, Petek, Wei, Chuansheng, Wang, Yue, Dong, Yue, Zhou, Jie +10 more·2024·Cell Death & Disease
DOI 10.1038/s41419-024-07069-8PMC PMC11408687
Open this paper in CoChat — free accountOpen PDF

Abstract

Liver regeneration is an intricate pathophysiological process that has been a subject of great interest to the scientific community for many years. The capacity of liver regeneration is very critical for patients with liver diseases. Therefore, exploring the mechanisms of liver regeneration and finding good ways to improve it are very meaningful. Mesencephalic astrocyte-derived neurotrophic factor (MANF), a member of newly identified neurotrophic factors (NTFs) family, extensively expresses in the liver and has demonstrated cytoprotective effects during ER stress and inflammation. However, the role of MANF in liver regeneration remains unclear. Here, we used hepatocyte-specific MANF knockout (MANF Hep−/−) mice to investigate the role of MANF in liver regeneration after 2/3 partial hepatectomy (PH). Our results showed that MANF expression was up-regulated in a time-dependent manner, and the peak level of mRNA and protein appeared at 24 h and 36 h after 2/3 PH, respectively. Notably, MANF knockout delayed hepatocyte proliferation, and the peak proliferation period was delayed by 24 h. Mechanistically, our in vitro results showed that MANF physically interacts with LRP5 and β-catenin, two essential components of Wnt/β-catenin pathway. Specifically, as a cofactor, MANF binds to the extracellular segment of LRP5 to activate Wnt/β-catenin signaling. On the other hand, MANF interacts with β-catenin to stabilize cytosolic β-catenin level and promote its nuclear translocation, which further enhance the Wnt/β-catenin signaling. We also found that MANF knockout does not affect the c-Met/β-catenin complex after 2/3 PH. In summary, our study confirms that MANF may serve as a novel hepatocyte factor that is closely linked to the activation of the Wnt/β-catenin pathway via intracellular and extracellular targets.

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 · 10.1038/s41419-024-07069-8

Cites

3 of 3 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?

  • MANF knockout delays the peak proliferation period by 24 hours after partial hepatectomy.

    “However, MANF knockout delayed the peak proliferation period by 24h.”

    From Liver regeneration after partial hepatectomy: Triggers and mechanisms (2025) · cites this paper as [52]

  • MANF physically interacts with LRP5 and β-catenin, two essential components of the Wnt/β-catenin pathway.

    “MANF physically interacts with lipoprotein receptor-related protein 5 (LRP5) and β-catenin, two essential components of Wnt/β-catenin pathway.”

    From Liver regeneration after partial hepatectomy: Triggers and mechanisms (2025) · cites this paper as [52]

  • MANF interacts with β-catenin to stabilize cytosolic β-catenin and promote its nuclear translocation, enhancing Wnt/β-catenin signaling.

    “On the other hand, MANF interacts with β-catenin to stabilize cytosolic β-catenin level and promote its nuclear translocation, which further enhance the Wnt/β-catenin signaling[52].”

    From Liver regeneration after partial hepatectomy: Triggers and mechanisms (2025) · cites this paper as [52]

  • As a cofactor, MANF binds to the extracellular segment of LRP5 to activate Wnt/β-catenin signaling.

    “Specifically, as a cofactor, MANF binds to the extracellular segment of LRP5 to activate Wnt/β-catenin signaling.”

    From Liver regeneration after partial hepatectomy: Triggers and mechanisms (2025) · cites this paper as [52]

  • MANF expression is up-regulated in a time-dependent manner, reaching a peak at 24 hours and 36 hours after 2/3 partial hepatectomy.

    “MANF expression was up-regulated in a time-dependent manner, reaching the peak at 24 hours and 36 hours after 2/3 PH, respectively.”

    From Liver regeneration after partial hepatectomy: Triggers and mechanisms (2025) · cites this paper as [52]

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: 44

  1. [1]Fausto N, Campbell JS, Riehle KJ. Liver regeneration. Hepatology. 2006;43:S45–53. 16447274 · DOI · Paper page
  2. [2]Michalopoulos G, DeFrances MJS. Liver regeneration. Science. 1997;276:60–66. 9082986 · DOI · Paper page
  3. [3]Taub. RJNrMcb. Liver regeneration: from myth to mechanism. Nat Rev Mol Cell Biol. 2004;5:836–47. 15459664 · DOI · Paper page
  4. [4]Si-Tayeb K, Lemaigre FP, Duncan SA. Organogenesis and development of the liver. Dev Cell. 2010;18:175–89. 20159590 · DOI · Paper page
  5. [5]Fausto N, Campbell JS, Riehle KJ. Liver regeneration. J Hepatol. 2012;57:692–4. 22613006 · DOI · Paper page
  6. [6]Bohm F, Kohler UA, Speicher T, Werner S. Regulation of liver regeneration by growth factors and cytokines. EMBO Mol Med. 2010;2:294–305. 20652897 PMC3377328 · DOI
  7. [7]Mitchell C, Willenbring H. A reproducible and well-tolerated method for 2/3 partial hepatectomy in mice. Nat Protoc. 2008;3:1167–70. 18600221 · DOI · Paper page
  8. [10]Petrova P, Raibekas A, Pevsner J, Vigo N, Anafi M, Moore MK, et al. MANF: a new mesencephalic, astrocyte-derived neurotrophic factor with selectivity for dopaminergic neurons. J Mol Neurosci. 2003;20:173–88. 12794311 · DOI
  9. [11]Henderson M, Richie C, Airavaara M, Wang Y, Harvey. BJTJobc. Mesencephalic astrocyte-derived neurotrophic factor (MANF) secretion and cell surface binding are modulated by KDEL receptors. J Biol Chem. 2013;288:4209–25. 23255601 PMC3567670 · DOI
  10. [12]Liu Y, Huo D, Zeng L, Fan G, Shen T, Zhang T, et al. Mesencephalic astrocyte-derived neurotrophic factor (MANF): Structure, functions and therapeutic potential. Ageing Res Rev. 2022;82:101763. 36272696 · DOI
  11. [13]Xu S, Di Z, He Y, Wang R, Ma Y, Sun R, et al. Mesencephalic astrocyte-derived neurotrophic factor (MANF) protects against Abeta toxicity via attenuating Abeta-induced endoplasmic reticulum stress. J Neuroinflammation. 2019;16:35. 30760285 PMC6373169 · DOI
  12. [14]Tseng KY, Anttila JE, Khodosevich K, Tuominen RK, Lindahl M, Domanskyi A, et al. MANF Promotes Differentiation and Migration of Neural Progenitor Cells with Potential Neural Regenerative Effects in Stroke. Mol Ther. 2018;26:238–55. 29050872 PMC5763030 · DOI
  13. [15]Eesmaa A, Yu LY, Goos H, Noges K, Kovaleva V, Hellman M, et al. The cytoprotective protein MANF promotes neuronal survival independently from its role as a GRP78 cofactor. J Biol Chem. 2021;296:100295. 33460650 PMC7949057 · DOI
  14. [16]Kovaleva V, Yu L, Ivanova L, Shpironok O, Nam J, Eesmaa A, et al. MANF regulates neuronal survival and UPR through its ER-located receptor IRE1α. Cell Rep. 2023;42:112066. 36739529 · DOI
  15. [17]Glembotski CC, Thuerauf DJ, Huang C, Vekich JA, Gottlieb RA, Doroudgar S. Mesencephalic astrocyte-derived neurotrophic factor protects the heart from ischemic damage and is selectively secreted upon sarco/endoplasmic reticulum calcium depletion. J Biol Chem. 2012;287:25893–904. 22637475 PMC3406674 · DOI
  16. [18]Zhang Y, Sun C, Li Y, Qin J, Amancherla K, Jing Y, et al. Hormonal therapies up-regulate MANF and overcome female susceptibility to immune checkpoint inhibitor myocarditis. Sci Transl Med. 2022;14:eabo1981. 36322628 PMC9809130 · DOI
  17. [19]Hakonen E, Chandra V, Fogarty CL, Yu NY, Ustinov J, Katayama S, et al. MANF protects human pancreatic beta cells against stress-induced cell death. Diabetologia. 2018;61:2202–14. 30032427 PMC6133171 · DOI
  18. [20]Montaser H, Patel KA, Balboa D, Ibrahim H, Lithovius V, Naatanen A, et al. Loss of MANf causes childhood-onset syndromic diabetes due to increased endoplasmic reticulum stress. Diabetes. 2021;70:1006–18. 33500254 PMC7610619 · DOI
  19. [21]Danilova T, Belevich I, Li H, Palm E, Jokitalo E, Otonkoski T, et al. MANF is required for the postnatal expansion and maintenance of pancreatic beta-cell mass in mice. Diabetes. 2019;68:66–80. 30305368 · DOI
  20. [22]Gao FJ, Wu JH, Li TT, Du SS, Wu Q. Identification of mesencephalic astrocyte-derived neurotrophic factor as a novel neuroprotective factor for retinal ganglion cells. Front Mol Neurosci. 2017;10:76. 28367115 PMC5355452 · DOI
  21. [23]Neves J, Zhu J, Sousa-Victor P, Konjikusic M, Riley R, Chew S, et al. Immune modulation by MANF promotes tissue repair and regenerative success in the retina. Science. 2016;353:aaf3646. 27365452 PMC5270511 · DOI
  22. [24]Yang Y, Wang P, Zhang C, Huang F, Pang G, Wei C, et al. Hepatocyte-derived MANF alleviates hepatic ischaemia-reperfusion injury via regulating endoplasmic reticulum stress-induced apoptosis in mice. Liver Int. 2021;41:623–39. 33064897 · DOI
  23. [25]Wang P, Yang Y, Pang G, Zhang C, Wei C, Tao X, et al. Hepatocyte-derived MANF is protective for rifampicin-induced cholestatic hepatic injury via inhibiting ATF4-CHOP signal activation. Free Radic Biol Med. 2021;162:283–97. 33127565 · DOI
  24. [26]Hou C, Wang D, Zhao M, Ballar P, Zhang X, Mei Q, et al. MANF brakes TLR4 signaling by competitively binding S100A8 with S100A9 to regulate macrophage phenotypes in hepatic fibrosis. Acta Pharm Sin B. 2023;13:4234–52. 37799387 PMC10547964 · DOI
  25. [27]Chhetri G, Liang Y, Shao J, Han D, Yang Y, Hou C, et al. Role of mesencephalic astrocyte-derived neurotrophic factor in alcohol-induced liver injury. Oxid Med Cell Longev. 2020;2020:9034864. 32724497 PMC7364207 · DOI
  26. [28]Michalopoulos GJH. Hepatostat: Liver regeneration and normal liver tissue maintenance. Hepatology. 2017;65:1384–92. 27997988 · DOI · Paper page
  27. [29]Monga SP. Beta-catenin signaling and roles in liver homeostasis, injury, and tumorigenesis. Gastroenterology. 2015;148:1294–310. 25747274 PMC4494085 · DOI
  28. [31]Tetsu O, McCormick FJN. Beta-catenin regulates expression of cyclin D1 in colon carcinoma cells. Nature. 1999;398:422–6. 10201372 · DOI · Paper page
  29. [32]Nejak-Bowen K, Monga SJO. Wnt/beta-catenin signaling in hepatic organogenesis. Organogenesis. 2008;4:92–99. 19279720 PMC2634254 · DOI
  30. [33]Perugorria M, Olaizola P, Labiano I, Esparza-Baquer A, Marzioni M, Marin J, et al. Wnt-β-catenin signalling in liver development, health and disease. Nat Rev Gastroenterol Hepatol. 2019;16:121–36. 30451972 · DOI
  31. [34]Oliva-Vilarnau N, Beusch C, Sabatier P, Sakaraki E, Tjaden A, Graetz L. et al. Wnt/β-catenin and NFκB signalingsynergize to trigger growth-factor-free regeneration of adult primary human hepatocytes. Hepatol. 2023;79:1337–1351. PMC11095891 37870288
  32. [35]Yang J, Mowry L, Nejak-Bowen K, Okabe H, Diegel C, Lang R, et al. β-catenin signaling in murine liver zonation and regeneration: a Wnt-Wnt situation! Hepatology. 2014;60:964–76. 24700412 PMC4139486 · DOI
  33. [36]Purcell R, Childs M, Maibach R, Miles C, Turner C, Zimmermann A, et al. HGF/c-Met related activation of β-catenin in hepatoblastoma. J Exp Clin Cancer Res. 2011;30:96. 21992464 PMC3207961 · DOI
  34. [37]Monga SJG. β-catenin signaling and roles in liver homeostasis, injury, and tumorigenesis. Gastroenterology. 2015;148:1294–310. 25747274 PMC4494085 · DOI
  35. [38]Lindholm P, Saarma. MJMp. Cerebral dopamine neurotrophic factor protects and repairs dopamine neurons by novel mechanism. Mol Psychiatry. 2022;27:1310–21. 34907395 PMC9095478 · DOI
  36. [39]Wu H, Reizel T, Wang Y, Lapiro J, Kren B, Schug J, et al. A negative reciprocal regulatory axis between cyclin D1 and HNF4α modulates cell cycle progression and metabolism in the liver. Proc Natl Acad Sci USA. 2020;117:17177–86. 32631996 PMC7382236 · DOI
  37. [40]Liu J, Xiao Q, Xiao J, Niu C, Li Y, Zhang X, et al. Wnt/β-catenin signalling: function, biological mechanisms, and therapeutic opportunities. Signal Transduct Target Ther. 2022;7:3. 34980884 PMC8724284 · DOI · Paper page
  38. [41]Sekine S, Gutiérrez P, Lan B, Feng S, Hebrok MJH. Liver-specific loss of beta-catenin results in delayed hepatocyte proliferation after partial hepatectomy. Hepatology. 2007;45:361–8. 17256747 · DOI
  39. [42]Tan X, Behari J, Cieply B, Michalopoulos G, Monga SJG. Conditional deletion of beta-catenin reveals its role in liver growth and regeneration. Gastroenterology. 2006;131:1561–72. 17101329 · DOI · Paper page
  40. [43]Nejak-Bowen K, Monga SJH. Wnt-β-catenin in hepatobiliary homeostasis, injury, and repair. Hepatology. 2023;78:1907–21. 37246413 PMC10687322
  41. [44]O’Brien S, Chidiac R, Angers S. Modulation of Wnt-β-catenin signaling with antibodies: therapeutic opportunities and challenges. Trends Pharm Sci. 2023;44:354–65. 37085400 · DOI
  42. [45]Huang P, Yan R, Zhang X, Wang L, Ke X, Qu YJP, et al. Activating Wnt/β-catenin signaling pathway for disease therapy: challenges and opportunities. Pharm Ther. 2019;196:79–90. 30468742 · DOI
  43. [46]Schunk S, Floege J, Fliser D, Speer. TJNrN. WNT-β-catenin signalling - a versatile player in kidney injury and repair. Nat Rev Nephrol. 2021;17:172–84. 32989282 · DOI
  44. [47]Ren Q, Chen J, Liu. YJFic, biology d. LRP5 and LRP6 in Wnt signaling: similarity and divergence. Front Cell Dev Biol. 2021;9:670960. 34026761 PMC8134664 · DOI

Cited by

Sorted by citations

Authors
Liang, Y., Mei, Q., He, E., Ballar, P., Wei, C., Wang, Y., Dong, Y., Zhou, J., Tao, X., Qu, W., Zhao, M., Chhetri, G., Wei, L., Shao, J., Shen, Y., Liu, J., Feng, L., & Shen, Y.
Affiliations
  • Anhui Medical University (CN)
  • Ege University (TR)
Corresponding author
  • Shen, Yujun
  • Shen, Yuxian
ORCID
Venue
Cell Death & Disease
Publisher
Springer Science and Business Media LLC
Published
2024-09-18
Volume
15
Issue
9
Pages
681-681
ISSN
2041-4889 (ISSN-L)
DOI
10.1038/s41419-024-07069-8
PMC
PMC11408687
OpenAlex
W4402620393
Cited by
9
References
3
Citations by year
2026: 4 · 2025: 5
FWCI
2.33
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Death and Disease (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
National Natural Science Foundation of China (U21A20345)
Topics
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
  • Health Sciences › Medicine › Surgery › Tissue Engineering and Regenerative Medicine
Keywords
MANF, liver regeneration, partial hepatectomy, Wnt/β-catenin signaling, LRP5, β-catenin stabilization, hepatocyte proliferation, hepatocyte-specific knockout, neurotrophic factors
MeSH terms
Animals, Hepatectomy, Humans, Liver, Liver Regeneration, Male, Mice, Inbred C57BL, Nerve Growth Factors, Mice, Knockout, Hepatocytes, Cell Proliferation, beta Catenin, Mice, Wnt Signaling Pathway, Low Density Lipoprotein Receptor-Related Protein-5

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