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Interleukin-4-mediated Pro-Regenerative Cellular Reprogramming in 3-dimensional Liver Culture.

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Τίτλος: Interleukin-4-mediated Pro-Regenerative Cellular Reprogramming in 3-dimensional Liver Culture.
Συγγραφείς: Camat D; Ajmera Transplant Centre, University Health Network, Toronto, Ontario, Canada; Department of Immunology, University of Toronto, Toronto, Ontario, Canada. Electronic address: damra.camat@mail.utoronto.ca., Nakib D; Ajmera Transplant Centre, University Health Network, Toronto, Ontario, Canada; Department of Immunology, University of Toronto, Toronto, Ontario, Canada. Electronic address: diana.nakib@mail.utoronto.ca., Chung SW; Ajmera Transplant Centre, University Health Network, Toronto, Ontario, Canada; Department of Immunology, University of Toronto, Toronto, Ontario, Canada., Sekhon M; Ajmera Transplant Centre, University Health Network, Toronto, Ontario, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada., Liu Y; Ajmera Transplant Centre, University Health Network, Toronto, Ontario, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada., Lumanto P; Ajmera Transplant Centre, University Health Network, Toronto, Ontario, Canada., Hyduk SJ; Ajmera Transplant Centre, University Health Network, Toronto, Ontario, Canada., Perciani CT; Ajmera Transplant Centre, University Health Network, Toronto, Ontario, Canada; Department of Immunology, University of Toronto, Toronto, Ontario, Canada., Bartczak AM; Ajmera Transplant Centre, University Health Network, Toronto, Ontario, Canada; Department of Immunology, University of Toronto, Toronto, Ontario, Canada., Cheng ML; Ajmera Transplant Centre, University Health Network, Toronto, Ontario, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada., Pezzutti OI; Ajmera Transplant Centre, University Health Network, Toronto, Ontario, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada., Kaltagian M; Ajmera Transplant Centre, University Health Network, Toronto, Ontario, Canada., Altaf F; Ajmera Transplant Centre, University Health Network, Toronto, Ontario, Canada., Jafari SM; Ajmera Transplant Centre, University Health Network, Toronto, Ontario, Canada., Manuel J; Ajmera Transplant Centre, University Health Network, Toronto, Ontario, Canada., Thoeni C; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada., Ogawa S; Ajmera Transplant Centre, University Health Network, Toronto, Ontario, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada; McEwen Stem Cell Institute, University Health Network, Toronto, Ontario, Canada., Ma XZ; Ajmera Transplant Centre, University Health Network, Toronto, Ontario, Canada., McGilvray ID; Ajmera Transplant Centre, University Health Network, Toronto, Ontario, Canada. Electronic address: ian.mcgilvray@uhn.ca., MacParland SA; Ajmera Transplant Centre, University Health Network, Toronto, Ontario, Canada; Department of Immunology, University of Toronto, Toronto, Ontario, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada. Electronic address: sonya.macparland@uhn.ca.
Πηγή: Cellular and molecular gastroenterology and hepatology [Cell Mol Gastroenterol Hepatol] 2026; Vol. 20 (2), pp. 101626. Date of Electronic Publication: 2025 Sep 02.
Τύπος έκδοσης: Journal Article
Γλώσσα: English
Στοιχεία περιοδικού: Publisher: American Gastroenterological Association Country of Publication: United States NLM ID: 101648302 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2352-345X (Electronic) Linking ISSN: 2352345X NLM ISO Abbreviation: Cell Mol Gastroenterol Hepatol Subsets: MEDLINE
Imprint Name(s): Original Publication: Philadelphia, PA : American Gastroenterological Association, [2015]-
Ιατρικοί όροι (MeSH): Interleukin-4*/pharmacology , Interleukin-4*/metabolism , Liver Regeneration*/drug effects , Cellular Reprogramming*/drug effects , Liver*/cytology , Liver*/drug effects , Liver*/pathology , Liver*/metabolism, Hepatocytes/metabolism ; Hepatocytes/drug effects ; Cell Proliferation/drug effects ; Thioacetamide/toxicity ; Adenosine Triphosphate/metabolism ; Animals ; Mice ; Mice, Inbred C57BL ; Male
Περίληψη: Background & Aims: Interleukin-4 (IL-4) is a key contributor to liver regeneration, but its effects remain poorly understood due to a lack of models that preserve the complex cellular interactions of the liver. Here, we use murine precision-cut liver slices (PCLS), a 3-dimensional tissue culture system that maintains both parenchymal and non-parenchymal cells, to investigate the role of IL-4 in hepatic cell reprogramming. Through longitudinal single-cell transcriptomics and protein-level validation, we demonstrate the proregenerative potential of IL-4.
Methods: We performed longitudinal single nucleus RNA sequencing on PCLS from 8- to 10-week-old C57BL/6 mice over 5 days of culture in the presence and absence of IL-4. We assessed intracellular ATP output to demonstrate slice viability. We further performed orthogonal evaluations of the impact of IL-4 treatment via immunhistochemical staining to confirm proliferation and cell identity within the slices. We then assessed the impact of IL-4 exposure in slices generated from the diseased livers (hepatonecrosis/fibrosis) of mice treated with thioacetamide.
Results: IL-4 induced transcriptional changes, including increased expression of tissue repair-associated markers in myeloid cells, expansion of hepatocyte and cholangiocyte progenitors, and inhibition of fibroblast activation. Additionally, IL-4 treatment significantly increased Ki67 protein expression and intracellular ATP production, indicating enhanced proliferation and viability. Notably, IL-4 also improved cellular viability in slices from thioacetamide-treated mice, highlighting its potential proregenerative effects in injured liver tissue.
Conclusions: Our study highlights the potential of IL-4-driven modulation of the liver microenvironment, paving the way for cytokine-based therapeutic strategies to enhance immune-mediated hepatic regeneration.
(Copyright © 2026 The Authors. Published by Elsevier Inc. All rights reserved.)
Contributed Indexing: Keywords: Hepatocytes; Liver 3D Culture; Regeneration; Single-cell Transcriptomics
Substance Nomenclature: 207137-56-2 (Interleukin-4)
075T165X8M (Thioacetamide)
8L70Q75FXE (Adenosine Triphosphate)
Entry Date(s): Date Created: 20250904 Date Completed: 20260117 Latest Revision: 20260117
Update Code: 20260130
PubMed Central ID: PMC12634858
DOI: 10.1016/j.jcmgh.2025.101626
PMID: 40907663
Βάση Δεδομένων: MEDLINE
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  Data: Interleukin-4-mediated Pro-Regenerative Cellular Reprogramming in 3-dimensional Liver Culture.
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  Data: <searchLink fieldCode="AU" term="%22Camat+D%22">Camat D</searchLink>; Ajmera Transplant Centre, University Health Network, Toronto, Ontario, Canada; Department of Immunology, University of Toronto, Toronto, Ontario, Canada. Electronic address: damra.camat@mail.utoronto.ca.<br /><searchLink fieldCode="AU" term="%22Nakib+D%22">Nakib D</searchLink>; Ajmera Transplant Centre, University Health Network, Toronto, Ontario, Canada; Department of Immunology, University of Toronto, Toronto, Ontario, Canada. Electronic address: diana.nakib@mail.utoronto.ca.<br /><searchLink fieldCode="AU" term="%22Chung+SW%22">Chung SW</searchLink>; Ajmera Transplant Centre, University Health Network, Toronto, Ontario, Canada; Department of Immunology, University of Toronto, Toronto, Ontario, Canada.<br /><searchLink fieldCode="AU" term="%22Sekhon+M%22">Sekhon M</searchLink>; Ajmera Transplant Centre, University Health Network, Toronto, Ontario, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.<br /><searchLink fieldCode="AU" term="%22Liu+Y%22">Liu Y</searchLink>; Ajmera Transplant Centre, University Health Network, Toronto, Ontario, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.<br /><searchLink fieldCode="AU" term="%22Lumanto+P%22">Lumanto P</searchLink>; Ajmera Transplant Centre, University Health Network, Toronto, Ontario, Canada.<br /><searchLink fieldCode="AU" term="%22Hyduk+SJ%22">Hyduk SJ</searchLink>; Ajmera Transplant Centre, University Health Network, Toronto, Ontario, Canada.<br /><searchLink fieldCode="AU" term="%22Perciani+CT%22">Perciani CT</searchLink>; Ajmera Transplant Centre, University Health Network, Toronto, Ontario, Canada; Department of Immunology, University of Toronto, Toronto, Ontario, Canada.<br /><searchLink fieldCode="AU" term="%22Bartczak+AM%22">Bartczak AM</searchLink>; Ajmera Transplant Centre, University Health Network, Toronto, Ontario, Canada; Department of Immunology, University of Toronto, Toronto, Ontario, Canada.<br /><searchLink fieldCode="AU" term="%22Cheng+ML%22">Cheng ML</searchLink>; Ajmera Transplant Centre, University Health Network, Toronto, Ontario, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.<br /><searchLink fieldCode="AU" term="%22Pezzutti+OI%22">Pezzutti OI</searchLink>; Ajmera Transplant Centre, University Health Network, Toronto, Ontario, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.<br /><searchLink fieldCode="AU" term="%22Kaltagian+M%22">Kaltagian M</searchLink>; Ajmera Transplant Centre, University Health Network, Toronto, Ontario, Canada.<br /><searchLink fieldCode="AU" term="%22Altaf+F%22">Altaf F</searchLink>; Ajmera Transplant Centre, University Health Network, Toronto, Ontario, Canada.<br /><searchLink fieldCode="AU" term="%22Jafari+SM%22">Jafari SM</searchLink>; Ajmera Transplant Centre, University Health Network, Toronto, Ontario, Canada.<br /><searchLink fieldCode="AU" term="%22Manuel+J%22">Manuel J</searchLink>; Ajmera Transplant Centre, University Health Network, Toronto, Ontario, Canada.<br /><searchLink fieldCode="AU" term="%22Thoeni+C%22">Thoeni C</searchLink>; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.<br /><searchLink fieldCode="AU" term="%22Ogawa+S%22">Ogawa S</searchLink>; Ajmera Transplant Centre, University Health Network, Toronto, Ontario, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada; McEwen Stem Cell Institute, University Health Network, Toronto, Ontario, Canada.<br /><searchLink fieldCode="AU" term="%22Ma+XZ%22">Ma XZ</searchLink>; Ajmera Transplant Centre, University Health Network, Toronto, Ontario, Canada.<br /><searchLink fieldCode="AU" term="%22McGilvray+ID%22">McGilvray ID</searchLink>; Ajmera Transplant Centre, University Health Network, Toronto, Ontario, Canada. Electronic address: ian.mcgilvray@uhn.ca.<br /><searchLink fieldCode="AU" term="%22MacParland+SA%22">MacParland SA</searchLink>; Ajmera Transplant Centre, University Health Network, Toronto, Ontario, Canada; Department of Immunology, University of Toronto, Toronto, Ontario, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada. Electronic address: sonya.macparland@uhn.ca.
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  Data: Background & Aims: Interleukin-4 (IL-4) is a key contributor to liver regeneration, but its effects remain poorly understood due to a lack of models that preserve the complex cellular interactions of the liver. Here, we use murine precision-cut liver slices (PCLS), a 3-dimensional tissue culture system that maintains both parenchymal and non-parenchymal cells, to investigate the role of IL-4 in hepatic cell reprogramming. Through longitudinal single-cell transcriptomics and protein-level validation, we demonstrate the proregenerative potential of IL-4.<br />Methods: We performed longitudinal single nucleus RNA sequencing on PCLS from 8- to 10-week-old C57BL/6 mice over 5 days of culture in the presence and absence of IL-4. We assessed intracellular ATP output to demonstrate slice viability. We further performed orthogonal evaluations of the impact of IL-4 treatment via immunhistochemical staining to confirm proliferation and cell identity within the slices. We then assessed the impact of IL-4 exposure in slices generated from the diseased livers (hepatonecrosis/fibrosis) of mice treated with thioacetamide.<br />Results: IL-4 induced transcriptional changes, including increased expression of tissue repair-associated markers in myeloid cells, expansion of hepatocyte and cholangiocyte progenitors, and inhibition of fibroblast activation. Additionally, IL-4 treatment significantly increased Ki67 protein expression and intracellular ATP production, indicating enhanced proliferation and viability. Notably, IL-4 also improved cellular viability in slices from thioacetamide-treated mice, highlighting its potential proregenerative effects in injured liver tissue.<br />Conclusions: Our study highlights the potential of IL-4-driven modulation of the liver microenvironment, paving the way for cytokine-based therapeutic strategies to enhance immune-mediated hepatic regeneration.<br /> (Copyright © 2026 The Authors. Published by Elsevier Inc. All rights reserved.)
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