Academic Journal
Interleukin-4-mediated Pro-Regenerative Cellular Reprogramming in 3-dimensional Liver Culture.
| Title: | Interleukin-4-mediated Pro-Regenerative Cellular Reprogramming in 3-dimensional Liver Culture. |
|---|---|
| Authors: | 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. |
| Source: | Cellular and molecular gastroenterology and hepatology [Cell Mol Gastroenterol Hepatol] 2026; Vol. 20 (2), pp. 101626. Date of Electronic Publication: 2025 Sep 02. |
| Publication Type: | Journal Article |
| Language: | English |
| Journal Info: | 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]- |
| MeSH Terms: | 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 |
| Abstract: | 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 |
| Database: | MEDLINE |
| ISSN: | 2352-345X |
|---|---|
| DOI: | 10.1016/j.jcmgh.2025.101626 |