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GVHD targets organoid-forming bile duct stem cells in a TGF-β-dependent manner.
- Source :
-
Blood [Blood] 2024 Aug 22; Vol. 144 (8), pp. 904-913. - Publication Year :
- 2024
-
Abstract
- Abstract: Graft-versus-host disease (GVHD) is a major life-threatening complication that occurs after allogeneic hematopoietic cell transplantation (HCT). Although adult tissue stem cells have been identified as targets of GVHD in the skin and gut, their role in hepatic GVHD is yet to be clarified. In the current study, we explored the fate of bile duct stem cells (BDSCs), capable of generating liver organoids in vitro, during hepatic GVHD after allogeneic HCT. We observed a significant expansion of biliary epithelial cells (BECs) on injury early after allogeneic HCT. Organoid-forming efficiency from the bile duct was also significantly increased early after allogeneic HCT. Subsequently, the organoid-forming efficiency from bile ducts was markedly decreased in association with the reduction of BECs and the elevation of plasma concentrations of bilirubin, suggesting that GVHD targets BDSCs and impairs the resilience of BECs. The growth of liver organoids in the presence of liver-infiltrating mononuclear cells from allogeneic recipients, but not from syngeneic recipients, was significantly reduced in a transforming growth factor-β (TGF-β)-dependent manner. Administration of SB-431542, an inhibitor of TGF-β signaling, from day 14 to day 28, protected organoid-forming BDSCs against GVHD and mitigated biliary dysfunction after allogeneic HCT, suggesting that BDSCs are a promising therapeutic target for hepatic GVHD.<br /> (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)
- Subjects :
- Animals
Mice
Stem Cells metabolism
Stem Cells cytology
Mice, Inbred C57BL
Male
Liver pathology
Liver metabolism
Dioxoles pharmacology
Benzamides pharmacology
Epithelial Cells metabolism
Transplantation, Homologous
Organoids
Graft vs Host Disease pathology
Graft vs Host Disease immunology
Graft vs Host Disease metabolism
Graft vs Host Disease prevention & control
Bile Ducts pathology
Transforming Growth Factor beta metabolism
Hematopoietic Stem Cell Transplantation
Subjects
Details
- Language :
- English
- ISSN :
- 1528-0020
- Volume :
- 144
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Blood
- Publication Type :
- Academic Journal
- Accession number :
- 38905638
- Full Text :
- https://doi.org/10.1182/blood.2023023060