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GVHD targets organoid-forming bile duct stem cells in a TGF-β-dependent manner.

Authors :
Hasegawa Y
Hashimoto D
Zhang Z
Miyajima T
Saito Y
Li W
Kikuchi R
Senjo H
Sekiguchi T
Tateno T
Chen X
Yokoyama E
Takahashi S
Ohigashi H
Ara T
Hayase E
Yokota I
Teshima T
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.)

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