Targeted Apoptosis of Ductular Reactive Cells Reduces Hepatic Fibrosis in a Mouse Model of Cholestasis.
In: Hepatology (Baltimore, Md.), Jg. 72 (2020-09-01), Heft 3, S. 1013-1028
Online
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Zugriff:
Background and Aims: In cholestatic liver diseases, ductular reactive (DR) cells extend into the hepatic parenchyma and promote inflammation and fibrosis. We have previously observed that multidrug-resistant 2 (Mdr2 -/- ) double knockout (DKO) mice lacking tumor necrosis factor-related apoptosis-inducing ligand receptor (Tr -/- ) display a more extensive ductular reaction and hepatic fibrosis compared to Mdr2 -/- mice. This observation suggests that the magnitude of the DR-cell population may be regulated by apoptosis.
Approach and Results: To examine this concept, we cultured epithelial cell adhesion molecule-positive reactive cholangioids (ERCs) obtained from wild-type (WT), Tr -/- , Mdr2 -/- and DKO mice. Single-cell transcriptomics and immunostaining of both WT and DKO ERCs confirmed their DR-cell phenotype. Moreover, DKO ERCs displayed a unique translational cluster with expression of chemokines, indicating a reactive state. Incubation with the myeloid cell leukemia 1 (MCL1) inhibitor S63845, a proapoptotic BH3-mimetic therapy, significantly decreased DKO and Mdr2 -/- ERC viability compared to WT. Intravenous administration of S63845 significantly reduced the DR-cell population and markers of inflammation and liver fibrosis in Mdr2 -/- and DKO mice. Furthermore, DKO mice treated with S63845 displayed a significant decrease in hepatic B lymphocytes compared to untreated mice as assessed by high-definition mass cytometry by time-of-flight. Coculture of bone marrow-derived macrophages with ERCs from DKO mouse livers up-regulated expression of the B cell-directed chemokine (C-C motif) ligand 5. Finally, DR cells were noted to be primed for apoptosis with Bcl-2 homologous antagonist/killer activation in vitro and in vivo in primary sclerosing cholangitis liver specimens.
Conclusions: DR cells appear to play a key role in recruiting immune cells to the liver to actively create an inflammatory and profibrogenic microenvironment. Pharmacologic targeting of MCL1 in a mouse model of chronic cholestasis reduces DR-cell and B-cell populations and hepatic fibrosis.
(© 2020 by the American Association for the Study of Liver Diseases.)
| Titel: |
Targeted Apoptosis of Ductular Reactive Cells Reduces Hepatic Fibrosis in a Mouse Model of Cholestasis.
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| Autor/in / Beteiligte Person: | Azad, AI ; Krishnan, A ; Troop, L ; Li, Y ; Katsumi, T ; Pavelko, K ; Kostallari, E ; Guicciardi, ME ; Gores, GJ |
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| Zeitschrift: | Hepatology (Baltimore, Md.), Jg. 72 (2020-09-01), Heft 3, S. 1013-1028 |
| Veröffentlichung: | 2023- : [Philadelphia] : Wolters Kluwer Health, Inc. ; <i>Original Publication</i>: Baltimore, MD : Williams & Wilkins, [c1981]-, 2020 |
| Medientyp: | academicJournal |
| ISSN: | 1527-3350 (electronic) |
| DOI: | 10.1002/hep.31211 |
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