Targeting senescent cholangiocytes and activated fibroblasts with B-cell lymphoma-extra large inhibitors ameliorates fibrosis in multidrug resistance 2 gene knockout (Mdr2−/−) mice

Anja Moncsek, Mohammed S. Al-Suraih, Christy E. Trussoni, Steven P. O'Hara, Patrick L. Splinter, Camille Zuber, Eleonora Patsenker, Piero V. Valli, Christian D. Fingas, Achim Weber, Yi Zhu, Tamar Tchkonia, James L Kirkland, Gregory James Gores, Beat Müllhaupt, Nicholas F La Russo, Joachim C. Mertens

Research output: Contribution to journalArticle

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Abstract

Cholangiocyte senescence has been linked to primary sclerosing cholangitis (PSC). Persistent secretion of growth factors by senescent cholangiocytes leads to the activation of stromal fibroblasts (ASFs), which are drivers of fibrosis. The activated phenotype of ASFs is characterized by an increased sensitivity to apoptotic stimuli. Here, we examined the mechanisms of apoptotic priming in ASFs and explored a combined targeting strategy to deplete senescent cholangiocytes and ASFs from fibrotic tissue to ameliorate liver fibrosis. Using a coculture system, we determined that senescent cholangiocytes promoted quiescent mesenchymal cell activation in a platelet-derived growth factor (PDGF)-dependent manner. We also identified B-cell lymphoma-extra large (Bcl-xL) as a key survival factor in PDGF-activated human and mouse fibroblasts. Bcl-xL was also up-regulated in senescent cholangiocytes. In vitro, inhibition of Bcl-xL by the small molecule Bcl-2 homology domain 3 mimetic, A-1331852, or Bcl-xL-specific small interfering RNA induced apoptosis in PDGF-activated fibroblasts, but not in quiescent fibroblasts. Likewise, inhibition of Bcl-xL reduced the survival and increased apoptosis of senescent cholangiocytes, compared to nonsenescent cells. Treatment of multidrug resistance 2 gene knockout (Mdr2−/−) mice with A-1331852 resulted in an 80% decrease in senescent cholangiocytes, a reduction of fibrosis-inducing growth factors and cytokines, decrease of α-smooth muscle actin–positive ASFs, and finally in a significant reduction of liver fibrosis. Conclusion: Bcl-xL is a key survival factor in ASFs as well as in senescent cholangiocytes. Treatment with the Bcl-xL-specific inhibitor, A-1331852, reduces liver fibrosis, possibly by a dual effect on activated fibroblasts and senescent cholangiocytes. This mechanism represents an attractive therapeutic strategy in biliary fibrosis. (Hepatology 2018;67:247-259).

Original languageEnglish (US)
Pages (from-to)247-259
Number of pages13
JournalHepatology
Volume67
Issue number1
DOIs
StatePublished - Jan 1 2018

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MDR Genes
Gene Knockout Techniques
B-Cell Lymphoma
Knockout Mice
Fibrosis
Fibroblasts
Platelet-Derived Growth Factor
Liver Cirrhosis
Survival
Intercellular Signaling Peptides and Proteins
Apoptosis
Sclerosing Cholangitis
Gastroenterology
Coculture Techniques
Small Interfering RNA
Smooth Muscle
Cytokines

ASJC Scopus subject areas

  • Hepatology

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Targeting senescent cholangiocytes and activated fibroblasts with B-cell lymphoma-extra large inhibitors ameliorates fibrosis in multidrug resistance 2 gene knockout (Mdr2−/−) mice. / Moncsek, Anja; Al-Suraih, Mohammed S.; Trussoni, Christy E.; O'Hara, Steven P.; Splinter, Patrick L.; Zuber, Camille; Patsenker, Eleonora; Valli, Piero V.; Fingas, Christian D.; Weber, Achim; Zhu, Yi; Tchkonia, Tamar; Kirkland, James L; Gores, Gregory James; Müllhaupt, Beat; La Russo, Nicholas F; Mertens, Joachim C.

In: Hepatology, Vol. 67, No. 1, 01.01.2018, p. 247-259.

Research output: Contribution to journalArticle

Moncsek, A, Al-Suraih, MS, Trussoni, CE, O'Hara, SP, Splinter, PL, Zuber, C, Patsenker, E, Valli, PV, Fingas, CD, Weber, A, Zhu, Y, Tchkonia, T, Kirkland, JL, Gores, GJ, Müllhaupt, B, La Russo, NF & Mertens, JC 2018, 'Targeting senescent cholangiocytes and activated fibroblasts with B-cell lymphoma-extra large inhibitors ameliorates fibrosis in multidrug resistance 2 gene knockout (Mdr2−/−) mice', Hepatology, vol. 67, no. 1, pp. 247-259. https://doi.org/10.1002/hep.29464
Moncsek, Anja ; Al-Suraih, Mohammed S. ; Trussoni, Christy E. ; O'Hara, Steven P. ; Splinter, Patrick L. ; Zuber, Camille ; Patsenker, Eleonora ; Valli, Piero V. ; Fingas, Christian D. ; Weber, Achim ; Zhu, Yi ; Tchkonia, Tamar ; Kirkland, James L ; Gores, Gregory James ; Müllhaupt, Beat ; La Russo, Nicholas F ; Mertens, Joachim C. / Targeting senescent cholangiocytes and activated fibroblasts with B-cell lymphoma-extra large inhibitors ameliorates fibrosis in multidrug resistance 2 gene knockout (Mdr2−/−) mice. In: Hepatology. 2018 ; Vol. 67, No. 1. pp. 247-259.
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abstract = "Cholangiocyte senescence has been linked to primary sclerosing cholangitis (PSC). Persistent secretion of growth factors by senescent cholangiocytes leads to the activation of stromal fibroblasts (ASFs), which are drivers of fibrosis. The activated phenotype of ASFs is characterized by an increased sensitivity to apoptotic stimuli. Here, we examined the mechanisms of apoptotic priming in ASFs and explored a combined targeting strategy to deplete senescent cholangiocytes and ASFs from fibrotic tissue to ameliorate liver fibrosis. Using a coculture system, we determined that senescent cholangiocytes promoted quiescent mesenchymal cell activation in a platelet-derived growth factor (PDGF)-dependent manner. We also identified B-cell lymphoma-extra large (Bcl-xL) as a key survival factor in PDGF-activated human and mouse fibroblasts. Bcl-xL was also up-regulated in senescent cholangiocytes. In vitro, inhibition of Bcl-xL by the small molecule Bcl-2 homology domain 3 mimetic, A-1331852, or Bcl-xL-specific small interfering RNA induced apoptosis in PDGF-activated fibroblasts, but not in quiescent fibroblasts. Likewise, inhibition of Bcl-xL reduced the survival and increased apoptosis of senescent cholangiocytes, compared to nonsenescent cells. Treatment of multidrug resistance 2 gene knockout (Mdr2−/−) mice with A-1331852 resulted in an 80{\%} decrease in senescent cholangiocytes, a reduction of fibrosis-inducing growth factors and cytokines, decrease of α-smooth muscle actin–positive ASFs, and finally in a significant reduction of liver fibrosis. Conclusion: Bcl-xL is a key survival factor in ASFs as well as in senescent cholangiocytes. Treatment with the Bcl-xL-specific inhibitor, A-1331852, reduces liver fibrosis, possibly by a dual effect on activated fibroblasts and senescent cholangiocytes. This mechanism represents an attractive therapeutic strategy in biliary fibrosis. (Hepatology 2018;67:247-259).",
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AU - Al-Suraih, Mohammed S.

AU - Trussoni, Christy E.

AU - O'Hara, Steven P.

AU - Splinter, Patrick L.

AU - Zuber, Camille

AU - Patsenker, Eleonora

AU - Valli, Piero V.

AU - Fingas, Christian D.

AU - Weber, Achim

AU - Zhu, Yi

AU - Tchkonia, Tamar

AU - Kirkland, James L

AU - Gores, Gregory James

AU - Müllhaupt, Beat

AU - La Russo, Nicholas F

AU - Mertens, Joachim C.

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