Targeting senescent cholangiocytes and activated fibroblasts with Bcl-xL inhibitors ameliorates fibrosis in Mdr2-/- mice

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 (ASF), which are drivers of fibrosis. The activated phenotype of ASF is characterized by an increased sensitivity to apoptotic stimuli. Here, we examined the mechanisms of apoptotic priming in ASF and explored a combined targeting strategy to deplete senescent cholangiocytes and ASF from fibrotic tissue to ameliorate liver fibrosis. Using a co-culture system, we determined that senescent cholangiocytes promoted quiescent mesenchymal cell activation in a PDGF-dependent manner. We also identified Bcl-xL as a key survival factor in PDGF-activated human and mouse fibroblasts. Bcl-xL was also upregulated in senescent cholangiocytes. In vitro, inhibition of Bcl-xL by the small molecule BH3 mimetic A-1331852 or Bcl-xL-specific siRNA 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 non-senescent cells. Treatment of Mdr2^-/- mice with A-1331852 resulted in an 80% decrease in senescent cholangiocytes, a reduction of fibrosis-inducing growth factors and cytokines, decrease of αSMA-positive ASF and finally in a significant reduction of liver fibrosis. Conclusions: Bcl-xL is a key survival factor in ASF 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 novel mechanism represents an attractive therapeutic strategy in biliary fibrosis. This article is protected by copyright. All rights reserved.

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