Survivin inhibition ameliorates liver fibrosis by inducing hepatic stellate cell senescence and depleting hepatic macrophage population

• Published in: Journal of cell communication and signaling 2024-03, Vol.18 (1), p.e12015-n/a
• Main Authors: Sharma, Sachin, Ghufran, Shaikh Maryam, Aftab, Mehreen, Bihari, Chhagan, Ghose, Sampa, Biswas, Subhrajit
• Format: Article
• Language: English
• Subjects: Apoptosis; Biopsy; Carbon tetrachloride; Cell activation; Cell cycle; Cirrhosis; Collagen; Cytokines; Cytoskeleton; Down-regulation; Fibrosis; Flow cytometry; Gene expression; hepatic stellate cells; Hepatocytes; inhibitor of apoptosis (IAP); Liver; Liver cirrhosis; liver fibrosis; macrophage polarization; macrophage subtype; Macrophages; p53 Protein; Population studies; Protein expression; Proteins; Senescence; Stellate cells; Survivin; survivin (BIRC5); Transforming growth factor-b; transforming growth factor‐β1 (TGF‐β1)
• ISSN: 1873-9601; 1873-961X
• DOI: 10.1002/ccs3.12015

Persistent activation of hepatic stellate cells (HSCs) in the injured liver leads to the progression of liver injury from fibrosis to detrimental cirrhosis. In a previous study, we have shown that survivin protein is upregulated during the early activation of HSCs, which triggers the onset of liver fibrosis. However, the therapeutic potential of targeting survivin in a fully established fibrotic liver needs to be investigated. In this study, we chemically induced hepatic fibrosis in mice using carbon tetrachloride (CCl4) for 6 weeks, which was followed by treatment with a survivin suppressant (YM155). We also evaluated survivin expression in fibrotic human liver tissues, primary HSCs, and HSC cell line by histological analysis. αSMA+ HSCs in human and mice fibrotic liver tissues showed enhanced survivin expression, whereas the hepatocytes and quiescent (qHSCs) displayed minimal expression. Alternatively, activated M2 macrophage subtype induced survivin expression in HSCs through the TGF‐β‐TGF‐β receptor‐I/II signaling. Inhibition of survivin in HSCs promoted cell cycle arrest and senescence, which eventually suppressed their activation. In vivo, YM155 treatment increased the expression of cell senescence makers in HSCs around fibrotic septa such as p53, p21, and β‐galactosidase. YM155 treatment in vivo also reduced the hepatic macrophage population and inflammatory cytokine expression in the liver. In conclusion, downregulation of survivin in the fibrotic liver decreases HSC activation by inducing cellular senescence and modulating macrophage cytokine expression that collectively ameliorates liver fibrosis. Survivin inhibition induces senescence in hepatic stellate cells and modulates macrophage plasticity. Schematics showing Survivin expression induces with activation of HSCs and M2‐macrophage promotes HSCs activation through TGF‐β1 mediated survivin expression. Inhibition of survivin decreased fibrogenic activity of activated HSCs and induces cellular senescence. Decreased proinflammtory macrophages in liver promotes switch of pro‐inflammatory fibrotic microenvironment toward pro‐resolving, collectively ameliorates liver fibrosis.