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Senescence in hepatic stellate cells as a mechanism of liver fibrosis reversal: a putative synergy between retinoic acid and PPAR-gamma signalings

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Abstract

Hepatic stellate cells (HSCs), also known as perisinusoidal cells, are pericytes found in the perisinusoidal space of the liver. HSCs are the major cell type involved in liver fibrosis, which is the formation of scar tissue in response to liver damage. When the liver is damaged, stellate cells can shift into an activated state, characterized by proliferation, contractility and chemotaxis. The activated HSCs secrete collagen scar tissue, which can lead to cirrhosis. Recent studies have shown that in vivo activation of HSCs by fibrogenic agents can eventually lead to senescence of these cells, which would contribute to reversal of fibrosis although it may also favor the insurgence of liver cancer. HSCs in their non-active form store huge amounts of retinoic acid derivatives in lipid droplets, which are progressively depleted upon cell activation in injured liver. Retinoic acid is a metabolite of vitamin A (retinol) that mediates the functions of vitamin A, generally required for growth and development. The precise function of retinoic acid and its alterations in HSCs has yet to be elucidated, and nonetheless in various cell types retinoic acid and its receptors (RAR and RXR) are known to act synergistically with peroxisome proliferator-activated receptor gamma (PPAR-gamma) signaling through the activity of transcriptional heterodimers. Here, we review the recent advancements in the understanding of how retinoic acid signaling modulates the fibrogenic potential of HSCs and proposes a synergistic combined action with PPAR-gamma in the reversal of liver fibrosis.

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Acknowledgments

VP and MV are supported by Italian Ministry of Health, Bando GR-2010-2311017. This study was supported by a grant from the Italian Ministry of Health through Division of Gastroenterology (RC1503GA39 to VP) IRCCS “Casa Sollievo della Sofferenza,” Hospital and by the “5 × 1000” voluntary contributions. MV is supported by a My First Grant-AIRC Grant no. 13419 Associazione Italiana Ricerca sul Cancro (AIRC) and by UCL.

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  1. Gastroenterology Unit, IRCCS “Casa Sollievo della Sofferenza” Hospital, Viale dei Cappuccini, 1, San Giovanni Rotondo, FG, Italy

    Concetta Panebianco & Valerio Pazienza

  2. Institute for Liver and Digestive Health, Royal Free Hospital, University College London (UCL), London, UK

    Jude A. Oben & Manlio Vinciguerra

  3. Center for Translational Medicine (CTM), International Clinical Research Center (ICRC), St. Anne’s University Hospital, Brno, Czech Republic

    Manlio Vinciguerra

  4. Centro Studi Fegato (CSF)-Liver Research Center, Fondazione Italiana Fegato, Trieste, Italy

    Manlio Vinciguerra

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  1. Concetta Panebianco
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  2. Jude A. Oben
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  4. Valerio Pazienza
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Correspondence to Valerio Pazienza.

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Panebianco, C., Oben, J.A., Vinciguerra, M. et al. Senescence in hepatic stellate cells as a mechanism of liver fibrosis reversal: a putative synergy between retinoic acid and PPAR-gamma signalings. Clin Exp Med 17, 269–280 (2017). https://doi.org/10.1007/s10238-016-0438-x

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