Senescent hepatic stellate cells promote liver regeneration through IL-6 and ligands of CXCR2
Naiyuan Cheng, Ki-Hyun Kim, Lester F. Lau
Naiyuan Cheng, Ki-Hyun Kim, Lester F. Lau
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Research Article Hepatology

Senescent hepatic stellate cells promote liver regeneration through IL-6 and ligands of CXCR2

Abstract

Senescent cells have long been associated with deleterious effects in aging-related pathologies, although recent studies have uncovered their beneficial roles in certain contexts, such as wound healing. We have found that hepatic stellate cells (HSCs) underwent senescence within 2 days after 2/3 partial hepatectomy (PHx) in young (2–3 months old) mice, and the elimination of these senescent cells by using the senolytic drug ABT263 or by using a genetic mouse model impaired liver regeneration. Senescent HSCs secrete IL-6 and CXCR2 ligands as part of the senescence-associated secretory phenotype, which induces multiple signaling pathways to stimulate liver regeneration. IL-6 activates STAT3, induces Yes-associated protein (YAP) activation through SRC family kinases, and synergizes with CXCL2 to activate ERK1/2 to stimulate hepatocyte proliferation. The administration of either IL-6 or CXCL2 partially restored liver regeneration in mice with senescent cell elimination, and the combination of both fully restored liver weight recovery. Furthermore, the matricellular protein central communication network factor 1 (CCN1, previously called CYR61) was rapidly elevated in response to PHx and induced HSC senescence. Knockin mice expressing a mutant CCN1 unable to bind integrin α6β1 were deficient in senescent cells and liver regeneration after PHx. Thus, HSC senescence, largely induced by CCN1, is a programmed response to PHx and plays a critical role in liver regeneration through signaling pathways activated by IL-6 and ligands of CXCR2.

Authors

Naiyuan Cheng, Ki-Hyun Kim, Lester F. Lau

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Figure 6

CCN1 induces senescence in HSCs and contributes to liver regeneration.

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CCN1 induces senescence in HSCs and contributes to liver regeneration. (...
(A) Liver protein extracts from WT mice at the indicated times (hours) after PHx were immunoblotted and probed with anti-CCN1 and anti–β-actin antibodies. (B) The remnant liver recovery rates were assessed for WT and Ccn1DM/DM (DM) mice at indicated times after PHx (day 0, n = 3; day 2 and 7, n = 4; day 4, n = 8). (C) SA-β-Gal staining of frozen liver sections from WT and DM mice 2 days after PHx. Liver sections were also double immunostained for p16 (red) and desmin (green) and counterstained with DAPI (blue). Yellow arrowheads are pointing to p16+ cells. The number of SA-β-Gal+ cells (n = 6) per microscopic field and percentage of p16+ cells (n = 4) were quantified by cell counting. (D) Expression of genes related to cell cycle arrest and the SASP in WT and Ccn1DM/DM mouse livers 2 days after PHx was measured by qRT-PCR (n = 3). (E) Schematic diagram illustrating proposed SASP signaling pathways contributing to liver regeneration. The matricellular protein CCN1 is released upon injury and induces cellular senescence in HSCs through integrin α6β1 within 2 days after PHx. Senescent cells secrete proteins of the SASP critical to liver regeneration, including IL-6, which engages IL-6R and gp130 to induce hepatocyte proliferation through activation of STAT3 and SFK-mediated phosphorylation of YAP. IL-6 also synergizes with CXCR2 ligands secreted as part of the SASP, including CXCL1, CXCL2, and CXCL5, to induce a robust activation of ERK1/2 that promotes hepatocyte proliferation. Scale bars: 50 μm. Data expressed as mean ± SD. *P < 0.033, **P < 0.002, ***P < 0.001 assessed by Student’s t test (C and D) or 2-way ANOVA (B).