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
Published June 16, 2022
Citation Information: JCI Insight. 2022;7(14):e158207. https://doi.org/10.1172/jci.insight.158207.
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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 2

SASP of senescent HSCs induces hepatocyte proliferation.

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SASP of senescent HSCs induces hepatocyte proliferation. (A) Primary hep...
(A) Primary hepatocytes isolated from WT male livers were cocultured with HSCs, senescent HSCs (Sen-HSC), and Sen-HSC with anti–IL-6 antibody (5 μg/mL) and/or SB225002 (SB; 1 μM) as indicated for 24 hours, then stained with anti-Ki67 (red). Ki67+ cells were quantified by counting (n = 6). (B) Immunoblots of protein extracts from hepatocytes cocultured with HSCs or Sen-HSCs were probed with antibodies against phosphorylated (p-) YAP (Y357), YAP, p-STAT3 (Y705), STAT3, p-AKT (S473), AKT1, p-ERK1/2 (T202/Y204), ERK1/2, and β-actin. (C) Primary hepatocytes cocultured with HSCs, Sen-HSC, and Sen-HSC with Super-TDU (TDU; 50 nM), WP1066 (WP; 5 μM), and SCH772984 (SCH; 1 μM) as indicated for 24 hours and were stained with anti-Ki67 antibodies. Ki67+ cells were counted (n > 5). (D) Immunoblots of protein extracts from hepatocytes treated with vehicle (PBS) or IL-6 (10 ng/mL) for 24 hours were probed with indicated antibodies. (E) Hepatocytes treated with vehicle, IL-6, and IL-6 with SCH, TDU, and WP as indicated for 24 hours were stained with Ki67 antibodies and Ki67+ cells counted (n = 5). (F) Immunoblots of protein extracts from hepatocytes treated with vehicle or CXCL2 (10 ng/mL) for 24 hours were probed with indicated antibodies and antibodies against p-p38 (T180/Y182) and p38. (G) Hepatocytes were treated with vehicle, CXCL2, MK2206 (MK; 1 μM), SCH, or in combination as indicated for 24 hours and were stained with Ki67 antibodies. Ki67+ cells were counted (n = 5). (H) Immunoblots of protein extracts from vehicle-, IL-6-, CXCL2-, or IL-6+CXCL2-treated hepatocytes for 24 hours were probed with indicated antibodies. (I) Hepatocytes treated with PBS, IL-6, CXCL2, IL-6+CXCL2, or IL-6+CXCL2 together with SCH, TDU, and WP alone and in combination for 24 hours were stained with anti-Ki67 antibodies; Ki67+ cells were counted (n = 4). Scale bar: 50 μm. Data expressed as mean ± SD. *P < 0.033, **P < 0.002, ***P < 0.001, Student’s t test.