Senescent hepatic stellate cells promote liver regeneration through IL-6 and ligands of CXCR2
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 par...
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| Format: | Article |
| Language: | English |
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American Society for Clinical investigation
2022-07-01
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| Series: | JCI Insight |
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| Online Access: | https://doi.org/10.1172/jci.insight.158207 |
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| author | Naiyuan Cheng Ki-Hyun Kim Lester F. Lau |
| author_facet | Naiyuan Cheng Ki-Hyun Kim Lester F. Lau |
| author_sort | Naiyuan Cheng |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-11T12:08:04Z |
| format | Article |
| id | doaj.art-b23b4b715faa42219b444b5d54d8ce62 |
| institution | Directory Open Access Journal |
| issn | 2379-3708 |
| language | English |
| last_indexed | 2024-03-11T12:08:04Z |
| publishDate | 2022-07-01 |
| publisher | American Society for Clinical investigation |
| record_format | Article |
| series | JCI Insight |
| spelling | doaj.art-b23b4b715faa42219b444b5d54d8ce622023-11-07T16:24:21ZengAmerican Society for Clinical investigationJCI Insight2379-37082022-07-01714Senescent hepatic stellate cells promote liver regeneration through IL-6 and ligands of CXCR2Naiyuan ChengKi-Hyun KimLester F. LauSenescent 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.https://doi.org/10.1172/jci.insight.158207Hepatology |
| spellingShingle | Naiyuan Cheng Ki-Hyun Kim Lester F. Lau Senescent hepatic stellate cells promote liver regeneration through IL-6 and ligands of CXCR2 JCI Insight Hepatology |
| title | Senescent hepatic stellate cells promote liver regeneration through IL-6 and ligands of CXCR2 |
| title_full | Senescent hepatic stellate cells promote liver regeneration through IL-6 and ligands of CXCR2 |
| title_fullStr | Senescent hepatic stellate cells promote liver regeneration through IL-6 and ligands of CXCR2 |
| title_full_unstemmed | Senescent hepatic stellate cells promote liver regeneration through IL-6 and ligands of CXCR2 |
| title_short | Senescent hepatic stellate cells promote liver regeneration through IL-6 and ligands of CXCR2 |
| title_sort | senescent hepatic stellate cells promote liver regeneration through il 6 and ligands of cxcr2 |
| topic | Hepatology |
| url | https://doi.org/10.1172/jci.insight.158207 |
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