Senescent 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 more recent studies have uncovered their beneficial roles in certain contexts such as wound healing. We have found that hepatic stellate cells (HSCs) undergo senescence within two days after 2/3 partial hepatectomy (PHx) in young (2-3 month-old) mice, and elimination of these senescent cells by the senolytic drug ABT263 or using a genetic mouse model impairs liver regeneration. Senescent HSCs secrete IL-6 and CXCR2 ligands as part of the senescence-associated secretory phenotype (SASP), which induces multiple signaling pathways to stimulate liver regeneration. IL-6 activates STAT3, induces 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 restores liver regeneration in mice with senescent cell elimination, and the combination of both fully restores liver weight recovery. Furthermore, the matricellular protein CCN1/CYR61 is rapidly elevated in response to PHx and induces HSC senescence. Knock-in mice expressing a mutant CCN1 unable to bind integrin α6β1 are deficient in senescent cells and regenerative responses after PHx. Thus, HSC senescence, in part 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.