JCI Insight. 2022 Jun 16;7(14):e158207. doi: 10.1172/jci.insight.158207.
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.
衰老细胞长期以来与衰老相关病理中的有害作用相关联，尽管最近的研究揭示了它们在某些情况下（如伤口愈合）的有益作用。我们发现，在年轻（2-3 个月大）小鼠的 2/3 部分肝切除术（PHx）后 2 天内，肝星状细胞（HSCs）发生衰老，并且通过使用衰老选择性药物 ABT263 或使用遗传小鼠模型消除这些衰老细胞会损害肝再生。衰老的 HSCs 会分泌 IL-6 和 CXCR2 配体，作为衰老相关分泌表型的一部分，这会诱导多种信号通路来刺激肝再生。IL-6 通过 SRC 家族激酶激活 STAT3，诱导 Yes 相关蛋白（YAP）的激活，并与 CXCL2 协同激活 ERK1/2 以刺激肝细胞增殖。在消除衰老细胞的小鼠中，给予 IL-6 或 CXCL2 中的任一种均可部分恢复肝再生，而联合使用则可完全恢复肝重恢复。此外，细胞外基质蛋白中央通讯网络因子 1（CCN1，以前称为 CYR61）在 PHx 后迅速升高，并诱导 HSC 衰老。表达不能与整合素 α6β1 结合的突变型 CCN1 的敲入小鼠在 PHx 后缺乏衰老细胞和肝再生。因此，HSC 衰老主要由 CCN1 诱导，是对 PHx 的一种程序性反应，并通过 IL-6 和 CXCR2 配体激活的信号通路在肝再生中发挥关键作用。
