SIRT7 counteracts mesenchymal stem cell senescence via stabilizing heterochromatin

Human mesenchymal stem cell (hMSC) senescence contributes to the imbalance of tissue homeostasis during aging. However, the connection between Sirtuin 7 (SIRT7) and hMSC homeostasis remains unclear. Here, we discovered a pivotal role of SIRT7 in protecting hMSC from senescence. We detected a decreased expression of SIRT7 during hMSC aging, while overexpression of which reversed premature hMSC senescence phenotypes. Mechanistically, we proved SIRT7 as a novel interacting protein of the heterochromatin complex, whose deficiency disrupted heterochromatin organization, thereby contributing to the derepression of the retrotransposon Long Interspersed Element 1 (LINE1 or L1). SIRT7-deficient hMSCs accumulated LINE1 in cytoplasm stimulating innate immune response by activated the cyclic GMP-AMP synthase (cGAS) and its downstream signaling effector stimulator of interferon genes (STING). Moreover, reverse-transcriptase inhibitors (RTis), such as Lamivudine (3TC), attenuated these senescence phenotypes of SIRT7-deficient hMSCs. Taken together, our findings identify SIRT7-heterochromatin via LINE1-cGAS/STING influence innate immune response, which contributes more comprehensive understanding of the physiological and function of SIRT7 and help us to find novel targets for the treatment of aging and aging relative diseases.

人间充质干细胞（human mesenchymal stem cell, hMSC）衰老会在衰老进程中引发组织稳态失衡。然而，沉默信息调节因子7（Sirtuin 7, SIRT7）与hMSC稳态之间的关联仍未明确。本研究揭示了SIRT7在保护hMSC免受衰老影响中的关键作用。我们检测到hMSC衰老过程中SIRT7的表达水平显著下调，而过表达SIRT7可逆转hMSC的过早衰老表型。机制层面，我们证实SIRT7是异染色质复合物的新型互作蛋白，其缺失会破坏异染色质结构，进而导致逆转录转座子长散在核元件1（Long Interspersed Element 1, LINE1或L1）发生去抑制。SIRT7缺失的hMSC会在细胞质中积累LINE1，通过激活环状GMP-AMP合酶（cyclic GMP-AMP synthase, cGAS）及其下游信号效应分子干扰素基因刺激因子（stimulator of interferon genes, STING）触发先天免疫应答。此外，逆转录酶抑制剂（reverse-transcriptase inhibitors, RTis）如拉米夫定（Lamivudine, 3TC）可减轻SIRT7缺失型hMSC的上述衰老表型。综上，本研究揭示了SIRT7通过LINE1-cGAS/STING通路调控先天免疫应答的全新机制，为深入理解SIRT7的生理功能提供了更全面的视角，并为衰老及衰老相关疾病的治疗发掘了全新的潜在靶点。