The age of bone marrow dictates the clonality of smooth muscle-derived cells in atherosclerotic plaques.
The age of bone marrow dictates the clonality of smooth muscle-derived cells in atherosclerotic plaques.
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DOI：
10.1038/s43587-022-00342-5
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发表时间：
2023-01
期刊：
影响因子：
--
通讯作者：
Greif, Daniel M. M.
中科院分区：
文献类型：
--
作者：
Kabir, Inamul;Zhang, Xinbo;Dave, Jui M. M.;Chakraborty, Raja;Qu, Rihao;Chandran, Rachana R. R.;Ntokou, Aglaia;Gallardo-Vara, Eunate;Aryal, Binod;Rotllan, Noemi;Garcia-Milian, Rolando;Hwa, John;Kluger, Yuval;Martin, Kathleen A. A.;Fernandez-Hernando, Carlos;Greif, Daniel M. M.
衰老（老龄化）是动脉粥样硬化的主要风险因素，而动脉粥样硬化是导致死亡的首要原因。罕见的平滑肌细胞（SMC）祖细胞会克隆性扩增，在动脉粥样硬化斑块细胞中所占比例可高达约70%；然而，年龄对SMC克隆性的影响尚不明确。我们的研究结果表明，衰老的骨髓（BM）来源的细胞非细胞自主性地诱导SMC多克隆性并使动脉粥样硬化恶化。事实上，在老年小鼠和人类的髓系细胞中，TET2水平降低，这会通过表观遗传方式使整合素β3沉默，从而导致肿瘤坏死因子[TNF]-α信号传导增加。TNFα通过SMC上的TNF受体1发出信号，促进增殖，并诱导多种SMC祖细胞募集和扩增进入动脉粥样硬化斑块。值得注意的是，在衰老的骨髓中过表达整合素β3可保持单个SMC祖细胞谱系的优势，并减轻斑块负荷。我们的研究结果揭示了衰老的巨噬细胞诱导SMC多克隆性和动脉粥样硬化形成的分子机制，并提出了新的治疗策略。
Aging is the predominant risk factor for atherosclerosis, the leading cause of death. Rare smooth muscle cell (SMC) progenitors clonally expand giving rise to up to ~70% of atherosclerotic plaque cells; however, the effect of age on SMC clonality is not known. Our results indicate that aged bone marrow (BM)-derived cells non-cell autonomously induce SMC polyclonality and worsen atherosclerosis. Indeed, in myeloid cells from aged mice and humans, TET2 levels are reduced which epigenetically silences integrin β3 resulting in increased tumor necrosis factor [TNF]-α signaling. TNFα signals through TNF receptor 1 on SMCs to promote proliferation and induces recruitment and expansion of multiple SMC progenitors into the atherosclerotic plaque. Notably, integrin β3 overexpression in aged BM preserves dominance of the lineage of a single SMC progenitor and attenuates plaque burden. Our results demonstrate a molecular mechanism of aged macrophage-induced SMC polyclonality and atherogenesis and suggest novel therapeutic strategies.
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