Senescence atlas reveals an aged-like inflamed niche that blunts muscle regeneration.
Senescence atlas reveals an aged-like inflamed niche that blunts muscle regeneration.
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DOI：
10.1038/s41586-022-05535-x
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发表时间：
2023-01
期刊：
影响因子：
64.8
通讯作者：
Munoz-Canoves, Pura
中科院分区：
文献类型：
--
作者：
Moiseeva, Victoria;Cisneros, Andres;Sica, Valentina;Deryagin, Oleg;Lai, Yiwei;Jung, Sascha;Andres, Eva;An, Juan;Segales, Jessica;Ortet, Laura;Lukesova, Vera;Volpe, Giacomo;Benguria, Alberto;Dopazo, Ana;Aznar-Benitah, Salvador;Urano, Yasuteru;del Sol, Antonio;Esteban, Miguel A.;Ohkawa, Yasuyuki;Serrano, Antonio L.;Perdiguero, Eusebio;Munoz-Canoves, Pura
组织再生需要常驻干细胞和局部小生境细胞之间的协调。在这里，我们确定衰老细胞是骨骼肌再生生态位的组成部分，在生命的各个阶段抑制再生。通过结合单细胞转录组学和衰老细胞富集分选方案，克服了衰老细胞稀缺的技术限制。我们从年轻和老年小鼠受损的肌肉中鉴定并分离出不同的衰老细胞类型。更深入的转录组，染色质和途径分析揭示了细胞身份特征的保守性以及跨细胞类型，再生时间和衰老的两个普遍衰老标志（炎症和纤维化）。衰老细胞创造了一个类似衰老的发炎小生境，反映了与衰老相关的炎症（炎症），并阻止了干细胞的增殖和再生。减少衰老细胞的负担，或通过CD36中和减少其炎症分泌组，加速年轻和老年小鼠的再生。相比之下，衰老细胞的移植延迟了再生。我们的研究结果提供了一种分离体内衰老细胞的技术，定义了肌肉的衰老蓝图，并揭示了可以克服的再生壁龛中衰老细胞和干细胞之间的非生产性功能相互作用。由于衰老细胞也在人体肌肉中积累，我们的发现为改善整个生命过程中的肌肉修复开辟了潜在的途径。体内衰老细胞的寿命绘图显示它们是异质的。衰老细胞产生了一个类似衰老的发炎小生境，反映了与衰老相关的炎症，并阻止了干细胞增殖和组织再生。
Tissue regeneration requires coordination between resident stem cells and local niche cells. Here we identify that senescent cells are integral components of the skeletal muscle regenerative niche that repress regeneration at all stages of life. The technical limitation of senescent-cell scarcity was overcome by combining single-cell transcriptomics and a senescent-cell enrichment sorting protocol. We identified and isolated different senescent cell types from damaged muscles of young and old mice. Deeper transcriptome, chromatin and pathway analyses revealed conservation of cell identity traits as well as two universal senescence hallmarks (inflammation and fibrosis) across cell type, regeneration time and ageing. Senescent cells create an aged-like inflamed niche that mirrors inflammation associated with ageing (inflammageing) and arrests stem cell proliferation and regeneration. Reducing the burden of senescent cells, or reducing their inflammatory secretome through CD36 neutralization, accelerates regeneration in young and old mice. By contrast, transplantation of senescent cells delays regeneration. Our results provide a technique for isolating in vivo senescent cells, define a senescence blueprint for muscle, and uncover unproductive functional interactions between senescent cells and stem cells in regenerative niches that can be overcome. As senescent cells also accumulate in human muscles, our findings open potential paths for improving muscle repair throughout life. A lifetime cartography of in vivo senescent cells shows that they are heterogeneous. Senescent cells create an aged-like inflamed niche that mirrors inflammation associated with ageing and arrests stem cell proliferation and tissue regeneration.
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影响因子：
7.7
作者：
Chan M;Yuan H;Soifer I;Maile TM;Wang RY;Ireland A;O'Brien JJ;Goudeau J;Chan LJG;Vijay T;Freund A;Kenyon C;Bennett BD;McAllister FE;Kelley DR;Roy M;Cohen RL;Levinson AD;Botstein D;Hendrickson DG
通讯作者：
Hendrickson DG
影响因子：
13.6
作者：
Freund A;Orjalo AV;Desprez PY;Campisi J
通讯作者：
Campisi J
影响因子：
64.8
作者：
Baker DJ;Childs BG;Durik M;Wijers ME;Sieben CJ;Zhong J;Saltness RA;Jeganathan KB;Verzosa GC;Pezeshki A;Khazaie K;Miller JD;van Deursen JM
通讯作者：
van Deursen JM
影响因子：
14.9
作者：
Frankish A;Diekhans M;Ferreira AM;Johnson R;Jungreis I;Loveland J;Mudge JM;Sisu C;Wright J;Armstrong J;Barnes I;Berry A;Bignell A;Carbonell Sala S;Chrast J;Cunningham F;Di Domenico T;Donaldson S;Fiddes IT;García Girón C;Gonzalez JM;Grego T;Hardy M;Hourlier T;Hunt T;Izuogu OG;Lagarde J;Martin FJ;Martínez L;Mohanan S;Muir P;Navarro FCP;Parker A;Pei B;Pozo F;Ruffier M;Schmitt BM;Stapleton E;Suner MM;Sycheva I;Uszczynska-Ratajczak B;Xu J;Yates A;Zerbino D;Zhang Y;Aken B;Choudhary JS;Gerstein M;Guigó R;Hubbard TJP;Kellis M;Paten B;Reymond A;Tress ML;Flicek P
通讯作者：
Flicek P
影响因子：
14.9
作者：
Cunningham F;Amode MR;Barrell D;Beal K;Billis K;Brent S;Carvalho-Silva D;Clapham P;Coates G;Fitzgerald S;Gil L;Girón CG;Gordon L;Hourlier T;Hunt SE;Janacek SH;Johnson N;Juettemann T;Kähäri AK;Keenan S;Martin FJ;Maurel T;McLaren W;Murphy DN;Nag R;Overduin B;Parker A;Patricio M;Perry E;Pignatelli M;Riat HS;Sheppard D;Taylor K;Thormann A;Vullo A;Wilder SP;Zadissa A;Aken BL;Birney E;Harrow J;Kinsella R;Muffato M;Ruffier M;Searle SM;Spudich G;Trevanion SJ;Yates A;Zerbino DR;Flicek P
通讯作者：
Flicek P