Aged skeletal stem cells generate an inflammatory degenerative niche.
Aged skeletal stem cells generate an inflammatory degenerative niche.
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老化的骨骼干细胞产生炎性退行性小生境。
DOI：
10.1038/s41586-021-03795-7
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发表时间：
2021-09
期刊：
影响因子：
64.8
通讯作者：
Chan CKF
中科院分区：
文献类型：
--
作者：
Ambrosi TH;Marecic O;McArdle A;Sinha R;Gulati GS;Tong X;Wang Y;Steininger HM;Hoover MY;Koepke LS;Murphy MP;Sokol J;Seo EY;Tevlin R;Lopez M;Brewer RE;Mascharak S;Lu L;Ajanaku O;Conley SD;Seita J;Morri M;Neff NF;Sahoo D;Yang F;Weissman IL;Longaker MT;Chan CKF
衰老和疾病期间骨骼完整性的丧失与成骨细胞和破骨细胞的相反作用的不平衡有关。在这里，我们发现小鼠骨骼干细胞（SSC）的内在老化改变了骨髓小生境中的信号传导，并扭曲了骨和血液谱系的分化，导致再生不良的脆弱骨骼。在功能上，老化的SSC具有降低的骨和软骨形成潜力，但产生更多表达高水平促炎和促吸收细胞因子的基质谱系。单细胞RNA测序研究将功能丧失与老年小鼠中SSC的转录组多样性减少联系起来，从而有助于骨髓生态位的转化。通过异时共生或年轻造血干细胞的全身重建暴露于年轻循环中并没有逆转老年SSC的骨软骨形成活性降低，也没有改善老年小鼠的骨量或骨骼愈合参数。相反，老化的SSC谱系通过造血干细胞和祖细胞促进骨形成活性和骨髓偏斜，这表明SSC的老化是造血老化的驱动因素。老年小鼠的骨再生不足只能通过局部应用BMP 2和CSF 1拮抗剂的组合治疗来恢复到年轻水平，这重新激活了老年SSC，同时消融了炎症性促骨细胞环境。我们的研究结果提供了复杂的，多因素的机制，骨骼衰老的基础，并提供了振兴老年骨骼系统的前景机械的见解。
Loss of skeletal integrity during ageing and disease is associated with an imbalance in the opposing actions of osteoblasts and osteoclasts. Here we show that intrinsic ageing of skeletal stem cells (SSCs) in mice alters signalling in the bone marrow niche and skews the differentiation of bone and blood lineages, leading to fragile bones that regenerate poorly. Functionally, aged SSCs have a decreased bone- and cartilage-forming potential but produce more stromal lineages that express high levels of pro-inflammatory and pro-resorptive cytokines. Single-cell RNA-sequencing studies link the functional loss to a diminished transcriptomic diversity of SSCs in aged mice, which thereby contributes to the transformation of the bone marrow niche. Exposure to a youthful circulation through heterochronic parabiosis or systemic reconstitution with young haematopoietic stem cells did not reverse the diminished osteochondrogenic activity of aged SSCs, or improve bone mass or skeletal healing parameters in aged mice. Conversely, the aged SSC lineage promoted osteoclastic activity and myeloid skewing by haematopoietic stem and progenitor cells, suggesting that the ageing of SSCs is a driver of haematopoietic ageing. Deficient bone regeneration in aged mice could only be returned to youthful levels by applying a combinatorial treatment of BMP2 and a CSF1 antagonist locally to fractures, which reactivated aged SSCs and simultaneously ablated the inflammatory, pro-osteoclastic milieu. Our findings provide mechanistic insights into the complex, multifactorial mechanisms that underlie skeletal ageing and offer prospects for rejuvenating the aged skeletal system.
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影响因子：
64.8
作者：
Chan, Charles K. F.;Chen, Ching-Cheng;Luppen, Cynthia A.;Kim, Jae-Beom;DeBoer, Anthony T.;Wei, Kevin;Helms, Jill A.;Kuo, Calvin J.;Kraft, Daniel L.;Weissman, Irving L.
通讯作者：
Weissman, Irving L.
影响因子：
64.8
作者：
Mizuhashi K;Ono W;Matsushita Y;Sakagami N;Takahashi A;Saunders TL;Nagasawa T;Kronenberg HM;Ono N
通讯作者：
Ono N
影响因子：
6.2
作者：
Halloran, BP;Ferguson, VL;Majumdar, S
通讯作者：
Majumdar, S
影响因子：
16.6
作者：
Foster, Deshka S.;Marshall, Clement D.;Longaker, Michael T.
通讯作者：
Longaker, Michael T.
影响因子：
23.9
作者：
Ambrosi TH;Scialdone A;Graja A;Gohlke S;Jank AM;Bocian C;Woelk L;Fan H;Logan DW;Schürmann A;Saraiva LR;Schulz TJ
通讯作者：
Schulz TJ