Reduction of senescent fibro-adipogenic progenitors in progeria-aged muscle by senolytics rescues the function of muscle stem cells.
Reduction of senescent fibro-adipogenic progenitors in progeria-aged muscle by senolytics rescues the function of muscle stem cells.
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DOI：
10.1002/jcsm.13101
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发表时间：
2022-12
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影响因子：
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肌肉中的纤维脂肪前体(FAP)与肌肉前体/干细胞(MPC)密切相互作用，在正常条件下促进肌肉再生。然而，FAP如何与衰老肌肉中的MPC相互作用尚不清楚。已经证明，感觉剂可以选择性地消除衰老细胞，并对衰老和多种与年龄相关的疾病模型产生治疗效果。通过对年龄匹配的WT小鼠和Hutchinson-Gilford早老症加速衰老模型Zmpste24−/−(Z24−/−)小鼠肌肉和原代细胞的研究，我们探讨了衰老肌肉中FAPs和MPC之间的相互作用，以及抗衰老药物FAPs在清除衰老的FAPs和改善MPC功能方面的潜在作用。我们观察到，与WT小鼠肌肉相比，Z24−/−小鼠肌肉中FAP的数量显著增加(2.4倍；n=6，P<0.0 5)，MPC数量显著减少(2.8倍；n=6，P<0.0 5)。从Z24−/−肌肉分离的FAP含有约44%的SA-β-GAL+衰老细胞，而从WT肌肉分离的FAP含有约3.5%的衰老细胞(n=6，P<0.001)。Z24−/−FAP与WT MPC共培养后，WT MPC的增殖和成肌能力减弱，BrdU阳性增殖细胞数减少3.3倍(n=6，P<0.001)，肌球蛋白重链(MHC)阳性肌管数减少4.5倍(n=6，P<0.001)。Z24−/−FAPs与WT MPC体外共培养体系中加入抗衰老药物非司匹林后，Z24−/−FAPs的凋亡率显著增加(n=6，P<0.001)，MPC功能受损的肌管数增加3.1倍(n=6，P<0.001)。在体内用菲斯汀治疗Z24−/−小鼠，能有效地减少衰老的FAP数量(2.2倍，n=6，P<0.05)和恢复肌肉干细胞的数量(2.6倍，n=6，P<0.05)，从而改善Z24−/−小鼠的肌肉病理。这些结果表明，在衰老肌肉中应用感觉剂可以有效地去除衰老细胞，包括衰老的FAP，从而改善肌肉祖细胞/干细胞的功能。衰老的FAPs可能成为治疗衰老相关肌肉疾病的潜在新靶点。
Fibro‐adipogenic progenitors (FAPs) in the muscles have been found to interact closely with muscle progenitor/stem cells (MPCs) and facilitate muscle regeneration at normal conditions. However, it is not clear how FAPs may interact with MPCs in aged muscles. Senolytics have been demonstrated to selectively eliminate senescent cells and generate therapeutic benefits on ageing and multiple age‐related disease models. By studying the muscles and primary cells of age matched WT mice and Zmpste24−/− (Z24−/−) mice, an accelerated ageing model for Hutchinson–Gilford progeria syndrome (HGPS), we examined the interaction between FAPs and MPCs in progeria‐aged muscle, and the potential effect of senolytic drug fisetin in removing senescent FAPs and improving the function of MPCs. We observed that, compared with muscles of WT mice, muscles of Z24−/− mice contained a significantly increased number of FAPs (2.4‐fold; n > =6, P < 0.05) and decreased number of MPCs (2.8‐fold; n > =6, P < 0.05). FAPs isolated from Z24−/− muscle contained about 44% SA‐β‐gal+ senescent cells, in contrast to about 3.5% senescent cells in FAPs isolated from WT muscle (n > =6, P < 0.001). The co‐culture of Z24−/− FAPs with WT MPCs resulted in impaired proliferation and myogenesis potential of WT MPCs, with the number of BrdU positive proliferative cells being reduced for 3.3 times (n > =6, P < 0.001) and the number of myosin heavy chain (MHC)‐positive myotubes being reduced for 4.5 times (n > =6, P < 0.001). The treatment of the in vitro co‐culture system of Z24−/− FAPs and WT MPCs with the senolytic drug fisetin led to increased apoptosis of Z24−/− FAPs (14.5‐fold; n > =6, P < 0.001) and rescued the impaired function of MPCs by increasing the number of MHC‐positive myotubes for 3.1 times (n > =6, P < 0.001). Treatment of Z24−/− mice with fisetin in vivo was effective in reducing the number of senescent FAPs (2.2‐fold, n > =6, P < 0.05) and restoring the number of muscle stem cells (2.6‐fold, n > =6, P < 0.05), leading to improved muscle pathology in Z24−/− mice. These results indicate that the application of senolytics in the progeria‐aged muscles can be an efficient strategy to remove senescent cells, including senescent FAPs, which results in improved function of muscle progenitor/stem cells. The senescent FAPs can be a potential novel target for therapeutic treatment of progeria ageing related muscle diseases.
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DOI：
10.1146/annurev-pharmtox-050120-105018
发表时间：
2021-01-06
影响因子：
12.5
作者：
Robbins PD;Jurk D;Khosla S;Kirkland JL;LeBrasseur NK;Miller JD;Passos JF;Pignolo RJ;Tchkonia T;Niedernhofer LJ
通讯作者：
Niedernhofer LJ
影响因子：
5.5
作者：
Gao Z;Lu A;Daquinag AC;Yu Y;Huard M;Tseng C;Gao X;Huard J;Kolonin MG
通讯作者：
Kolonin MG
影响因子：
5.6
作者：
Good SC;Dewison KM;Radford SE;van Oosten-Hawle P
通讯作者：
van Oosten-Hawle P
影响因子：
16.6
作者：
Fuhrmann-Stroissnigg H;Ling YY;Zhao J;McGowan SJ;Zhu Y;Brooks RW;Grassi D;Gregg SQ;Stripay JL;Dorronsoro A;Corbo L;Tang P;Bukata C;Ring N;Giacca M;Li X;Tchkonia T;Kirkland JL;Niedernhofer LJ;Robbins PD
通讯作者：
Robbins PD
影响因子：
7.7
作者：
Miller HA;Dean ES;Pletcher SD;Leiser SF
通讯作者：
Leiser SF