Autophagy in mesenchymal progenitors protects mice against bone marrow failure after severe intermittent stress.
Autophagy in mesenchymal progenitors protects mice against bone marrow failure after severe intermittent stress.
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DOI：
10.1182/blood.2021011775
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发表时间：
2022-02-03
期刊：
影响因子：
20.3
通讯作者：
Oostendorp RAJ
中科院分区：
文献类型：
--
作者：
Landspersky T;Saçma M;Rivière J;Hecker JS;Hettler F;Hameister E;Brandstetter K;Istvánffy R;Romero Marquez S;Ludwig R;Götz M;Buck M;Wolf M;Schiemann M;Ruland J;Strunk D;Shimamura A;Myers K;Yamaguchi TP;Kieslinger M;Leonhardt H;Bassermann F;Götze KS;Geiger H;Schreck C;Oostendorp RAJ
间充质祖细胞的自噬缺陷与严重应激后的骨髓细胞减少和死亡率相关。对小鼠进行为期 4 天的短暂体内药理治疗以减弱 CDC42 激活，可防止血细胞减少并提高生存率。确保造血生态位稳态所需的细胞机制以及该生态位在应激时支持造血的能力仍然难以捉摸。我们在此确定 Osterix+ 间充质祖细胞和干细胞 (MSPC) 中的 Wnt5a 是生态位依赖性造血的关键因素。 MSPC 中缺乏 Wnt5a 的小鼠会遭受应激相关的骨髓 (BM) 衰竭和死亡率增加。由于小 GTPase CDC42 的活性升高，缺乏 Wnt5a 的生态位细胞表现出有缺陷的肌动蛋白应力纤维方向。这导致自噬体和溶酶体的定位不正确，从而减少自噬并增加氧化应激。在具有外周血细胞减少和低细胞 BM 特征的 BM 衰竭状态患者的 MSPC 中，我们发现肌动蛋白应力纤维方向、自噬体和溶酶体的共定位减少和不正确以及 CDC42 激活方面存在类似缺陷。引人注目的是，通过短暂的药物干预来减弱小鼠体内 CDC42 升高的激活，可以防止 MSPC 中肌动蛋白锚定的自噬缺陷，挽救造血功能并防止应激时出现致命的血细胞减少。总之，我们的研究确定 Wnt5a 通过影响 CDC42 调节的肌动蛋白应力纤维方向和应激时的自噬来作为生态位稳态的限制因素。我们的数据进一步表明，自噬在 MSPC 中发挥着关键作用，在应激时以及以外周血细胞减少和低细胞 BM 为特征的人类疾病中，自噬对于通过微生境充分支持造血作用具有关键作用。
Defective autophagy in mesenchymal progenitors associates with BM hypocellularity and mortality after severe stress. A short 4-day pharmacological in vivo treatment of mice to attenuate CDC42 activation protects against cytopenia and improves survival. The cellular mechanisms required to ensure homeostasis of the hematopoietic niche and the ability of this niche to support hematopoiesis upon stress remain elusive. We here identify Wnt5a in Osterix+ mesenchymal progenitor and stem cells (MSPCs) as a critical factor for niche-dependent hematopoiesis. Mice lacking Wnt5a in MSPCs suffer from stress-related bone marrow (BM) failure and increased mortality. Niche cells devoid of Wnt5a show defective actin stress fiber orientation due to an elevated activity of the small GTPase CDC42. This results in incorrect positioning of autophagosomes and lysosomes, thus reducing autophagy and increasing oxidative stress. In MSPCs from patients from BM failure states which share features of peripheral cytopenia and hypocellular BM, we find similar defects in actin stress fiber orientation, reduced and incorrect colocalization of autophagosomes and lysosomes, and CDC42 activation. Strikingly, a short pharmacological intervention to attenuate elevated CDC42 activation in vivo in mice prevents defective actin-anchored autophagy in MSPCs, salvages hematopoiesis and protects against lethal cytopenia upon stress. In summary, our study identifies Wnt5a as a restriction factor for niche homeostasis by affecting CDC42-regulated actin stress-fiber orientation and autophagy upon stress. Our data further imply a critical role for autophagy in MSPCs for adequate support of hematopoiesis by the niche upon stress and in human diseases characterized by peripheral cytopenias and hypocellular BM.
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线粒体自噬是骨髓间充质干细胞针对氧化损伤的保护性反应
影响因子：
6.1
作者：
Fan, Pan;Yu, Xiao-Yu;Wang, Yun-Tao
通讯作者：
Wang, Yun-Tao
DOI：
10.1074/jbc.m112.435941
发表时间：
2013-03-22
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Hong L;Kenney SR;Phillips GK;Simpson D;Schroeder CE;Nöth J;Romero E;Swanson S;Waller A;Strouse JJ;Carter M;Chigaev A;Ursu O;Oprea T;Hjelle B;Golden JE;Aubé J;Hudson LG;Buranda T;Sklar LA;Wandinger-Ness A
通讯作者：
Wandinger-Ness A
影响因子：
14
作者：
Lin H;Sohn J;Shen H;Langhans MT;Tuan RS
通讯作者：
Tuan RS
影响因子：
7.8
作者：
Florian MC;Leins H;Gobs M;Han Y;Marka G;Soller K;Vollmer A;Sakk V;Nattamai KJ;Rayes A;Zhao X;Setchell K;Mulaw M;Wagner W;Zheng Y;Geiger H
通讯作者：
Geiger H
影响因子：
23.9
作者：
Florian, Maria Carolina;Doerr, Karin;Niebel, Anja;Daria, Deidre;Schrezenmeier, Hubert;Rojewski, Markus;Filippi, Marie-Dominique;Hasenberg, Anja;Gunzer, Matthias;Scharffetter-Kochanek, Karin;Zheng, Yi;Geiger, Hartmut
通讯作者：
Geiger, Hartmut