Multiomics reveals glutathione metabolism as a driver of bimodality during stem cell aging

被引：27

作者：

Benjamin, Daniel I. ^{[1
,2
]}

O. Brett, Jamie O. ^{[1
,2
,3
,4
]}

Both, Pieter ^{[1
,2
,3
]}

S. Benjamin, Joel ^{[1
,2
]}

Ishak, Heather L. ^{[2
]}

Kang, Jengmin ^{[1
,2
]}

Kim, Sooch ^{[1
,2
]}

Chung, Mingy ^{[1
,2
]}

Arjona, Marina ^{[1
,2
]}

Nutter, Christopher W. ^{[2
]}

Tan, Jenna H. ^{[2
]}

Krishnan, Ananya K. ^{[2
]}

Dulay, Hunter ^{[2
]}

Louie, Sharon M. ^{[5
]}

de Morre, Antoine ^{[1
,2
,7
]}

Nomura, Daniel K. ^{[5
]}

Rando, Thomas A. ^{[1
,2
,6
,8
]}

机构：

[1] Stanford Univ, Dept Neurol & Neurol Sci, Sch Med, Stanford, CA 94305 USA

[2] Stanford Univ, Paul F Glenn Labs Biol Aging, Sch Med, Stanford, CA 94305 USA

[3] Stanford Univ, Stem Cell Biol & Regenerat Med Grad Program, Sch Med, Stanford, CA USA

[4] Stanford Univ, Med Scientist Training Program, Sch Med, Stanford, CA USA

[5] Univ Calif Berkeley, Dept Nutr Sci & Toxicol, Berkeley, CA 94720 USA

[6] Vet Affairs Palo Alto Healthcare Syst, Neurol Serv, Palo Alto, CA 94304 USA

[7] Aarhus Univ, Dept Biomed, DK-8000 Aarhus, Denmark

[8] Univ Calif Los Angeles, Broad Stem Cell Res Ctr, Los Angeles, CA 90095 USA

来源：

CELL METABOLISM | 2023年 / 35卷 / 03期

关键词：

NF-KAPPA-B; DNA METHYLATION; SKELETAL-MUSCLE; GENE-EXPRESSION; SATELLITE CELLS; CROSS-TALK; NO LONGER; QUIESCENCE; INHIBITION; CHROMATIN;

D O I：

10.1016/j.cmet.2023.02.001

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

With age, skeletal muscle stem cells (MuSCs) activate out of quiescence more slowly and with increased death, leading to defective muscle repair. To explore the molecular underpinnings of these defects, we com-bined multiomics, single-cell measurements, and functional testing of MuSCs from young and old mice. The multiomics approach allowed us to assess which changes are causal, which are compensatory, and which are simply correlative. We identified glutathione (GSH) metabolism as perturbed in old MuSCs, with both causal and compensatory components. Contrary to young MuSCs, old MuSCs exhibit a population dichot-omy composed of GSHhigh cells (comparable with young MuSCs) and GSHlow cells with impaired function-ality. Mechanistically, we show that antagonism between NRF2 and NF-KB maintains this bimodality. Exper-imental manipulation of GSH levels altered the functional dichotomy of aged MuSCs. These findings identify a novel mechanism of stem cell aging and highlight glutathione metabolism as an accessible target for reversing MuSC aging.

引用

页码：472 / +

页数：22

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