Age-associated imbalance in immune cell regeneration varies across individuals and arises from a distinct subset of stem cells  

作　　者：Anna Nogalska Jiya Eerdeng Samir Akre Mary Vergel-Rodriguez Yeachan Lee Charles Bramlett Adnan Y.Chowdhury Bowen Wang Colin G.Cess Stacey D.Finley Rong Lu 

机构地区：[1]Department of Stem Cell Biology and Regenerative Medicine,Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research,Keck School of Medicine,Los Angeles,CA 90033,USA [2]Alfred E.Mann Department of Biomedical Engineering,University of Southern California,Los Angeles,CA 90089,USA [3]Department of Quantitative and Computational Biology,University of Southern California,Los Angeles,CA 90089,USA

出　　处：《Cellular & Molecular Immunology》2024年第12期1459-1473,共15页中国免疫学杂志(英文版)

基　　金：supported by NIH-R00-HL113104,R01HL138225,and R35HL150826;R.Lu is a scholar of the Leukemia&Lymphoma Society(LLS-1370-20);The project described was supported in part by award number P30CA014089 from the National Cancer Institute;CB is supported by National Institutes of Health grant 1F31HL149278-01A1;JE is supported by the California Institute for Regenerative Medicine grant EDUC4-12756.

摘　　要：The age-associated decline in immunity manifests as imbalanced adaptive and innate immune cells,which originate from the aging of the stem cells that sustain their regeneration.Aging variation across individuals is well recognized,but its mechanism remains unclear.Here,we used high-throughput single-cell technologies to compare mice of the same chronological age that exhibited early or delayed immune aging phenotypes.We found that some hematopoietic stem cells(HSCs)in early aging mice upregulated genes related to aging,myeloid differentiation,and stem cell proliferation.Delayed aging was instead associated with genes involved in stem cell regulation and the response to external signals.These molecular changes align with shifts in HSC function.We found that the lineage biases of 30%to 40%of the HSC clones shifted with age.Moreover,their lineage biases shifted in opposite directions in mice exhibiting an early or delayed aging phenotype.In early aging mice,the HSC lineage bias shifted toward the myeloid lineage,driving the aging phenotype.In delayed aging mice,HSC lineage bias shifted toward the lymphoid lineage,effectively counteracting aging progression.Furthermore,the anti-aging HSC clones did not increase lymphoid production but instead decreased myeloid production.Additionally,we systematically quantified the frequency of various changes in HSC differentiation and their roles in driving the immune aging phenotype.Taken together,our findings suggest that temporal variation in the aging of immune cell regeneration among individuals primarily arises from differences in the myelopoiesis of a distinct subset of HSCs.Therefore,interventions to delay aging may be possible by targeting a subset of stem cells.

关 键 词：aging clonal tracking hematopoietic stem cells lineage bias MYELOPOIESIS 

分 类 号：R392[医药卫生—免疫学]