Abstract
Although DNA mutation drives stem cell aging, how mutation-accumulated stem cells obtain clonal advantage during aging remains poorly understood. Here, using a mouse model of irradiation-induced premature aging and middle-aged mice, we show that DNA mutation accumulation in hematopoietic stem cells (HSCs) during aging upregulates their surface expression of major histocompatibility complex class II (MHCII). MHCII upregulation increases the chance for recognition by bone marrow (BM)-resident regulatory T cells (Tregs), resulting in their clonal expansion and accumulation in the HSC niche. On the basis of the establishment of connexin 43 (Cx43)-mediated gap junctions, BM Tregs transfer cyclic adenosine monophosphate (cAMP) to aged HSCs to diminish apoptotic priming and promote their survival via activation of protein kinase A (PKA) signaling. Importantly, targeting the HSC–Treg interaction or depleting Tregs effectively prevents the premature/physiological aging of HSCs. These findings show that aged HSCs use an active self-protective mechanism by entrapping local Tregs to construct a prosurvival niche and obtain a clonal advantage.
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Data availability
Transcriptome, TCR-seq, and WES datasets generated in this study are available in the GEO database (GSE211007, GSE211136, GSE211203, GSE211205, GSE211206) and in the Sequence Read Archive (PRJNA866671, PRJNA866602, PRJNA866684). Published datasets (GSE156807, GSE20366, GSE69408, GSE104379, GSE175604) were reanalyzed in this paper with the authors’ permission.
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Acknowledgements
We thank Liting Wang for technical assistance with immunofluorescence. This study was supported by the Key Program of the National Natural Science Foundation of China (No. 81930090), the National Science Foundation for Distinguished Young Scholars of China (No. 81725019), and the National Natural Science Foundation of China (Nos. 82273571, 32171104, U22A20279, 81874256, and 81872556), Chongqing Natural Science Foundation (2023NSCQ-JQX0076).
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WL, CL, and KY designed and performed experiments, analyzed data, and wrote the manuscript. JC, YW, SZ, and KY contributed to flow cytometric analysis and animal experiments. LW and LR contributed to mouse model creation and animal experiments. MC and FC contributed to the ex vivo experiments and data analysis. YX and SW contributed to bioinformatics analysis and assisted with writing the manuscript. FW, QZ, and JZ contributed to the experimental design and data interpretation. LY, CD, and JW conceived and supervised the study, interpreted the data, and revised the manuscript.
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Liao, W., Liu, C., Yang, K. et al. Aged hematopoietic stem cells entrap regulatory T cells to create a prosurvival microenvironment. Cell Mol Immunol 20, 1216–1231 (2023). https://doi.org/10.1038/s41423-023-01072-3
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DOI: https://doi.org/10.1038/s41423-023-01072-3
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