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• W4385983021 abstract "HSCs increase in number and show myeloid/platelet biased differentiation and increased risk of transformation with aging. However, it remains unknown whether HSCs age uniformly or whether heterogeneous HSC populations coordinate hematopoietic aging. To address this question, we performed single-cell RNA-seq analysis and identified that expression of Clusterin (Clu), which encodes a secreted chaperone, is upregulated in the majority of aged HSCs. Detailed analysis of Clu reporter mice with a BAC transgenic Clu-eGFP reporter gene revealed that Clu expression is confined to a part of HSCs and progenitors in young mice and significantly upregulated within the HSC compartment with aging (GFP+ HSCs, 15 and 90 % in young and aged mice, respectively). In competitive repopulation assays, aged Clu-positive HSCs showed impaired repopulation with myeloid/platelet-biased differentiation, whereas Clu-negative HSCs largely retained repopulation capacity and showed balanced differentiation. RNA-seq and ATAC-seq analyses revealed that Clu-positive aged HSCs represent classical aged HSCs, showing myeloid-biased aged HSC gene signatures, while Clu-negative cells significantly retain young HSC-like transcriptome and chromatin accessibility. Of note, Clu-positive aged HSCs had more elongated and swollen mitochondria and lower mitochondrial membrane potential than young HSCs, while Clu-negative aged HSCs largely maintained young-like compact mitochondrial structure and MMP levels. g-H2A levels were elevated in Clu-positive aged HSCs but not in Clu-negative aged HSCs. These results clearly demonstrate that Clu-negative cells represent an undescribed minor aged HSC population that considerably retains young HSC-like features. Collectively, our findings indicate that altered balance between the two distinct HSC populations coordinate aging of hematopoietic system. HSCs increase in number and show myeloid/platelet biased differentiation and increased risk of transformation with aging. However, it remains unknown whether HSCs age uniformly or whether heterogeneous HSC populations coordinate hematopoietic aging. To address this question, we performed single-cell RNA-seq analysis and identified that expression of Clusterin (Clu), which encodes a secreted chaperone, is upregulated in the majority of aged HSCs. Detailed analysis of Clu reporter mice with a BAC transgenic Clu-eGFP reporter gene revealed that Clu expression is confined to a part of HSCs and progenitors in young mice and significantly upregulated within the HSC compartment with aging (GFP+ HSCs, 15 and 90 % in young and aged mice, respectively). In competitive repopulation assays, aged Clu-positive HSCs showed impaired repopulation with myeloid/platelet-biased differentiation, whereas Clu-negative HSCs largely retained repopulation capacity and showed balanced differentiation. RNA-seq and ATAC-seq analyses revealed that Clu-positive aged HSCs represent classical aged HSCs, showing myeloid-biased aged HSC gene signatures, while Clu-negative cells significantly retain young HSC-like transcriptome and chromatin accessibility. Of note, Clu-positive aged HSCs had more elongated and swollen mitochondria and lower mitochondrial membrane potential than young HSCs, while Clu-negative aged HSCs largely maintained young-like compact mitochondrial structure and MMP levels. g-H2A levels were elevated in Clu-positive aged HSCs but not in Clu-negative aged HSCs. These results clearly demonstrate that Clu-negative cells represent an undescribed minor aged HSC population that considerably retains young HSC-like features. Collectively, our findings indicate that altered balance between the two distinct HSC populations coordinate aging of hematopoietic system." @default.
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• W4385983021 date "2023-01-01" @default.
• W4385983021 modified "2023-10-14" @default.
• W4385983021 title "3013 – HEMATOPOIETIC AGING IS REGULATED BY THE BALANCE BETWEEN TWO DISTINCT HEMATOPOIETIC STEM CELL POPULATIONS" @default.
• W4385983021 doi "https://doi.org/10.1016/j.exphem.2023.06.120" @default.
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