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筛选: 部门 Pediatrics Experimental Hematology 出版者 DOI: 10.1016/j.stem.2025.12.018

Activation of a branched chain amino acid rheostat restores replication-dependent hematopoietic stem cell fitness

Type:

Article

摘抄:

Adult hematopoietic stem cells (HSCs) sustain the lifelong production of all mature blood and immune cells. HSCs possess extensive regenerative potential, but their self-renewal is limited. A long-standing question has been why replicative history negatively impacts HSC functions. We found that accrued divisions alter HSC production; generating low-output bone-marrow landscapes that are highly variable in lineage contribution and transcriptionally divergent within individual lineages. Division-driven HSC functional alterations arise from redirecting branched chain amino acid (BCAA) usage from catabolic towards anabolic activity, causing faster HSC cell cycle kinetics. Adding a BCAA transamination product overcomes the BCAA catabolic checkpoint and slows down the cell cycle, durably rescuing balanced lineage output of HSCs with accrued divisions. Hence, our study suggests the paradigm whereby replicative history causes metabolic and transcriptional drift, generating divergent HSC output. Division-dependent HSC functional drift can be restored by metabolite replacement, which has long-term therapeutic implications for HSC regenerative medicine.

作者:

H. Leighton Grimes; Sydney Treichel; Madeline Frangiosa; Waseem Nasr; Marie-Dominique Filippi; Juying Xu; Nathan Salomonis; Baobao Song; Andrew Harley; Devyani Sharma; James Bartram; Angelo D’Alessandro, and Travis Nemkov

提交者:

Marie-Dominique Filippi

上传日期:

06/26/2026

更改日期:

06/26/2026

证书:

Attribution-ShareAlike 4.0 International

Activation of a branched chain amino acid rheostat restores replication-dependent hematopoietic stem cell fitness

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Activation of a branched chain amino acid rheostat restores replication-dependent hematopoietic stem cell fitness

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