2. Academic Validation
  3. Activation of a branched-chain amino acid rheostat restores replication-dependent hematopoietic stem cell fitness

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

  • Cell Stem Cell. 2026 Feb 5;33(2):289-305.e6. doi: 10.1016/j.stem.2025.12.018.
James Bartram 1,  Sydney Treichel 2,  Baobao Annie Song 3,  Juying Xu 4,  Devyani Sharma 1,  Waseem Nasr 4,  Madeline Frangiosa 4,  Andrew Harley 4,  Travis Nemkov 5,  Angelo D'Alessandro 5,  Nathan Salomonis 6,  H Leighton Grimes 7,  Marie-Dominique Filippi 8
Affiliations

Affiliations

  • 1 Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Research Foundation, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA; Cancer and Cell Biology graduate program, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
  • 2 Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Research Foundation, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA; Molecular and Developmental Biology Graduate Program, Medical Scientist Training Program, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
  • 3 Division of Immunobiology and Center for Systems Immunology, Cincinnati Children's Hospital Research Foundation, Cincinnati, OH, USA; Immunobiology Graduate Program, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
  • 4 Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Research Foundation, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
  • 5 Department of Biochemistry and Molecular Genetics, University of Colorado CU Anschutz Medical Campus, Aurora, CO, USA.
  • 6 Division of Biomedical Informatics, Cincinnati Children's Hospital Research Foundation, Cincinnati, OH, USA.
  • 7 Division of Immunobiology and Center for Systems Immunology, Cincinnati Children's Hospital Research Foundation, Cincinnati, OH, USA.
  • 8 Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Research Foundation, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA. Electronic address: [email protected].
PMID: 41534523 DOI: 10.1016/j.stem.2025.12.018
Abstract

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 toward 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.

Keywords

branch chain amino acid catabolism; hematopoietic stem cells; metabolism; self-renewal.

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