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Augmenting regenerative hematopoietic stem cell self-renewal by intervening in peroxisomal β-oxidation

ABSTRACT: Robust tissue regeneration relies on extensive stem cell self-renewal. However, the molecular mechanisms promoting stem cell self-renewal during regeneration remain unclear. Here we investigate the role of peroxisomes, a key metabolic organelle, in regulating hematopoietic stem cells (HSCs). We found that disrupting peroxisome biogenesis by deleting Pex5 does not significantly impact HSC number or hematopoiesis at steady state. Strikingly, Pex5-deficient HSCs self-renew extensively and give rise to robust multilineage reconstitution upon multiple rounds of serial transplantation into recipients. Pex5-deficient HSCs are more resistant to stress and have enhanced capacity to regenerate the hematopoietic system following chemo drug treatment or irradiation. Deletion of Pex5 promotes the expansion of HSCs and hematopoietic progenitors with extensive serial ex vivo plating capacity. Pharmacological inhibition of peroxisomal β-oxidation also promotes extensive plating by HSCs and hematopoietic progenitors. We propose that intervening in peroxisomal β-oxidation can be exploited to promote HSC and progenitor function for regenerative medicine.

ORGANISM(S): Mus musculus

PROVIDER: GSE294155 | GEO | 2025/09/01

REPOSITORIES: GEO

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