BMAL1 modulates glutamine supply to control hematopoietic stem and progenitor cell expansion

Mar 19, 2026Development (Cambridge, England)

BMAL1 controls blood stem cell growth by regulating glutamine supply

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Circadian Biology on OpenScience ↗PubMed ↗DOI ↗OA ↗

Abstract

A striking increase in hematopoietic stem and progenitor cell numbers in zebrafish is linked to the expression of bmal1a in endothelial cells.

Bmal1a is expressed in endothelial cells of the caudal hematopoietic tissue in zebrafish.
Endothelial cell-specific inhibition of bmal1a leads to enhanced proliferation of hematopoietic stem and progenitor cells.
RNA sequencing indicates that downregulation of glud1a in dominant-negative bmal1a endothelial cells results in increased glutamine levels.
The bmal1a-glud1a-glutamine pathway appears to support hematopoietic stem and progenitor cell expansion.
Evidence suggests that this glutamine synthesis mechanism may also be present in the mouse fetal liver niche.

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Following specification in the dorsal aorta, hematopoietic stem and progenitor cells (HSPCs) proliferate in the HSPC niche, known as the caudal hematopoietic tissue (CHT) in zebrafish. Here we demonstrate that bmal1a, a core component of the circadian clock machinery, is expressed in CHT endothelial cells (ECs) and affects HSPCs in a non-cell autonomous manner. Using endothelial cell-specific dominant-negative Bmal1a zebrafish lines, we demonstrate a striking increase in HSPC numbers in the CHT, resulting from enhanced HSPC proliferation. RNA-sequencing of dominant-negative bmal1a ECs sorted from the CHT shows a downregulation of glud1a, resulting in increased glutamine levels in the CHT. This newly discovered bmal1a-glud1a-glutamine pathway fuels HSPC expansion. We demonstrate that this glutamine synthesis pathway controlling HSPC expansion is likely conserved in the mouse fetal liver (FL) niche, in which hepatocytes are the likely source of glutamine. Together, our data uncover a novel mechanism of HSPC homeostasis, in which EC BMAL1, expressed by the niche, controls the amount of bioavailable glutamine for HSPCs by regulating the expression of genes involved in glutamine synthesis.

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BMAL1 modulates glutamine supply to control hematopoietic stem and progenitor cell expansion

Abstract

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