Kainate receptors coordinate primitive hematopoiesis and hemogenic niche organization to promote hematopoietic stem cell development

During embryonic development, the mammalian blood system originates in specialized transient blood-forming niches, yet the signaling pathways that orchestrate this process are still largely unknown. Our research reveals a previously unrecognized role for kainate receptors (KARs), a class of glutamate-gated ion channels, in shaping these critical early events.

KARs are normally associated with excitatory neurotransmission; however, we discovered that they play a vital part in regulating the formation of primitive blood cells and the structure of the hemogenic niche.

When the genes responsible for KAR subunits (grik1b or grik5) are absent, the embryonic blood cells are significantly reduced, and the hemogenic niche organization is disrupted. These disruptions are linked to endothelial oxidative stress and impaired Notch signaling, both of which contribute to a decrease in the generation of hematopoietic stem cells (HSPCs) and a reduction in the diversity of the adult HSPC pool.

By altering the balance between erythropoiesis (red blood cell production) and myelopoiesis (white blood cell production), the researchers were able to restore macrophage niche colonization, endothelial Notch activity, and eventually, HSPC formation in KAR-deficient embryos. This suggests that KARs are crucial for the regulation of HSPC production through endothelial Notch signaling.

Interestingly, the expression of KARs is conserved across zebrafish, mice, and humans, indicating that these receptors may play a similar role in blood development across multiple species. Our findings suggest that glutamate receptor signaling, traditionally understood in the context of neuronal transmission, extends its influence to the broader developmental processes that establish the blood system.