Effect of Slc31a1 deletion on gene expression of Lin-Sca1+c-Kit cell in the bone marrow of mice

Copper homeostasis has been linked to human health and hematopoiesis. However, the underlying mechanisms remain elusive. Here, we demonstrate the pivotal role of the transporter Slc31a1(Ctr1) in copper uptake, during postnatal hematopoiesis. Specifically, Slc31a1-mediated copper transport sustains the differentiation and commitment of multipotent progenitors from short-term hematopoietic stem cells (HSCs). By transcriptome analyses we reveal a disrupted differentiation program in the hematopoietic stem and progenitor cells (HSPCs) derived from diet-induced copper deficiency mice or hematopoietic-specific Slc31a1 knockout (vKO) mice. Further, we show that Slc31a1 and copper are indispensable for sustaining mitochondrial activity via Complex IV within HSPCs. Notably, the copper ionophore elesclomol significantly ameliorates severe anemia in vKO mice and partially recovers mitochondrial function in vKO HSPCs. These findings demonstrate the critical role of Slc31a1/copper in maintaining HSC homeostasis via modulation of mitochondrial energy metabolism; thus, shedding light on the molecular basis of HSC fate decisions while opening new avenues to maintaining functional HSCs.