Metabolically Primed Multipotent Hematopoietic Progenitors Fuel Innate Immunity
Innate immune cells are typically short-lived and must be constantly regenerated by hematopoietic stem and progenitor cells (HSPCs) in the bone marrow, but the metabolic cues that fuel this process are not well characterised. To address this question we applied in situ RNA barcoding, metabolomics, metabolic profiling, and genetic perturbation approaches to identify metabolic regulators of HSPC fate. This approach identified an expression program of enzymes and transporters that confers differences in myeloid production potential in a subset of HSPCs that express CD62L. Relative to other HSPC subsets, CD62Lhigh myeloid-biased progenitors have an increased dependency on oxidative phosphorylation, and a higher rate of translation. Importantly, metabolism actively regulates immune-cell production, with overexpression of the glucose-6-phosphate dehydrogenase enzyme of the pentose phosphate pathway skewing HSPC output from B-lymphocytes towards the myeloid lineages, and expansion of CD62Lhigh HSPCs occurring to support emergency myelopoiesis. Collectively, our data reveal the metabolic cues that guide immune cell development, highlighting a regulatory role for the pentose phosphate pathway. More broadly, our results show that HSPC metabolism can be manipulated to alter the magnitude and specificity of immune cell regeneration in vivo.
