Title: Metabolic regulation of hematopoietic stem cells
Description: Hematopoiesis is essential for life and is sustained by a rare population of hematopoietic stem cells (HSCs) that simultaneously sense and maintain their own numbers (via self-renewal and expansion) while efficiently responding (via differentiation) to mature hematopoietic cell loss. How HSCs integrate these competing cell fate signals into a biological decision remains an outstanding question. Conversely, the role of metabolites in these processes is largely unknown. We hypothesized that the metabolite 1α,25(OH) 2 D and the intracellular metabolites involved in catabolic ATP synthesis play instructive roles in these processes. We are publishing a review on the role of metabolites in HSC function. In addition, to investigate the relationship between metabolites involved in catabolic ATP synthesis and HSC cell fate decisions, we are creating conditional knock-out mice for a critical regulator of anaerobic ATP synthesis, lactate dehydrogenase (LDH). The results of these studies will answer a critical biological question--the mode of metabolism used by HSCs in vivo --and may also lead to new ex vivo expansion protocols for human HSCs.

To interrogate the role of 1α,25(OH) 2 D in HSC behavior, we examined the hematopoietic compartment of mice lacking the receptor (the 'VDR') for 1α,25(OH) 2 D and found that loss of the VDR had little effect on the number of HSCs in the bone marrow but profoundly increased splenic HSC localization. This latter effect was due to loss of the VDR in non-hematopoietic compartments. In addition, we found a serial transplant defect in female VDR -/- mice, suggesting that the VDR controls HSC response to the stress of multiple transplants. Our results underscore the complexity of the in vivo regulation of HSC self-renewal and highlight the role of calcium in specifying the site of HSC residence. Together, the results of our two studies advance our understanding of the relationship between key extracellular regulators of HSC behavior and of the role of metabolism in HSC function.