Bone Marrow Metabolic Niches Regulate Hematopoiesis – MetaNiche

Hematopoiesis is the process by which hematopoietic stem (HSC) and progenitor cells (HSPCs) create tens of billions of new immune cells each day. Large amounts of protein, lipids, nucleotides and ATP are required to sustain this high rate of biosynthesis, but the role of metabolism in hematopoiesis remains poorly characterized. Here, we hypothesize that metabolic niches in the bone marrow regulate HSPC differentiation through the provision of specific metabolites, nutrients and growth factors. To identify and characterize metabolic niches in the bone marrow, we have set the following aims:

Aim 1: Identify nutrient/metabolite transporters that distinguish fate committed HSPCS in different metabolic states. This will be achieved using MetaFate – a new approach to perform parallel profiling of RNA, transporter/enzyme proteins and fate in single HSPCs.

Aim 2: Map the spatial distribution of nutrient/metabolite transporters, and metabolic activity in the bone marrow. For this, we will develop spatial-SCENITH, a novel method to functionally profile energy metabolism and nutrient transporter expression in single cells in situ.

Aim 3: Validate the identified metabolic interactions and their role on hematopoiesis by targeting nutrient transporters on the surface of HSPCs. This will be achieved by the modulation of identified nutrient transporters on HSPC using targeted genetic and pharmacological approaches and quantifying their effect on HSPC fate in vitro and in vivo.

In summary, we will combine the expertise of the Perieì, Argu?ello, and Bousso teams to understand the link between metabolism and immune cell production. To address this question we will develop new single cell tools to the field of immunometabolism, adding both spatial and fate dimensions to metabolic studies.