Stefano Comazzetto Research Group

Research summary

We study how nutrients derived from the diet regulate stem cell function in normal and clonal haematopoiesis. Clonal haematopoiesis refers to the expansion of haematopoietic stem cells that harbour genetic mutations conferring them a competitive advantage over normal stem cells. Our goal is to translate our basic discoveries into novel pharmacological strategies that promote the function of normal stem cells and prevent the expansion of mutant stem cells in clonal haematopoiesis.

Regulation of HSC function by nutrient transporters

Nutrients and metabolites derived from the diet are the fuel that support all the cells in our body, including stem cells. So how do diet-derived nutrients regulate the maintenance and function of haematopoietic stem cells (HSCs)? Cells take up most nutrients from the microenvironment using specialized nutrient transporters. We recently discovered that deletion of Slc23a2, the main transporter of ascorbate (vitamin C) in haematopoietic cells, depleted intracellular ascorbate levels and enhanced the self-renewal of HSCs in mice (Comazzetto et al., 2024). We will now expand these findings by unbiasedly testing the function of nutrient transporters on HSC self-renewal using loss-of-function genetic screens in cultured mouse HSCs and in vivo after bone marrow transplantation. Our goal is to identify novel metabolic regulators of HSC self-renewal and function that can be exploited to promote blood recovery after haematopoietic stress and bone marrow transplant.

Identification of metabolites controlling clonal haematopoiesis

Clonal haematopoiesis (CH) is common in aged individuals (10-20% of people over 60 years old), and associates with a reduced overall survival because it increases the risk of haematological, cardiovascular and other diseases. The risk of developing haematological and cardiovascular diseases increases with the percentage of mutant CH cells among haematopoietic cells. Interestingly, the incidence of CH positively correlates with an unhealthy diet, obesity and ascorbate deficiency. However little is known on how dietary and metabolic perturbations affect the development and expansion of mutant HSCs in CH. We will use a combination of in vitro and in vivo assays to quantify the effects of metabolic perturbations on the kinetics of expansion of mutant CH cells. Our goal is to identify novel metabolic vulnerabilities of CH mutant cells that can be harnessed to prevent the expansion of CH cells and the development of diseases associated with CH.

If you are enthusiastic about haematopoiesis and metabolism, get in touch. We are always welcoming new students and postdocs to join our group.

Selected recent publications

Comazzetto S, Cassidy DL, DeVilbiss AW, Jeffery EC, Ottesen BR, Reyes AR, Muh S, Mathews TP, Chen B, Zhao Z, Morrison SJ. Vitamin C limits the self-renewal potential of hematopoietic stem cells and multipotent progenitors. Biorxiv (2024) PMID: 38617357 doi: 10.1101/2024.04.01.587574

Comazzetto S*, Shen B*, Morrison SJ. Niches that regulate stem cells and hematopoiesis in the adult bone marrow. Developmental Cell (2021), 56(13):1848-1860. PMID: 34146467. doi: 10.1016/j.devcel.2021.05.018 *Equal contributions

Comazzetto S, Murphy MM, Berto S, Jeffery E, Zhao Z, Morrison SJ. Restricted hematopoietic progenitors and erythropoiesis require SCF from Leptin Receptor+ niche cells in the bone marrow. Cell Stem Cell (2019), 24(3):477-486. PMID: 30661958 doi: 10.1016/j.stem.2018.11.022

Crossley JL, Ostashevskaya-Gohstand S, Comazzetto S, Hook JS, Guo L, Vishlaghi N, Juan C, Xu L, Horswill AR, Hoxhaj G, Moreland JG, Tower RJ, Levi B. Itaconate-producing neutrophils regulate local and systemic inflammation following trauma. JCI Insight (2023), 8(20): e169208. PMID: 37707952 doi: 10.1172/jci.insight.169208

Kara N*, Xue Y*, Zhao Z, Murphy MM, Comazzetto S, Lesser A, Du L, Morrison SJ. Endothelial cells and Leptin Receptor⁺ cells promote the maintenance of stem cells and hematopoiesis in early postnatal bone marrow. Developmental Cell (2023), 58(5): 348-360. PMID: 36868235 doi: 10.1016/j.devcel.2023.02.003

Collaborators

• Professor Katrin Ottersbach - University of Edinburgh
• Prof. Keisuke Kaji - University of Edinburgh
• Dr. Alex Von Kriegsheim - University of Edinburgh
• Dr. Linus Schumacher - University of Edinburgh

Funders

Chancellor's Fellowship, University of Edinburgh