Dr. Stefano Comazzetto

Chancellor's Fellow and Group Leader

Biography

Background

After graduating in Molecular Biology at the University of Padua, I earned my Ph.D. from the European Molecular Biology Laboratory (EMBL) and the University of Dundee in 2014 for my work in Prof. Prof. Dónal O'Carroll laboratory. In 2015 I was awarded an EMBO long-term postdoctoral fellowship to work with Dr. Sean Morrison’s at UT Southwestern Medical Center in Dallas. In 2024 I joined the Centre for Regenerative Medicine at the University of Edinburgh as a Chancellor's Fellow and Group Leader. In my laboratory, I will investigate how diet-derived metabolites control stem cell function in normal and clonal haematopoiesis.

Research summary

Metabolic regulation of normal and clonal haematopoiesis

Haematopoietic stem cells (HSCs) sustain the production of blood cells necessary for life. Nutrients and metabolites derived from the diet are the fuel that support all the cells in our body, including stem cells. But how do diet-derived metabolites regulate the maintenance and function of HSCs? During ageing HSCs accumulate genetic mutations, that in some cases confer a competitive advantage to mutant cells and lead to the expansion of the mutant clones. This process, called clonal haematopoiesis (CH), positively correlates with an unhealthy diet and obesity. Hence, do diet-derived metabolites influence the expansion of mutant cells in CH? In my laboratory, I will investigate how metabolites derived from the diet regulate the self-renewal of HSCs in normal and clonal haematopoiesis.

Regulation of HSC self-renewal by nutrient transporters

In cells most nutrients are taken up from the microenvironment and moved across membranes using specialized nutrient transporters. A significant fraction of the human and mouse genome encodes for nutrient transporters, with ~500 transporters from the Solute Carrier (Slc) and ATP-binding cassette (ABC) transporter superfamilies. In my postdoctoral studies, I discovered that deletion of Slc23a2, the main ascorbate (vitamin C) transporter in haematopoietic cells, depleted intracellular ascorbate levels and enhanced the self-renewal of HSCs and multipotent progenitors downstream of HSCs. This suggests that the metabolites taken up through nutrient transporters are key regulators of HSC self-renewal and function. To systematically address this question, my lab will perform genome-wide loss-of-function genetic screens targeting nutrient transporters in HSCs. Our goal is to identify novel metabolic regulators of HSC function that can in turn by exploit to promote haematopoietic regeneration after injury.

Dietary regulation of Clonal Haematopoiesis

Clonal haematopoiesis (CH) is common in aged individuals, and associates with a reduction in overall survival due to an increased risk of development of haematological, cardiovascular and other diseases. Although the mutations in CH are known, clones with mutations in the same gene show a great variability in their kinetics of expansion among individuals. So what are the factors that regulate the expansion of CH mutant clones? Since the presence of CH positively correlate with an unhealthy diet and obesity, it is possible that changes in diet-derive metabolites influence the kinetics of expansion of CH clones. To start addressing this question, my lab will use a combination of in vitro and in vivo cell competition assays, metabolomic profiling, and genetic screens. Our ultimate goal is to identify metabolic vulnerabilities of CH mutant clones that can be exploited to prevent the expansion of mutant CH clones and the development of haematological and other diseases associated to CH.  

Current research interests

haematopoietic stem cells, self-renewal, clonal haematopoiesis, metabolism, diet

Past research interests

epigenetics, small non-coding RNAs, germ cell, haematopoiesis, bone marrow niche

Affiliated research centres

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