Investigation of the metabolic changes in the haematopoietic stem cell compartment in response to stress

Mistry, Jayna (2021) Investigation of the metabolic changes in the haematopoietic stem cell compartment in response to stress. Doctoral thesis, University of East Anglia.

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Abstract

Haematopoietic stem cells (HSCs) exist in a fine balance between self-renewal and differentiation. The maintenance of this balance is critical for sustaining long term multilineage haematopoietic reconstitution. Quiescent HSCs heavily rely on glycolysis over oxidative phosphorylation (OXPHOS)to produce adenosine triphosphate (ATP). This is thought to be an adaptation to the hypoxic bone marrow (BM) microenvironment and reflects the low metabolic demands of quiescent HSCs, but also may allow for long-term survival. The transition from quiescent to active HSCs is accompanied by a metabolic switch towards OXPHOS which is essential for HSC differentiation. Stress stimuli such as infection initiate rapid expansion and differentiation of HSCs, which requires extensive ATP production. The underlying mechanisms involved in this process remain largely unknown. Here I examine the immuno-metabolic processes which facilitate HSC expansion in response to acute infection.

This research shows that infection drives an increase in mitochondrial mass in HSCs, resulting in a metabolic switch from glycolysis towards OXPHOS. The initial mitochondrial mass increase occurred as a result of mitochondrial transfer from BM stromal cells (BMSCs) to the HSCs. This process was mediated by macrophage derived NADPH oxidase 2 (NOX2) reactive oxygen species facilitating the opening of connexin-43 channels. Moreover, mitochondrial transfer was regulated by activation of phosphoinositide3-kinase and this process occurred before the cells transcriptional program to generate new mitochondria. Furthermore, following infection HSCs also take up free fatty acids (FFA) and subsequently have an increased dependency on β-oxidation. Mechanistically, CD36upregulation mediates FFA uptake into HSCs, enabling CPT1A to transport fatty acyl chains into the mitochondria. Without uptake of FFA HSC expansion is reduced, leading to increased susceptibility and enhanced mortality in response to infection. Together, these findings provide mechanistic understanding of the interplay between HSCs and the BM microenvironment which supports the metabolic demands of HSCs during pathogenic stress.

Item Type:	Thesis (Doctoral)
Faculty \ School:	Faculty of Medicine and Health Sciences > Norwich Medical School
Depositing User:	Chris White
Date Deposited:	07 Jun 2021 14:57
Last Modified:	07 Jun 2021 14:57
URI:	https://ueaeprints.uea.ac.uk/id/eprint/80212
DOI:

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