Free fatty-acid transport via CD36 drives \u03b2-oxidation-mediated hematopoietic stem cell response to infection

Jayna J Mistry,Mar Moreno-Gonzalez,Iain Macaulay,Naiara Beraza,Federica Di Palma,Stuart A Rushworth,Kristian M Bowles,Jamie A Moore,Charlotte Hellmich,Aisha Jibril

doi:10.1038/s41467-021-27460-9

Abstract

Acute infection is known to induce rapid expansion of hematopoietic stem cells (HSCs), but the mechanisms supporting this expansion remain incomplete. Using mouse models, we show that inducible CD36 is required for free fatty acid uptake by HSCs during acute infection, allowing the metabolic transition from glycolysis towards β-oxidation. Mechanistically, high CD36 levels promote FFA uptake, which enables CPT1A to transport fatty acyl chains from the cytosol into the mitochondria. Without CD36-mediated FFA uptake, the HSCs are unable to enter the cell cycle, subsequently enhancing mortality in response to bacterial infection. These findings enhance our understanding of HSC metabolism in the bone marrow microenvironment, which supports the expansion of HSCs during pathogenic challenge.

Highlights

Acute infection is known to induce rapid expansion of hematopoietic stem cells (HSCs), but the mechanisms supporting this expansion remain incomplete
HSC metabolism is finely balanced between glycolysis and oxidative phosphorylation (OXPHOS), to maintain the intrinsic needs of the cell within the constraints imposed by the microenvironment[5,6]
We show that significantly increased cell cycling of HSC in response to LPS and S. typhimurium is occurring at 16 hours and 72 hours post exposure, respectively (Supplementary Fig. 1f, g)

Summary

Introduction

Acute infection is known to induce rapid expansion of hematopoietic stem cells (HSCs), but the mechanisms supporting this expansion remain incomplete. Without CD36-mediated FFA uptake, the HSCs are unable to enter the cell cycle, subsequently enhancing mortality in response to bacterial infection These findings enhance our understanding of HSC metabolism in the bone marrow microenvironment, which supports the expansion of HSCs during pathogenic challenge. We have shown that free fatty acids are acquired by acute myeloid leukemia (AML) blasts to enhance their proliferation in vitro and in vivo through a mechanism that increased β oxidation[12,13]. This leads us to hypothesize that the β-oxidationdependent metabolic switch in leukemia has its “origins” in the physiology of the HSC response to infection. We have recently reported that in the context of the challenge of acute S. typhimurium infection, the BM microenvironment drives rapid HSC and leukocyte expansion necessary for host survival, through a process dependent on mitochondria transfer into the HSC from tissue-resident BM stromal cells[15]

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