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Metabolic regulation of hematopoietic stem cell commitment and erythroid differentiation

Oburoglu, Leal; Romano, Manuela; Taylor, Naomi; Kinet, Sandrina

Current Opinion in Hematology: May 2016 - Volume 23 - Issue 3 - p 198–205
doi: 10.1097/MOH.0000000000000234
Editor's Choice

Purpose of review Hematopoietic stem cell (HSC) renewal and lineage differentiation are finely tuned processes, regulated by cytokines, transcription factors and cell–cell contacts. However, recent studies have shown that fuel utilization also conditions HSC fate. This review focuses on our current understanding of the metabolic pathways that govern HSC self-renewal, commitment and specification to the erythroid lineage.

Recent findings HSCs reside in a hypoxic bone marrow niche that favors anaerobic glycolysis. Although this metabolic pathway is required for stem cell maintenance, other pathways also play critical roles. Fatty acid oxidation preserves HSC self-renewal by promoting asymmetric division, whereas oxidative phosphorylation induces lineage commitment. Committed erythroid progenitors support the production of 2.4 million erythrocytes per second in human adults via a synchronized regulation of iron, amino acid and glucose metabolism. Iron is indispensable for heme biosynthesis in erythroblasts; a process finely coordinated by at least two hormones, hepcidin and erythroferrone, together with multiple cell surface iron transporters. Furthermore, hemoglobin production is promoted by amino acid-induced mTOR signaling. Erythropoiesis is also strictly dependent on glutamine metabolism; under conditions where glutaminolysis is inhibited, erythropoietin-signaled progenitors are diverted to a myelomonocytic fate. Indeed, the utilization of both glutamine and glucose in de-novo nucleotide biosynthesis is a sine qua non for erythroid differentiation.

Summary Diverse metabolic networks function in concert with transcriptional, translational and epigenetic programs to regulate HSC potential and orient physiological as well as pathological erythroid differentiation.

Institut de Génétique Moléculaire de Montpellier, Centre National de la Recherche Scientifique UMR5535, Université de Montpellier, Montpellier and Laboratory of Excellence GR-Ex, Paris, France

Correspondence to Naomi Taylor and Sandrina Kinet, Institut de Génétique Moléculaire de Montpellier, 1919 Route de Mende, 34293 Montpellier, Cedex 5, France. Tel: +33 4 67 61 36 28; fax: +33 4 67 04 02 31; e-mails: and

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