Metabolic regulation of hematopoietic stem cell commitment and erythroid differentiation

Curr Opin Hematol. 2016 May;23(3):198-205. doi: 10.1097/MOH.0000000000000234.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Erythroid Cells / cytology*
  • Erythroid Cells / metabolism*
  • Erythropoiesis*
  • Hematopoietic Stem Cells / cytology*
  • Hematopoietic Stem Cells / metabolism*
  • Humans