The onset of circulation triggers a metabolic switch required for endothelial to hematopoietic transition

Emanuele Azzoni; Vincent Frontera; Giorgio Anselmi; Christina Rode; Chela James; Elitza M Deltcheva; Atanasiu S Demian; John Brown; Cristiana Barone; Arianna Patelli; Joe R Harman; Matthew Nicholls; Simon J Conway; Edward Morrissey; Sten Eirik W Jacobsen; Duncan B Sparrow; Adrian L Harris; Tariq Enver; Marella F T R de Bruijn

doi:10.1016/j.celrep.2021.110103

The onset of circulation triggers a metabolic switch required for endothelial to hematopoietic transition

Cell Rep. 2021 Dec 14;37(11):110103. doi: 10.1016/j.celrep.2021.110103.

Authors

Emanuele Azzoni¹, Vincent Frontera², Giorgio Anselmi², Christina Rode², Chela James³, Elitza M Deltcheva³, Atanasiu S Demian⁴, John Brown³, Cristiana Barone⁵, Arianna Patelli⁵, Joe R Harman², Matthew Nicholls², Simon J Conway⁶, Edward Morrissey⁴, Sten Eirik W Jacobsen⁷, Duncan B Sparrow⁸, Adrian L Harris⁹, Tariq Enver¹⁰, Marella F T R de Bruijn¹¹

Affiliations

¹ MRC Molecular Hematology Unit, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 9DS, UK. Electronic address: emanuele.azzoni@unimib.it.
² MRC Molecular Hematology Unit, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 9DS, UK.
³ Department of Cancer Biology, UCL Cancer Institute, University College London, London, WC1E 6DD, UK.
⁴ MRC WIMM Centre for Computational Biology, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 9DS, UK.
⁵ School of Medicine and Surgery, University of Milano-Bicocca, Monza, 20900, Italy.
⁶ HB Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana, IN 46033, USA.
⁷ MRC Molecular Hematology Unit, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 9DS, UK; Hematopoietic Stem Cell Laboratory, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 9DS, UK; Department of Cell and Molecular Biology, Wallenberg Institute for Regenerative Medicine and Department of Medicine, Center for Hematology and Regenerative Medicine, Karolinska Institutet and Karolinska University Hospital, 171 77 Stockholm, Sweden.
⁸ Department of Physiology, Anatomy and Genetics, BHF Centre of Research Excellence, University of Oxford, Oxford, OX1 3PT, UK.
⁹ Department of Oncology, Molecular Oncology Laboratories, MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DS, UK.
¹⁰ Department of Cancer Biology, UCL Cancer Institute, University College London, London, WC1E 6DD, UK; Division of Molecular Medicine and Gene Therapy, Lund University, Lund, 22184, Sweden.
¹¹ MRC Molecular Hematology Unit, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 9DS, UK. Electronic address: marella.debruijn@imm.ox.ac.uk.

Abstract

Hematopoietic stem cells (HSCs) emerge during development from the vascular wall of the main embryonic arteries. The onset of circulation triggers several processes that provide critical external factors for HSC generation. Nevertheless, it is not fully understood how and when the onset of circulation affects HSC emergence. Here we show that in Ncx1^-/- mouse embryos devoid of circulation the HSC lineage develops until the phenotypic pro-HSC stage. However, these cells reside in an abnormal microenvironment, fail to activate the hematopoietic program downstream of Runx1, and are functionally impaired. Single-cell transcriptomics shows that during the endothelial-to-hematopoietic transition, Ncx1^-/- cells fail to undergo a glycolysis to oxidative phosphorylation metabolic switch present in wild-type cells. Interestingly, experimental activation of glycolysis results in decreased intraembryonic hematopoiesis. Our results suggest that the onset of circulation triggers metabolic changes that allow HSC generation to proceed.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Cell Differentiation*
Cell Lineage*
Endothelium, Vascular / metabolism
Endothelium, Vascular / pathology*
Female
Glycolysis*
Hematopoiesis*
Hematopoietic Stem Cells / metabolism
Hematopoietic Stem Cells / pathology*
Mice
Mice, Inbred C57BL
Mice, Knockout
Oxidative Phosphorylation
Single-Cell Analysis
Sodium-Calcium Exchanger / physiology*
Transcriptome

Substances

NCX1 protein, mouse
Sodium-Calcium Exchanger

Abstract

Publication types

MeSH terms

Substances

Grants and funding