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
Affiliations
Emanuele Azzoni
MRC Molecular Hematology Unit, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 9DS, UK; Corresponding author
Vincent Frontera
MRC Molecular Hematology Unit, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 9DS, UK
Giorgio Anselmi
MRC Molecular Hematology Unit, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 9DS, UK
Christina Rode
MRC Molecular Hematology Unit, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 9DS, UK
Chela James
Department of Cancer Biology, UCL Cancer Institute, University College London, London, WC1E 6DD, UK
Elitza M. Deltcheva
Department of Cancer Biology, UCL Cancer Institute, University College London, London, WC1E 6DD, UK
Atanasiu S. Demian
MRC WIMM Centre for Computational Biology, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 9DS, UK
John Brown
Department of Cancer Biology, UCL Cancer Institute, University College London, London, WC1E 6DD, UK
Cristiana Barone
School of Medicine and Surgery, University of Milano-Bicocca, Monza, 20900, Italy
Arianna Patelli
School of Medicine and Surgery, University of Milano-Bicocca, Monza, 20900, Italy
Joe R. Harman
MRC Molecular Hematology Unit, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 9DS, UK
Matthew Nicholls
MRC Molecular Hematology Unit, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 9DS, UK
Simon J. Conway
HB Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana, IN 46033, USA
Edward Morrissey
MRC WIMM Centre for Computational Biology, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 9DS, UK
Sten Eirik W. Jacobsen
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
Duncan B. Sparrow
Department of Physiology, Anatomy and Genetics, BHF Centre of Research Excellence, University of Oxford, Oxford, OX1 3PT, UK
Adrian L. Harris
Department of Oncology, Molecular Oncology Laboratories, MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DS, UK
Tariq Enver
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
Marella F.T.R. de Bruijn
MRC Molecular Hematology Unit, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 9DS, UK; Corresponding author
Summary: 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.
