Transitions in lineage specification and gene regulatory networks in hematopoietic stem/progenitor cells over human development
Anindita Roy,
Guanlin Wang,
Deena Iskander,
Sorcha O’Byrne,
Natalina Elliott,
Jennifer O’Sullivan,
Gemma Buck,
Elisabeth F. Heuston,
Wei Xiong Wen,
Alba Rodriguez Meira,
Peng Hua,
Anastasios Karadimitris,
Adam J. Mead,
David M. Bodine,
Irene Roberts,
Bethan Psaila,
Supat Thongjuea
Affiliations
Anindita Roy
Department of Paediatrics, Children’s Hospital, John Radcliffe Hospital, and MRC WIMM, University of Oxford, Oxford OX3 9DS, UK; MRC Molecular Haematology Unit, MRC WIMM, University of Oxford, Oxford OX3 9DS, UK; National Institute for Health Research (NIHR) Oxford Biomedical Research Centre, Oxford OX4 2PG, UK; Corresponding author
Guanlin Wang
MRC Molecular Haematology Unit, MRC WIMM, University of Oxford, Oxford OX3 9DS, UK; Centre for Computational Biology, Medical Research Council Weatherall Institute of Molecular Medicine (MRC WIMM), University of Oxford, Oxford OX3 9DS, UK
Deena Iskander
Centre for Haematology, Department of Immunology and Inflammation, Imperial College London, London W12 0NN, UK
Sorcha O’Byrne
Department of Paediatrics, Children’s Hospital, John Radcliffe Hospital, and MRC WIMM, University of Oxford, Oxford OX3 9DS, UK
Natalina Elliott
Department of Paediatrics, Children’s Hospital, John Radcliffe Hospital, and MRC WIMM, University of Oxford, Oxford OX3 9DS, UK
Jennifer O’Sullivan
MRC Molecular Haematology Unit, MRC WIMM, University of Oxford, Oxford OX3 9DS, UK
Gemma Buck
Department of Paediatrics, Children’s Hospital, John Radcliffe Hospital, and MRC WIMM, University of Oxford, Oxford OX3 9DS, UK; MRC Molecular Haematology Unit, MRC WIMM, University of Oxford, Oxford OX3 9DS, UK
Elisabeth F. Heuston
Hematopoiesis Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892-4442, USA
Wei Xiong Wen
MRC Molecular Haematology Unit, MRC WIMM, University of Oxford, Oxford OX3 9DS, UK; Centre for Computational Biology, Medical Research Council Weatherall Institute of Molecular Medicine (MRC WIMM), University of Oxford, Oxford OX3 9DS, UK
Alba Rodriguez Meira
MRC Molecular Haematology Unit, MRC WIMM, University of Oxford, Oxford OX3 9DS, UK; Centre for Computational Biology, Medical Research Council Weatherall Institute of Molecular Medicine (MRC WIMM), University of Oxford, Oxford OX3 9DS, UK
Peng Hua
MRC Molecular Haematology Unit, MRC WIMM, University of Oxford, Oxford OX3 9DS, UK
Anastasios Karadimitris
Centre for Haematology, Department of Immunology and Inflammation, Imperial College London, London W12 0NN, UK
Adam J. Mead
MRC Molecular Haematology Unit, MRC WIMM, University of Oxford, Oxford OX3 9DS, UK; National Institute for Health Research (NIHR) Oxford Biomedical Research Centre, Oxford OX4 2PG, UK
David M. Bodine
Hematopoiesis Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892-4442, USA
Irene Roberts
Department of Paediatrics, Children’s Hospital, John Radcliffe Hospital, and MRC WIMM, University of Oxford, Oxford OX3 9DS, UK; MRC Molecular Haematology Unit, MRC WIMM, University of Oxford, Oxford OX3 9DS, UK; National Institute for Health Research (NIHR) Oxford Biomedical Research Centre, Oxford OX4 2PG, UK
Bethan Psaila
MRC Molecular Haematology Unit, MRC WIMM, University of Oxford, Oxford OX3 9DS, UK; National Institute for Health Research (NIHR) Oxford Biomedical Research Centre, Oxford OX4 2PG, UK; Corresponding author
Supat Thongjuea
MRC Molecular Haematology Unit, MRC WIMM, University of Oxford, Oxford OX3 9DS, UK; National Institute for Health Research (NIHR) Oxford Biomedical Research Centre, Oxford OX4 2PG, UK; Centre for Computational Biology, Medical Research Council Weatherall Institute of Molecular Medicine (MRC WIMM), University of Oxford, Oxford OX3 9DS, UK; Corresponding author
Summary: Human hematopoiesis is a dynamic process that starts in utero 18–21 days post-conception. Understanding the site- and stage-specific variation in hematopoiesis is important if we are to understand the origin of hematological disorders, many of which occur at specific points in the human lifespan. To unravel how the hematopoietic stem/progenitor cell (HSPC) compartment changes during human ontogeny and the underlying gene regulatory mechanisms, we compare 57,489 HSPCs from 5 different tissues spanning 4 developmental stages through the human lifetime. Single-cell transcriptomic analysis identifies significant site- and developmental stage-specific transitions in cellular architecture and gene regulatory networks. Hematopoietic stem cells show progression from cycling to quiescence and increased inflammatory signaling during ontogeny. We demonstrate the utility of this dataset for understanding aberrant hematopoiesis through comparison to two cancers that present at distinct time points in postnatal life—juvenile myelomonocytic leukemia, a childhood cancer, and myelofibrosis, which classically presents in older adults.
