Blood and immune development in human fetal bone marrow and Down syndrome.
Laura Jardine, Simone Webb, Issac Goh, Mariana Quiroga Londo��o, Gary Reynolds, Michael Mather, Bayanne Olabi, Emily Stephenson, Rachel A Botting, Dave Horsfall, Justin Engelbert, Daniel Maunder, Nicole Mende, Caitlin Murnane, Emma Dann, Jim McGrath, Hamish King, Iwo Kucinski, Rachel Queen, Christopher D Carey, Caroline Shrubsole, Elizabeth Poyner, Meghan Acres, Claire Jones, Thomas Ness, Rowen Coulthard, Natalina Elliott, Sorcha O'Byrne, Myriam L R Haltalli, John E Lawrence, Steven Lisgo, Petra Balogh, Kerstin B Meyer, Elena Prigmore, Kirsty Ambridge, Mika Sarkin Jain, Mirjana Efremova, Keir Pickard, Thomas Creasey, Jaume Bacardit, Deborah Henderson, Jonathan Coxhead, Andrew Filby, Rafiqul Hussain, David Dixon, David McDonald, Dorin-Mirel Popescu, Monika S Kowalczyk, Bo Li, Orr Ashenberg, Marcin Tabaka, Danielle Dionne, Timothy L Tickle, Michal Slyper, Orit Rozenblatt-Rosen, Aviv Regev, Sam Behjati, Elisa Laurenti, Nicola K Wilson, Anindita Roy, Berthold G��ttgens, Irene Roberts, Sarah A Teichmann, Muzlifah Haniffa
Author Information
Laura Jardine: Biosciences Institute, Newcastle University, Newcastle upon Tyne, UK.
Simone Webb: Biosciences Institute, Newcastle University, Newcastle upon Tyne, UK. ORCID
Issac Goh: Biosciences Institute, Newcastle University, Newcastle upon Tyne, UK. ORCID
Mariana Quiroga Londo��o: Department of Haematology, Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK. ORCID
Gary Reynolds: Biosciences Institute, Newcastle University, Newcastle upon Tyne, UK.
Michael Mather: Biosciences Institute, Newcastle University, Newcastle upon Tyne, UK. ORCID
Bayanne Olabi: Biosciences Institute, Newcastle University, Newcastle upon Tyne, UK.
Emily Stephenson: Biosciences Institute, Newcastle University, Newcastle upon Tyne, UK.
Rachel A Botting: Biosciences Institute, Newcastle University, Newcastle upon Tyne, UK. ORCID
Dave Horsfall: Biosciences Institute, Newcastle University, Newcastle upon Tyne, UK. ORCID
Justin Engelbert: Biosciences Institute, Newcastle University, Newcastle upon Tyne, UK.
Daniel Maunder: Biosciences Institute, Newcastle University, Newcastle upon Tyne, UK.
Nicole Mende: Department of Haematology, Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK. ORCID
Caitlin Murnane: Department of Paediatrics, University of Oxford, Oxford, UK.
Emma Dann: Wellcome Sanger Institute, Hinxton, UK. ORCID
Jim McGrath: Biosciences Institute, Newcastle University, Newcastle upon Tyne, UK.
Hamish King: Centre for Immunobiology, Blizard Institute, Queen Mary University of London, London, UK. ORCID
Iwo Kucinski: Department of Haematology, Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK. ORCID
Rachel Queen: Biosciences Institute, Newcastle University, Newcastle upon Tyne, UK.
Christopher D Carey: Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK.
Caroline Shrubsole: Haematology Department, Freeman Hospital, Newcastle-upon-Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.
Elizabeth Poyner: Biosciences Institute, Newcastle University, Newcastle upon Tyne, UK.
Meghan Acres: Biosciences Institute, Newcastle University, Newcastle upon Tyne, UK.
Claire Jones: NovoPath, Department of Pathology, Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.
Thomas Ness: NovoPath, Department of Pathology, Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.
Rowen Coulthard: NovoPath, Department of Pathology, Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.
Natalina Elliott: Department of Paediatrics, University of Oxford, Oxford, UK.
Sorcha O'Byrne: Department of Paediatrics, University of Oxford, Oxford, UK.
Myriam L R Haltalli: Department of Haematology, Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK. ORCID
John E Lawrence: Wellcome Sanger Institute, Hinxton, UK.
Steven Lisgo: Biosciences Institute, Newcastle University, Newcastle upon Tyne, UK.
Petra Balogh: Wellcome Sanger Institute, Hinxton, UK.
Kerstin B Meyer: Wellcome Sanger Institute, Hinxton, UK. ORCID
Elena Prigmore: Wellcome Sanger Institute, Hinxton, UK.
Kirsty Ambridge: Wellcome Sanger Institute, Hinxton, UK.
Mika Sarkin Jain: Wellcome Sanger Institute, Hinxton, UK.
Mirjana Efremova: Barts Cancer Institute, Queen Mary University of London, London, UK. ORCID
Keir Pickard: Haematology Department, Freeman Hospital, Newcastle-upon-Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.
Thomas Creasey: Haematology Department, Freeman Hospital, Newcastle-upon-Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK. ORCID
Jaume Bacardit: School of Computing, Newcastle University, Newcastle upon Tyne, UK. ORCID
Deborah Henderson: Biosciences Institute, Newcastle University, Newcastle upon Tyne, UK.
Jonathan Coxhead: Biosciences Institute, Newcastle University, Newcastle upon Tyne, UK. ORCID
Andrew Filby: Biosciences Institute, Newcastle University, Newcastle upon Tyne, UK.
Rafiqul Hussain: Biosciences Institute, Newcastle University, Newcastle upon Tyne, UK.
David Dixon: Biosciences Institute, Newcastle University, Newcastle upon Tyne, UK.
David McDonald: Biosciences Institute, Newcastle University, Newcastle upon Tyne, UK.
Dorin-Mirel Popescu: Biosciences Institute, Newcastle University, Newcastle upon Tyne, UK.
Monika S Kowalczyk: Klarman Cell Observatory, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
Bo Li: Klarman Cell Observatory, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
Orr Ashenberg: Klarman Cell Observatory, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
Marcin Tabaka: Klarman Cell Observatory, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
Danielle Dionne: Klarman Cell Observatory, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
Timothy L Tickle: Klarman Cell Observatory, Broad Institute of Harvard and MIT, Cambridge, MA, USA. ORCID
Michal Slyper: Klarman Cell Observatory, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
Orit Rozenblatt-Rosen: Klarman Cell Observatory, Broad Institute of Harvard and MIT, Cambridge, MA, USA. ORCID
Aviv Regev: Klarman Cell Observatory, Broad Institute of Harvard and MIT, Cambridge, MA, USA. ORCID
Sam Behjati: Wellcome Sanger Institute, Hinxton, UK. ORCID
Elisa Laurenti: Department of Haematology, Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK. ORCID
Nicola K Wilson: Department of Haematology, Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK. ORCID
Anindita Roy: Department of Paediatrics, University of Oxford, Oxford, UK. ORCID
Berthold G��ttgens: Department of Haematology, Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK. ORCID
Irene Roberts: Department of Paediatrics, University of Oxford, Oxford, UK.
Sarah A Teichmann: Wellcome Sanger Institute, Hinxton, UK. ORCID
Muzlifah Haniffa: Biosciences Institute, Newcastle University, Newcastle upon Tyne, UK. m.a.haniffa@ncl.ac.uk. ORCID
Haematopoiesis in the bone marrow (BM) maintains blood and immune cell production throughout postnatal life. Haematopoiesis first emerges in human BM at 11-12 weeks after conception, yet almost nothing is known about how fetal BM (FBM) evolves to meet the highly specialized needs of the fetus and newborn. Here we detail the development of FBM, including stroma, using multi-omic assessment of mRNA and multiplexed protein epitope expression. We find that the full blood and immune cell repertoire is established in FBM in a short time window of 6-7 weeks early in the second trimester. FBM promotes rapid and extensive diversification of myeloid cells, with granulocytes, eosinophils and dendritic cell subsets emerging for the first time. The substantial expansion of B lymphocytes in FBM contrasts with fetal liver at the same gestational age. Haematopoietic progenitors from fetal liver, FBM and cord blood exhibit transcriptional and functional differences that contribute to tissue-specific identity and cellular diversification. Endothelial cell types form distinct vascular structures that we show are regionally compartmentalized within FBM. Finally, we reveal selective disruption of B lymphocyte, erythroid and myeloid development owing to a cell-intrinsic differentiation bias as well as extrinsic regulation through an altered microenvironment in Down syndrome (trisomy 21).
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