Blood and immune development in human fetal bone marrow and Down syndrome

Laura Jardine, Simone Webb, Issac Goh, Mariana Quiroga Londoño, 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 Göttgens, Irene Roberts, Sarah A. Teichmann and Muzlifah Haniffa ()
Additional contact information
Laura Jardine: Newcastle University
Simone Webb: Newcastle University
Issac Goh: Newcastle University
Mariana Quiroga Londoño: University of Cambridge
Gary Reynolds: Newcastle University
Michael Mather: Newcastle University
Bayanne Olabi: Newcastle University
Emily Stephenson: Newcastle University
Rachel A. Botting: Newcastle University
Dave Horsfall: Newcastle University
Justin Engelbert: Newcastle University
Daniel Maunder: Newcastle University
Nicole Mende: University of Cambridge
Caitlin Murnane: University of Oxford
Emma Dann: Wellcome Sanger Institute
Jim McGrath: Newcastle University
Hamish King: Queen Mary University of London
Iwo Kucinski: University of Cambridge
Rachel Queen: Newcastle University
Christopher D. Carey: Newcastle University
Caroline Shrubsole: Newcastle-upon-Tyne Hospitals NHS Foundation Trust
Elizabeth Poyner: Newcastle University
Meghan Acres: Newcastle University
Claire Jones: Newcastle Hospitals NHS Foundation Trust
Thomas Ness: Newcastle Hospitals NHS Foundation Trust
Rowen Coulthard: Newcastle Hospitals NHS Foundation Trust
Natalina Elliott: University of Oxford
Sorcha O’Byrne: University of Oxford
Myriam L. R. Haltalli: University of Cambridge
John E. Lawrence: Wellcome Sanger Institute
Steven Lisgo: Newcastle University
Petra Balogh: Wellcome Sanger Institute
Kerstin B. Meyer: Wellcome Sanger Institute
Elena Prigmore: Wellcome Sanger Institute
Kirsty Ambridge: Wellcome Sanger Institute
Mika Sarkin Jain: Wellcome Sanger Institute
Mirjana Efremova: Queen Mary University of London
Keir Pickard: Newcastle-upon-Tyne Hospitals NHS Foundation Trust
Thomas Creasey: Newcastle-upon-Tyne Hospitals NHS Foundation Trust
Jaume Bacardit: Newcastle University
Deborah Henderson: Newcastle University
Jonathan Coxhead: Newcastle University
Andrew Filby: Newcastle University
Rafiqul Hussain: Newcastle University
David Dixon: Newcastle University
David McDonald: Newcastle University
Dorin-Mirel Popescu: Newcastle University
Monika S. Kowalczyk: Broad Institute of Harvard and MIT
Bo Li: Broad Institute of Harvard and MIT
Orr Ashenberg: Broad Institute of Harvard and MIT
Marcin Tabaka: Broad Institute of Harvard and MIT
Danielle Dionne: Broad Institute of Harvard and MIT
Timothy L. Tickle: Broad Institute of Harvard and MIT
Michal Slyper: Broad Institute of Harvard and MIT
Orit Rozenblatt-Rosen: Broad Institute of Harvard and MIT
Aviv Regev: Broad Institute of Harvard and MIT
Sam Behjati: Wellcome Sanger Institute
Elisa Laurenti: University of Cambridge
Nicola K. Wilson: University of Cambridge
Anindita Roy: University of Oxford
Berthold Göttgens: University of Cambridge
Irene Roberts: University of Oxford
Sarah A. Teichmann: Wellcome Sanger Institute
Muzlifah Haniffa: Newcastle University

Nature, 2021, vol. 598, issue 7880, 327-331

Abstract: Abstract 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 conception1,2, 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).

Date: 2021
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DOI: 10.1038/s41586-021-03929-x

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