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

Lookup NU author(s): Dr Laura Jardine, Simone Webb, Issac Goh, Dr Gary Reynolds, Dr Michael Mather, Dr Bayanne Olabi, Emily Stephenson, Dr Rachel Botting, Dave Horsfall, Justin Engelbert, Daniel Maunder, Jim McGrath, Dr Rachel Queen, Dr Christopher Carey, Dr Caroline Shrubsole, Dr Beth Poyner, Dr Meghan Acres, Dr Steven Lisgo, Dr Keir Pickard, Dr Tom Creasey, Dr Jaume Bacardit, Professor Deborah Henderson, Dr Jonathan Coxhead, Dr Andrew Filby, Raf Hussain, Dr David McDonald, Dr Dorin-Mirel Popescu, Professor Muzlifah Haniffa

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Abstract

© 2021, The Author(s), under exclusive licence to Springer Nature Limited.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).


Publication metadata

Author(s): Jardine L, Webb S, Goh I, Quiroga Londono M, Reynolds G, Mather M, Olabi B, Stephenson E, Botting RA, Horsfall D, Engelbert J, Maunder D, Mende N, Murnane C, Dann E, McGrath J, King H, Kucinski I, Queen R, Carey CD, Shrubsole C, Poyner E, Acres M, Jones C, Ness T, Coulthard R, Elliott N, O'Byrne S, Haltalli MLR, Lawrence JE, Lisgo S, Balogh P, Meyer KB, Prigmore E, Ambridge K, Jain MS, Efremova M, Pickard K, Creasey T, Bacardit J, Henderson D, Coxhead J, Filby A, Hussain R, Dixon D, McDonald D, Popescu D-M, Kowalczyk MS, Li B, Ashenberg O, Tabaka M, Dionne D, Tickle TL, Slyper M, Rozenblatt-Rosen O, Regev A, Behjati S, Laurenti E, Wilson NK, Roy A, Gottgens B, Roberts I, Teichmann SA, Haniffa M

Publication type: Article

Publication status: Published

Journal: Nature

Year: 2021

Issue: ePub ahead of Print

Online publication date: 29/09/2021

Acceptance date: 18/08/2021

ISSN (print): 0028-0836

ISSN (electronic): 1476-4687

Publisher: Nature Research

URL: https://doi.org/10.1038/s41586-021-03929-x

DOI: 10.1038/s41586-021-03929-x


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