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, Muzlifah Haniffa
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).
Datasets
1. Fetal Bone Marrow (10x)
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pre B progenitor14229 cells early erythroid7474 cells pro B progenitor5528 cells pre pro B progenitor5427 cells immature B cell1988 cells stromal macrophage1464 cells osteoblast precursor456 cells monocytoid macrophage290 cells early osteoblast280 cells muscle stem cell254 cells osteochondral precursor191 cells eo/baso/mast precursor175 cells erythroid macrophage92 cells arteriolar fibroblast83 cells endosteal fibroblast54 cells myeloid DC progenitor31 cells WSSS_F_BON87106383048 cells WSSS_F_BON87106403019 cells WSSS_F_BON87106362853 cells WSSS_F_BON87106422826 cells WSSS_F_BON87106392563 cells WSSS_F_BON87106372316 cells WSSS_F_BON87106431875 cells WSSS_F_BON8710641826 cells HSC/MPP and pro3795 cells HsapDv:000005254975 cells HsapDv:000005619326 cells HsapDv:000005416068 cells NCBITaxon:9606103228 cells UBERON:0002371103228 cells precursor B cell14229 cells CD14-positive monocyte8763 cells primitive red blood cell7474 cells fraction A pre-pro B cell5427 cells progenitor cell3838 cells immature B cell1988 cells early lymphoid progenitor1357 cells granulocyte monocyte progenitor cell1281 cells plasmacytoid dendritic cell712 cells endothelial cell of sinusoid550 cells CD16-negative, CD56-bright natural killer cell, human449 cells common myeloid progenitor425 cells endothelial tip cell362 cells CD4-positive, alpha-beta T cell327 cells megakaryocyte-erythroid progenitor cell285 cells muscle precursor cell254 cells common dendritic progenitor224 cells basophil mast progenitor cell175 cells CD8-positive, alpha-beta T cell171 cells natural killer cell136 cells mature NK T cell111 cells myeloid lineage restricted progenitor cell92 cells hematopoietic multipotent progenitor cell92 cells myofibroblast cell78 cells immature innate lymphoid cell67 cells regulatory T cell62 cells lymphoid lineage restricted progenitor cell34 cells macrophage dendritic cell progenitor31 cells immature natural killer cell26 cells 15th week post-fertilization human stage54975 cells 19th week post-fertilization human stage19326 cells 17th week post-fertilization human stage16068 cells 13th week post-fertilization human stage6602 cells 16th week post-fertilization human stage3142 cells 14th week post-fertilization human stage3115 cells 2. CD34+ Fetal Bone Marrow, Fetal Liver, Cord Blood (CITE-seq)
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Late EryP I (Pro-erythroblast)1627 cells Late EryP II (Erythroblast)725 cells DC progenitor II619 cells HsapDv:000019914747 cells NCBITaxon:960627998 cells UBERON:000210716099 cells RBG33508_F90_F103_F1077401 cells RBG33507_F90_F103_F1077346 cells RBG31066_XN33925749 cells RBG33500_F109_F94_F961352 cells RBG33496_F107_CIMA-90_CIMA-100779 cells RBG33494_CIMA-60_CIMA-58_F103638 cells hematopoietic multipotent progenitor cell6422 cells erythroid progenitor cell5428 cells lymphoid lineage restricted progenitor cell2778 cells common lymphoid progenitor1919 cells myeloid lineage restricted progenitor cell1733 cells megakaryocyte-erythroid progenitor cell1666 cells proerythroblast1627 cells precursor B cell1537 cells common dendritic progenitor796 cells umbilical cord blood5749 cells fifth LMP month human stage14747 cells newborn human stage5749 cells 14th week post-fertilization human stage4733 cells fourth LMP month human stage1352 cells 3. Fetal Bone Marrow (10x) - Down Syndrome
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early erythroid1348 cells eo/baso/mast precursor53 cells transitional NK cell11 cells HsapDv:000004912775 cells NCBITaxon:960616743 cells UBERON:000237116743 cells D1_D2_D3_pool_sample_21788 cells D1_D2_D3_pool_sample_3439 cells D1_D2_D3_pool_sample_1388 cells D1_D2_D3_pool_unassigned179 cells primitive red blood cell1348 cells CD14-positive monocyte320 cells CD8-positive, alpha-beta T cell181 cells natural killer cell158 cells megakaryocyte-erythroid progenitor cell130 cells plasmacytoid dendritic cell124 cells precursor B cell115 cells endothelial cell111 cells hematopoietic multipotent progenitor cell105 cells CD16-negative, CD56-bright natural killer cell, human79 cells basophil mast progenitor cell53 cells mesenchymal stem cell53 cells common myeloid progenitor50 cells immature innate lymphoid cell13 cells 12th week post-fertilization human stage12775 cells fourth LMP month human stage2355 cells 13th week post-fertilization human stage1613 cells 4. Human Fetal Bone Marrow (CITE-seq)
Metadata
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pre B progenitor2241 cells pro B progenitor366 cells pre pro B progenitor248 cells stromal macrophage47 cells precursor B cell2241 cells CD14-positive monocyte1384 cells primitive red blood cell517 cells fraction A pre-pro B cell248 cells early lymphoid progenitor177 cells plasmacytoid dendritic cell139 cells granulocyte monocyte progenitor cell108 cells common myeloid progenitor78 cells CD16-negative, CD56-bright natural killer cell, human66 cells endothelial cell of sinusoid42 cells CD4-positive, alpha-beta T cell39 cells hematopoietic multipotent progenitor cell36 cells endothelial tip cell11 cells fifth LMP month human stage8978 cells Analyze this study
Source data
https://cellxgene.cziscience.com/collections/793fdaec-5067-428a-a9db-ecefe135c945
Alias names
GSE166895, ERP125305, E-MTAB-10042, E-MTAB-9389, PMID34588693, PMC7612688
Cite this study
Jardine, L., Webb, S., Goh, I., Quiroga Londoño, M., Reynolds, G., Mather, M., Olabi, B., Stephenson, E., Botting, R.A., Horsfall, D. and Engelbert, J., 2021. Blood and immune development in human fetal bone marrow and Down syndrome. Nature, 598(7880), pp.327-331. https://doi.org/10.1038/s41586-021-03929-x
