{"id":["DOI:10.1038/s41586-021-03929-x"],"title":["Blood and immune development in human fetal bone marrow and Down syndrome"],"publication_date":["2021-10-14"],"authors":{"ORCID:0000-0003-4495-8205":{"id":["ORCID:0000-0003-4495-8205"],"family_name":["Jardine"],"personal_name":["Laura"],"affiliations":{"ROR:05cy4wa09":{"organization_name":["Wellcome Sanger Institute"]},"ROR:01kj2bm70":{"organization_name":["Newcastle University"]},"ROR:00cdwy346":{"organization_name":["Freeman Hospital, Newcastle-upon-Tyne Hospitals NHS Foundation Trust"]}}},"ORCID:0000-0003-3058-8952":{"id":["ORCID:0000-0003-3058-8952"],"family_name":["Webb"],"personal_name":["Simone"],"affiliations":{"ROR:05cy4wa09":{"organization_name":["Wellcome Sanger Institute"]},"ROR:01kj2bm70":{"organization_name":["Newcastle University"]}}},"ORCID:0000-0002-6397-3518":{"id":["ORCID:0000-0002-6397-3518"],"family_name":["Goh"],"personal_name":["Issac"],"affiliations":{"ROR:05cy4wa09":{"organization_name":["Wellcome Sanger 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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)."],"HDBItheme":["BloodAndImmune"],"datasets":{"ArrayExpress:E-MTAB-9389":{"id":["ArrayExpress:E-MTAB-9389"],"title":["Single cell analysis of emergent haematopoiesis in the human fetal bone marrow (10X)"],"description":["Haematopoeisis emerges in the human fetal bone marrow (BM) at around 12 post conception weeks. This constitutes the second wave of definitive haematopoiesis following on from the first wave in fetal liver from around 6 post conception weeks. The BM emerges as the dominant site of haematopoiesis, responsible for lifelong blood and immune cell production. Yet, little is known about how the composition of the fetal BM, the microenvironment permissive to establishing haematopoiesis and the interplay with other sites of fetal haematopoiesis in fetal health or disease. Herein we utilise single cell RNA sequencing to describe fetal haematopoeisis throughout gestation and better understand the development of the human immune system."],"authors":{"ORCID:0000-0002-3927-2084":{"id":["ORCID:0000-0002-3927-2084"],"family_name":["Haniffa"],"personal_name":["Muzlifah"],"affiliations":{"ROR:05cy4wa09":{"organization_name":["Wellcome Sanger Institute"]},"ROR:01kj2bm70":{"organization_name":["Newcastle University"]},"ROR:05p40t847":{"organization_name":["Newcastle upon Tyne Hospitals NHS Foundation Trust"]},"ROR:0187kwz08":{"organization_name":["National Institute for Health Research"]}},"HDBItheme":["BloodAndImmune"]}},"tags":["sequencing"]},"ArrayExpress:E-MTAB-10042":{"id":["ArrayExpress:E-MTAB-10042"],"title":["Single cell analysis of emergent haematopoiesis in the human fetal bone marrow (10X) CITE-seq"],"description":["Haematopoeisis emerges in the human fetal bone marrow (BM) at around 12 post conception weeks. This constitutes the second wave of definitive haematopoiesis following on from the first wave in fetal liver from around 6 post conception weeks. The BM emerges as the dominant site of haematopoiesis, responsible for lifelong blood and immune cell production. Yet, little is known about how the composition of the fetal BM, the microenvironment permissive to establishing haematopoiesis and the interplay with other sites of fetal haematopoiesis in fetal health or disease. Herein we utilise single cell RNA sequencing and surface protein characterisation using CITE-seq technology to describe fetal haematopoeisis throughout gestation and better understand the development of the human immune system."],"authors":{"ORCID:0000-0002-3927-2084":{"id":["ORCID:0000-0002-3927-2084"],"family_name":["Haniffa"],"personal_name":["Muzlifah"],"affiliations":{"ROR:05cy4wa09":{"organization_name":["Wellcome Sanger Institute"]},"ROR:01kj2bm70":{"organization_name":["Newcastle University"]},"ROR:05p40t847":{"organization_name":["Newcastle upon Tyne Hospitals NHS Foundation Trust"]},"ROR:0187kwz08":{"organization_name":["National Institute for Health Research"]}},"HDBItheme":["BloodAndImmune"]}},"tags":["sequencing"]},"ArrayExpress:E-MTAB-9801":{"id":["ArrayExpress:E-MTAB-9801"],"title":["Single cell analysis of emergent haematopoiesis in the human fetal bone marrow (SS2)"],"description":["Haematopoeisis emerges in the human fetal bone marrow (BM) at around 12 post conception weeks. This constitutes the second wave of definitive haematopoiesis following on from the first wave in fetal liver from around 6 post conception weeks. The BM emerges as the dominant site of haematopoiesis, responsible for lifelong blood and immune cell production. Yet, little is known about how the composition of the fetal BM, the microenvironment permissive to establishing haematopoiesis and the interplay with other sites of fetal haematopoiesis in fetal health or disease. Herein we utilise single cell RNA sequencing to describe fetal haematopoeisis throughout gestation and better understand the development of the human immune system."],"authors":{"ORCID:0000-0002-3927-2084":{"id":["ORCID:0000-0002-3927-2084"],"family_name":["Haniffa"],"personal_name":["Muzlifah"],"affiliations":{"ROR:05cy4wa09":{"organization_name":["Wellcome Sanger Institute"]},"ROR:01kj2bm70":{"organization_name":["Newcastle University"]},"ROR:05p40t847":{"organization_name":["Newcastle upon Tyne Hospitals NHS Foundation Trust"]},"ROR:0187kwz08":{"organization_name":["National Institute for Health Research"]}},"HDBItheme":["BloodAndImmune"]}},"tags":["sequencing"]},"GEO:GSE166895":{"id":["GEO:GSE166895"],"title":["Blood and immune cell development in human fetal bone marrow and in Down syndrome"],"description":["Throughout postnatal life, haematopoiesis in the bone marrow (BM) maintains blood and immune cell production. Haematopoiesis first emerges in human BM at 11-12 post conception weeks while fetal liver (FL) haematopoiesis is still expanding. Yet, almost nothing is known about how fetal BM evolves to meet the highly specialised needs of the fetus and newborn infant. Here, we detail the development of fetal BM including stroma using single cell RNA-sequencing. We find that the full blood and immune cell repertoire is established in fetal BM in a short time window of 6-7 weeks early in the second trimester. Fetal BM promotes rapid and extensive diversification of myeloid cells, with granulocytes, eosinophils and dendritic cell subsets emerging for the first time.  B-lymphocytes expansion occurs, in contrast with erythroid predominance in FL at the same gestational age. We identify transcriptional and functional differences that underlie tissue-specific identity and cellular diversification in fetal BM and FL. Finally, we reveal selective disruption of B-lymphocyte, erythroid and myeloid development due to cell intrinsic differentiation bias as well as extrinsic regulation through an altered microenvironment in the fetal BM from constitutional chromosome anomaly Down syndrome during this crucial developmental time window."],"authors":{"ORCID:0000-0003-0477-7792":{"id":["ORCID:0000-0003-0477-7792"],"family_name":["Hannah"],"personal_name":["Rebecca"],"affiliations":{"ROR:05nz0zp31":{"organization_name":["Wellcome/MRC Cambridge Stem Cell Institute"]}}},"ORCID:0000-0003-0865-7333":{"id":["ORCID:0000-0003-0865-7333"],"family_name":["Wilson"],"personal_name":["Nicola K."],"affiliations":{"ROR:05nz0zp31":{"organization_name":["Wellcome/MRC Cambridge Stem Cell Institute"]}}},"ORCID:0000-0003-2352-0773":{"id":["ORCID:0000-0003-2352-0773"],"family_name":["Quiroga Londoño"],"personal_name":["Mariana"],"affiliations":{"ROR:05nz0zp31":{"organization_name":["Wellcome/MRC Cambridge Stem Cell Institute"]}}},"ORCID:0000-0001-6302-5705":{"id":["ORCID:0000-0001-6302-5705"],"family_name":["Göttgens"],"personal_name":["Berthold"],"affiliations":{"ROR:05nz0zp31":{"organization_name":["Wellcome/MRC Cambridge Stem Cell Institute"]}},"HDBItheme":["BloodAndImmune"]}},"tags":["sequencing"]},"ENA:PRJEB41514":{"id":["ENA:PRJEB41514"],"title":["HCA_Bone_Foetal_WSSS_RNA_SB"],"description":{},"authors":{},"tags":["sequencing"]}},"code":{"SWHID:swh:1:dir:daa0730c1d55df10d4d3d4685a036f6f0db3d4c3":{"id":["SWHID:swh:1:dir:daa0730c1d55df10d4d3d4685a036f6f0db3d4c3"],"title":["FCA bone marrow study"],"description":["This repository contains all analysis scripts used to explore single cell datasets for: Jardine and Webb et al., 2021, Nature, 'Blood and immune development in human fetal bone marrow and in Down syndrome'."],"authors":{"ORCID:0000-0003-3058-8952":{"id":["ORCID:0000-0003-3058-8952"],"family_name":["Webb"],"personal_name":["Simone"],"affiliations":{"ROR:05cy4wa09":{"organization_name":["Wellcome Sanger Institute"]},"ROR:01kj2bm70":{"organization_name":["Newcastle University"]}}},"ORCID:0000-0002-6397-3518":{"id":["ORCID:0000-0002-6397-3518"],"family_name":["Goh"],"personal_name":["Issac"],"affiliations":{"ROR:05cy4wa09":{"organization_name":["Wellcome Sanger Institute"]},"ROR:01kj2bm70":{"organization_name":["Newcastle University"]}}},"AUTHTEMP:00024":{"id":["AUTHTEMP:00024"],"family_name":["McGrath"],"personal_name":["Jim"],"affiliations":{"ROR:01kj2bm70":{"organization_name":["Newcastle University"]}}},"ORCID:0000-0003-2352-0773":{"id":["ORCID:0000-0003-2352-0773"],"family_name":["Quiroga Londoño"],"personal_name":["Mariana"],"affiliations":{"ROR:05nz0zp31":{"organization_name":["Wellcome/MRC Cambridge Stem Cell Institute"]}}},"ORCID:0000-0002-8142-8708":{"id":["ORCID:0000-0002-8142-8708"],"family_name":["Reynolds"],"personal_name":["Gary"],"affiliations":{"ROR:01kj2bm70":{"organization_name":["Newcastle University"]}}}}}}}