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^1,2, 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).

骨髓 (BM) 中的造血在整个出生后维持血液和免疫细胞的产生。造血在受孕后 11-12 周首次出现在人类 BM 中^1,2，但对于胎儿 BM (FBM) 如何进化以满足胎儿和新生儿的高度专业化需求几乎一无所知。在这里，我们使用 mRNA 和多重蛋白质表位表达的多组学评估详细介绍了 FBM 的发展，包括基质。我们发现，在妊娠中期早期的 6-7 周的短时间内，在 FBM 中建立了全血和免疫细胞库。FBM 促进了骨髓细胞的快速和广泛的多样化，粒细胞、嗜酸性粒细胞和树突状细胞亚群首次出现。FBM中B淋巴细胞的大量扩增与相同胎龄的胎儿肝脏形成对比。来自胎儿肝脏、FBM 和脐带血的造血祖细胞表现出转录和功能差异，这有助于组织特异性身份和细胞多样化。内皮细胞类型形成不同的血管结构，我们显示这些结构在 FBM 内区域划分。最后，我们揭示了 B 淋巴细胞、红细胞和骨髓发育的选择性破坏，这是由于唐氏综合征（21 三体）中细胞内在分化偏向以及通过改变的微环境进行的外在调节。