Intrinsic and extrinsic regulation of human fetal bone marrow haematopoiesis and perturbations in Down syndrome
Intrinsic and extrinsic regulation of human fetal bone marrow haematopoiesis and perturbations in Down syndrome
复制标题
DOI：
10.1101/2021.06.25.449771
复制
发表时间：
2021-06
期刊：
影响因子：
--
通讯作者：
Laura Jardine;S. Webb;Issac Goh;Mariana Quiroga Londoño;G. Reynolds;M. Mather;B. Olabi;Emily Stephenson;R. Botting;D. Horsfall;J. Engelbert;Daniel Maunder;N. Mende;Caitlin Murnane;Emma Dann;J. McGrath;Hamish W. King;I. Kucinski;R. Queen;Christopher D. Carey;C. Shrubsole;Elizabeth Poyner;M. Acres;Claire Jones;T. Ness;Rowan Coulthard;N. Elliott;Sorcha O’Byrne;M. Haltalli;Johnathan E. Lawrence;S. Lisgo;P. Balogh;K. Meyer;E. Prigmore;K. Ambridge;M. S. Jain;M. Efremova;K. Pickard;T. Creasey;J. Bacardit;D. Henderson;J. Coxhead;A. Filby;Rafiqul Hussain;D. Dixon;David McDonald;Dorin-Mirel Popescu;Monika S. Kowalczyk;Bo Li-;Orr Ashenberg;M. Tabaka;Danielle Dionne;Timothy L. Tickle;M. Slyper;O. Rozenblatt-Rosen;A. Regev;S. Behjati;E. Laurenti;Nicola K. Wilson;A. Roy;B. Göttgens;I. Roberts;S. Teichmann;M. Haniffa
中科院分区：
文献类型：
--
作者：
Laura Jardine;S. Webb;Issac Goh;Mariana Quiroga Londoño;G. Reynolds;M. Mather;B. Olabi;Emily Stephenson;R. Botting;D. Horsfall;J. Engelbert;Daniel Maunder;N. Mende;Caitlin Murnane;Emma Dann;J. McGrath;Hamish W. King;I. Kucinski;R. Queen;Christopher D. Carey;C. Shrubsole;Elizabeth Poyner;M. Acres;Claire Jones;T. Ness;Rowan Coulthard;N. Elliott;Sorcha O’Byrne;M. Haltalli;Johnathan E. Lawrence;S. Lisgo;P. Balogh;K. Meyer;E. Prigmore;K. Ambridge;M. S. Jain;M. Efremova;K. Pickard;T. Creasey;J. Bacardit;D. Henderson;J. Coxhead;A. Filby;Rafiqul Hussain;D. Dixon;David McDonald;Dorin-Mirel Popescu;Monika S. Kowalczyk;Bo Li-;Orr Ashenberg;M. Tabaka;Danielle Dionne;Timothy L. Tickle;M. Slyper;O. Rozenblatt-Rosen;A. Regev;S. Behjati;E. Laurenti;Nicola K. Wilson;A. Roy;B. Göttgens;I. Roberts;S. Teichmann;M. Haniffa
在出生后的整个生命过程中，骨髓 (BM) 中的造血作用维持着血液和免疫细胞的产生。人类骨髓中在受孕后 12 周首次出现造血作用，而胎儿肝脏 (FL) 造血作用仍在扩大。然而，对于胎儿骨髓如何进化以满足胎儿和新生儿高度专业化的需求几乎一无所知。在这里，我们使用单细胞 RNA 测序详细介绍了胎儿 BM（包括基质）的发育。我们发现，在妊娠中期早期 6-7 周的短时间内，胎儿 BM 中就建立了完整的血液和免疫细胞库。胎儿骨髓促进骨髓细胞快速、广泛多样化，粒细胞、嗜酸性粒细胞和树突状细胞 (DC) 亚群首次出现。与相同胎龄的 FL 中红细胞占优势相反，B 淋巴细胞发生扩增。我们确定了胎儿 BM 和 FL 中组织特异性身份和细胞多样化背后的转录和功能差异。最后，我们揭示了由于细胞内在分化偏差以及在这个关键的发育时间窗口期间由于体质性染色体异常唐氏综合症导致胎儿骨髓微环境改变的外在调节，B淋巴细胞、红细胞和骨髓发育的选择性破坏。
Throughout postnatal life, haematopoiesis in the bone marrow (BM) maintains blood and immune cell production. Haematopoiesis first emerges in human BM at 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 (DC) subsets emerging for the first time. B-lymphocyte 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.