Single-cell transcriptomics of human embryos identifies multiple sympathoblast lineages with potential implications for neuroblastoma origin
Kameneva, Polina; Artemov, Artem V.; Kastriti, Maria Eleni; Faure, Louis; Olsen, Thale K.; Otte, Jörg; Erickson, Alek; Semsch, Bettina; Andersson, Emma R.; Ratz, Michael; Frisén, Jonas; Tischler, Arthur S.; de Krijger, Ronald R.; Bouderlique, Thibault; Akkuratova, Natalia; Vorontsova, Maria; Gusev, Oleg; Fried, Kaj; Sundström, Erik; Mei, Shenglin; Kogner, Per; Baryawno, Ninib; Kharchenko, Peter V.; Adameyko, Igor
(2021) Nature Genetics, volume 53, issue 5, pp. 694 - 706
(Article)
Abstract
Characterization of the progression of cellular states during human embryogenesis can provide insights into the origin of pediatric diseases. We examined the transcriptional states of neural crest– and mesoderm-derived lineages differentiating into adrenal glands, kidneys, endothelium and hematopoietic tissue between post-conception weeks 6 and 14 of human development. Our results
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reveal transitions connecting the intermediate mesoderm and progenitors of organ primordia, the hematopoietic system and endothelial subtypes. Unexpectedly, by using a combination of single-cell transcriptomics and lineage tracing, we found that intra-adrenal sympathoblasts at that stage are directly derived from nerve-associated Schwann cell precursors, similarly to local chromaffin cells, whereas the majority of extra-adrenal sympathoblasts arise from the migratory neural crest. In humans, this process persists during several weeks of development within the large intra-adrenal ganglia-like structures, which may also serve as reservoirs of originating cells in neuroblastoma.
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Keywords: Animals, Cell Lineage, Chromaffin Cells/metabolism, Cluster Analysis, Embryo, Mammalian/metabolism, Embryonic Development, Gene Expression Regulation, Developmental, Gene Expression Regulation, Neoplastic, Humans, Infant, Mice, Neural Stem Cells/metabolism, Neuroblastoma/embryology, Schwann Cells/metabolism, Single-Cell Analysis, Sympathoadrenal System/embryology, Transcriptome/genetics, Tumor Microenvironment, Genetics, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Journal Article, Research Support, N.I.H., Extramural
ISSN: 1061-4036
Publisher: Nature Publishing Group
Note: Funding Information: I.A. was supported by the Paradifference Foundation, the Swedish Cancer Society, the Bertil Hallsten Research Foundation, a Knut and Alice Wallenberg Foundation project grant, an ERACoSysMed 4D-Healing grant, the Swedish Research Council, ERC Consolidator (‘STEMMING FROM NERVE’, 647844), ERC Synergy (‘KILL OR DIFFERENTIATE’, 856529, ERC-2019-SyG), an Austrian Science Fund (FWF) grant and EMBO Young Investigator grants. O.G. was supported by the Russian Science Foundation (grant N19-14-00260 for regulatory element analysis). M.V. was supported by the Ministry of Science and Higher Education of the Russian Federation (agreement no. 075-15-2020-784). L.F. was supported by the Austrian Science Fund (DOC 33-B27). M.E.K. was supported by the Novo Nordisk Foundation (Postdoctoral Fellowship in Endocrinology and Metabolism at International Elite Environments, NNF17OC0026874) and Stiftelsen Riksbankens Jubileumsfond (Erik Rönnbergs fond stipend). P. Kogner was funded by the Swedish Research Council, the Swedish Childhood Cancer Fund, the Swedish Cancer Society and the Swedish Foundation for Strategic Research. T.K.O., N.B. and P. Kogner were financially supported by the Knut and Alice Wallenberg Foundation as part of the National Bioinformatics Infrastructure Sweden at SciLifeLab. N.A. was supported by the Russian Science Foundation (grant no. 16-15-10273 for immunohistochemical validation of bioinformatic predictions). A.V.A. was supported by the Russian Science Foundation (grant no. 19-15-00241 for bioinformatic analysis of the mouse dataset) and an ERACoSysMed 4D-Healing grant. T.B. was supported by the Lise Meitner Programme. A.E. was supported by StratNeuro SRP Postdoctoral Research 2020–2021 (C333740002), E.R.A. and B.S. were supported by the Swedish Research Council, Karolinska Institutet (KI Foundations, Career Development grant, PhD student KID funding and SFO StratNeuro funding, the Center of Innovative Medicine), the Ollie and Elof Ericssons Foundation, the Tornspiran Foundation, the Jeanssons Foundation, a Sven and Ebba-Christina Hagbergs prize and research grant, a Knut and Alice Wallenberg project grant, the Fredrik and Ingrid Thurings Foundation, Lars Hiertas Minne, the Childhood Cancer Foundation (Barncancerfonden), the Åhlen Foundation, the Åke Wibergs Foundation, the Tore Nilssons Foundation and a Swedish Foundations starting grant. E.S. acknowledges the Knut and Alice Wallenberg Foundation and the Erling Person Foundation for generous support. M.R. was supported by a DFG research fellowship (RA 2889/1-1). J.F. was supported by the Swedish Foundation for Strategic Research. P.V.K. and S.M. were supported by the NIH (1R01HL131768 from NHLBI) and the NSF (CAREER 1452964). We thank the KI Developmental Tissue Bank for providing prenatal human tissue. We thank O. Kharchenko for help with illustrations. We also thank the Karolinska Eukaryotic Single Cell Genomics Facility (M. Erickson and K. Wallenborg) at SciLifeLab, Sweden for assistance with sequencing single cells. The 2h3 antibody (P12839) developed by T.M. Jessell and J. Dodd was obtained from the Developmental Studies Hybridoma Bank, created by the NICHD of the NIH and maintained at the Department of Biology, University of Iowa, Iowa City, IA 52242. Publisher Copyright: © 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.
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