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Nature
10, 2019;574 (7778): 365-371.

Decoding human fetal liver haematopoiesis.

Dorin-Mirel Popescu, Rachel A Botting, Emily Stephenson, Kile Green, Simone Webb, Laura Jardine, Emily F Calderbank, Krzysztof Polanski, Issac Goh, Mirjana Efremova, Meghan Acres, Daniel Maunder, Peter Vegh, Yorick Gitton, Jong-Eun Park, Roser Vento-Tormo, Zhichao Miao, David Dixon, Rachel Rowell, David McDonald, James Fletcher, Elizabeth Poyner, Gary Reynolds, Michael Mather, Corina Moldovan, Lira Mamanova, Frankie Greig, Matthew D Young, Kerstin B Meyer, Steven Lisgo, Jaume Bacardit, Andrew Fuller, Ben Millar, Barbara Innes, Susan Lindsay, Michael J T Stubbington, Monika S Kowalczyk, Bo Li, Orr Ashenberg, Marcin Tabaka, Danielle Dionne, Timothy L Tickle, Michal Slyper, Orit Rozenblatt-Rosen, Andrew Filby, Peter Carey, Alexandra-Chlo�� Villani, Anindita Roy, Aviv Regev, Alain Ch��dotal, Irene Roberts, Berthold G��ttgens, Sam Behjati, Elisa Laurenti, Sarah A Teichmann, Muzlifah Haniffa
Author Information
  1. Dorin-Mirel Popescu: Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
  2. Rachel A Botting: Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
  3. Emily Stephenson: Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
  4. Kile Green: Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
  5. Simone Webb: Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
  6. Laura Jardine: Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
  7. Emily F Calderbank: Department of Haematology and Wellcome and MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK.
  8. Krzysztof Polanski: Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK.
  9. Issac Goh: Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
  10. Mirjana Efremova: Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK.
  11. Meghan Acres: Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
  12. Daniel Maunder: Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
  13. Peter Vegh: Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
  14. Yorick Gitton: Sorbonne Universit��, INSERM, CNRS, Institut de la Vision, Paris, France.
  15. Jong-Eun Park: Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK.
  16. Roser Vento-Tormo: Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK.
  17. Zhichao Miao: Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK.
  18. David Dixon: Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
  19. Rachel Rowell: Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
  20. David McDonald: Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
  21. James Fletcher: Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
  22. Elizabeth Poyner: Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
  23. Gary Reynolds: Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
  24. Michael Mather: Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
  25. Corina Moldovan: Department of Pathology, Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.
  26. Lira Mamanova: Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK.
  27. Frankie Greig: Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
  28. Matthew D Young: Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK.
  29. Kerstin B Meyer: Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK.
  30. Steven Lisgo: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK.
  31. Jaume Bacardit: School of Computing, Newcastle University, Newcastle upon Tyne, UK.
  32. Andrew Fuller: Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
  33. Ben Millar: Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
  34. Barbara Innes: Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
  35. Susan Lindsay: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK.
  36. Michael J T Stubbington: Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK.
  37. Monika S Kowalczyk: Klarman Cell Observatory, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
  38. Bo Li: Klarman Cell Observatory, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
  39. Orr Ashenberg: Klarman Cell Observatory, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
  40. Marcin Tabaka: Klarman Cell Observatory, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
  41. Danielle Dionne: Klarman Cell Observatory, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
  42. Timothy L Tickle: Klarman Cell Observatory, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
  43. Michal Slyper: Klarman Cell Observatory, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
  44. Orit Rozenblatt-Rosen: Klarman Cell Observatory, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
  45. Andrew Filby: Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
  46. Peter Carey: Broad Institute of Harvard and MIT, Cambridge, MA, USA.
  47. Alexandra-Chlo�� Villani: Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, MA, USA.
  48. Anindita Roy: Department of Paediatrics, University of Oxford, Oxford, UK.
  49. Aviv Regev: Klarman Cell Observatory, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
  50. Alain Ch��dotal: Sorbonne Universit��, INSERM, CNRS, Institut de la Vision, Paris, France.
  51. Irene Roberts: Department of Paediatrics, University of Oxford, Oxford, UK.
  52. Berthold G��ttgens: Department of Haematology and Wellcome and MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK.
  53. Sam Behjati: Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK. sb31@sanger.ac.uk.
  54. Elisa Laurenti: Department of Haematology and Wellcome and MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK. el422@cam.ac.uk.
  55. Sarah A Teichmann: Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK. st9@sanger.ac.uk.
  56. Muzlifah Haniffa: Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK. m.a.haniffa@newcastle.ac.uk.
PMID: 31597962 DOI: 10.1038/s41586-019-1652-y

Abstract

Definitive haematopoiesis in the fetal liver supports self-renewal and differentiation of haematopoietic stem cells and multipotent progenitors (HSC/MPPs) but remains poorly defined in humans. Here, using single-cell transcriptome profiling of approximately 140,000 liver and 74,000 skin, kidney and yolk sac cells, we identify the repertoire of human blood and immune cells during development. We infer differentiation trajectories from HSC/MPPs and evaluate the influence of the tissue microenvironment on blood and immune cell development. We reveal physiological erythropoiesis in fetal skin and the presence of mast cells, natural killer and innate lymphoid cell precursors in the yolk sac. We demonstrate a shift in the haemopoietic composition of fetal liver during gestation away from being predominantly erythroid, accompanied by a parallel change in differentiation potential of HSC/MPPs, which we functionally validate. Our integrated map of fetal liver haematopoiesis provides a blueprint for the study of paediatric blood and immune disorders, and a reference for harnessing the therapeutic potential of HSC/MPPs.

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Grants

  1. 110104/Wellcome Trust
  2. 206194/Wellcome Trust
  3. MR/R006237/1/Medical Research Council
  4. MC_PC_16040/Medical Research Council
  5. /Wellcome Trust
  6. MC_UU_00016/13/Medical Research Council
  7. MC_UU_12009/14/Medical Research Council
  8. MC_PC_12009/Medical Research Council
  9. 107931/Wellcome Trust
  10. 211276/Wellcome Trust

MeSH Term

Blood Cells
Cellular Microenvironment
Female
Fetus
Flow Cytometry
Gene Expression Profiling
Hematopoiesis
Humans
Liver
Lymphoid Tissue
Single-Cell Analysis
Stem Cells
Journal Article

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