Multipotent RAG1+ progenitors emerge directly from haemogenic endothelium in human pluripotent stem cell-derived haematopoietic organoids

Ali Motazedian, Freya F. Bruveris, Santhosh V. Kumar, Jacqueline V. Schiesser, Tyrone Chen, Elizabeth S. Ng, Ann P. Chidgey, Christine A. Wells, Andrew G. Elefanty, Edouard G. Stanley

Research output: Contribution to journalArticleResearchpeer-review

3 Citations (Scopus)

Abstract

Defining the ontogeny of the human adaptive immune system during embryogenesis has implications for understanding childhood diseases including leukaemias and autoimmune conditions. Using RAG1:GFP human pluripotent stem cell reporter lines, we examined human T-cell genesis from pluripotent-stem-cell-derived haematopoietic organoids. Under conditions favouring T-cell development, RAG1+ cells progressively upregulated a cohort of recognized T-cell-associated genes, arresting development at the CD4+CD8+ stage. Sort and re-culture experiments showed that early RAG1+ cells also possessed B-cell, myeloid and erythroid potential. Flow cytometry and single-cell-RNA-sequencing data showed that early RAG1+ cells co-expressed the endothelial/haematopoietic progenitor markers CD34, VECAD and CD90, whereas imaging studies identified RAG1+ cells within CD31+ endothelial structures that co-expressed SOX17+ or the endothelial marker CAV1. Collectively, these observations provide evidence for a wave of human T-cell development that originates directly from haemogenic endothelium via a RAG1+ intermediate with multilineage potential.

Original languageEnglish
Pages (from-to)60-73
Number of pages14
JournalNature Cell Biology
Volume22
Issue number1
DOIs
Publication statusPublished - 6 Jan 2020

Keywords

  • cell biology
  • stem cells

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