Potently Cytotoxic Natural Killer Cells Initially Emerge from Erythro-Myeloid Progenitors during Mammalian Development

Carissa Dege, Katherine H. Fegan, J. Philip Creamer, Melissa M. Berrien-Elliott, Stephanie A. Luff, Darren Kim, Julia A. Wagner, Paul D. Kingsley, Kathleen E. McGrath, Todd A. Fehniger, James Palis, Christopher M. Sturgeon

Research output: Contribution to journalArticlepeer-review

54 Scopus citations


Natural killer (NK) cells are a critical component of the innate immune system. However, their ontogenic origin has remained unclear. Here, we report that NK cell potential first arises from Hoxaneg/low Kit+CD41+CD16/32+ hematopoietic-stem-cell (HSC)-independent erythro-myeloid progenitors (EMPs) present in the murine yolk sac. EMP-derived NK cells and primary fetal NK cells, unlike their adult counterparts, exhibit robust degranulation in response to stimulation. Parallel studies using human pluripotent stem cells (hPSCs) revealed that HOXAneg/low CD34+ progenitors give rise to NK cells that, similar to murine EMP-derived NK cells, harbor a potent cytotoxic degranulation bias. In contrast, hPSC-derived HOXA+ CD34+ progenitors, as well as human cord blood CD34+ cells, give rise to NK cells that exhibit an attenuated degranulation response but robustly produce inflammatory cytokines. Collectively, our studies identify an extra-embryonic origin of potently cytotoxic NK cells, suggesting that ontogenic origin is a relevant factor in designing hPSC-derived adoptive immunotherapies.

Original languageEnglish
Pages (from-to)229-239.e7
JournalDevelopmental cell
Issue number2
StatePublished - Apr 20 2020


  • EMP
  • HSC-independent
  • adoptive immunotherapy
  • definitive hematopoiesis
  • erythro-myeloid progenitor
  • human pluripotent stem cells
  • natural killer cells
  • ontogeny
  • primitive hematopoiesis
  • yolk sac


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