Robust temporal map of human in vitro myelopoiesis using single-cell genomics

Author:

Alsinet ClaraORCID,Primo Maria NascimentoORCID,Lorenzi ValentinaORCID,Bello EricaORCID,Kelava Iva,Jones Carla P.ORCID,Vilarrasa-Blasi RoserORCID,Sancho-Serra Carmen,Knights Andrew J.ORCID,Park Jong-EunORCID,Wyspianska Beata S.,Trynka GosiaORCID,Tough David F.,Bassett AndrewORCID,Gaffney Daniel J.ORCID,Alvarez-Errico DamianaORCID,Vento-Tormo RoserORCID

Abstract

AbstractMyeloid cells are central to homeostasis and immunity. Characterising in vitro myelopoiesis protocols is imperative for their use in research, immunotherapies, and understanding human myelopoiesis. Here, we generate a >470K cells molecular map of human induced pluripotent stem cells (iPSC) differentiation into macrophages. Integration with in vivo single-cell atlases shows in vitro differentiation recapitulates features of yolk sac hematopoiesis, before definitive hematopoietic stem cells (HSC) emerge. The diversity of myeloid cells generated, including mast cells and monocytes, suggests that HSC-independent hematopoiesis can produce multiple myeloid lineages. We uncover poorly described myeloid progenitors and conservation between in vivo and in vitro regulatory programs. Additionally, we develop a protocol to produce iPSC-derived dendritic cells (DC) resembling cDC2. Using CRISPR/Cas9 knock-outs, we validate the effects of key transcription factors in macrophage and DC ontogeny. This roadmap of myeloid differentiation is an important resource for investigating human fetal hematopoiesis and new therapeutic opportunities.

Publisher

Springer Science and Business Media LLC

Subject

General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary

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