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Tissue-resident macrophages, such as microglia, Kupffer cells, and Langerhans cells, derive from Myb-independent yolk sac (YS) progenitors generated before the emergence of hematopoietic stem cells (HSCs). Myb-independent YS-derived resident macrophages self-renew locally, independently of circulating monocytes and HSCs. In contrast, adult blood monocytes, as well as infiltrating, gut, and dermal macrophages, derive from Myb-dependent HSCs. These findings are derived from the mouse, using gene knockouts and lineage tracing, but their applicability to human development has not been formally demonstrated. Here, we use human induced pluripotent stem cells (iPSCs) as a tool to model human hematopoietic development. By using a CRISPR-Cas9 knockout strategy, we show that human iPSC-derived monocytes/macrophages develop in an MYB-independent, RUNX1-, and SPI1 (PU.1)-dependent fashion. This result makes human iPSC-derived macrophages developmentally related to and a good model for MYB-independent tissue-resident macrophages, such as alveolar and kidney macrophages, microglia, Kupffer cells, and Langerhans cells.

Original publication

DOI

10.1016/j.stemcr.2016.12.020

Type

Journal article

Journal

Stem Cell Reports

Publication Date

14/02/2017

Volume

8

Pages

334 - 345

Keywords

MYB, RUNX1, SPI1, hematopoiesis, human iPSC macrophages, Biomarkers, Cell Differentiation, Cell Line, Core Binding Factor Alpha 2 Subunit, Embryoid Bodies, Erythrocytes, Gene Expression, Gene Expression Regulation, Developmental, Gene Knockout Techniques, Genes, myb, Granulocytes, Hematopoietic Stem Cells, Humans, Induced Pluripotent Stem Cells, Macrophages, Monocytes, Organ Specificity, Phenotype, Proto-Oncogene Proteins, Trans-Activators