Holistic genetic barcoding reveals a lineage tree of tissue macrophage development

Abstract

Tissue macrophages are crucial for organ development and homeostasis, yet the developmental routes leading to tissue macrophages remain controversial. By combining unbiased Polylox barcoding with computational inference, we comprehensively mapped tissue macrophage ontogeny in mice from gastrulation to adult organs. Our data reveal a lineage tree of all tissue macrophages. This tree originates from a pan-hematopoietic progenitor at embryonic day (E)6.5 and branches, via oligolineage progenitors (E7.5-E9.5), into organ-specific macrophage lineages by E10.5. Barcode analysis in embryonic tissues and adult organ fragments suggests that local macrophage colonies, formed by organ-specific progenitors, persist into adulthood. Indeed, spatial fate mapping with Polytope barcoding detects local Kupffer cell colonies of the size predicted by the lineage tree model. Our findings uncover the origin of tissue-resident macrophages from a lineage tree, and show how holistic barcoding can comprehensively map complex cellular lineage specification. One-Sentence SummaryHolistic, time- and space-resolved barcoding in the embryo reveals a unified lineage tree for all tissue macrophages, generating local macrophage colonies persisting in adult organs.