Establishment of tissue-resident macrophage core and tissue specific programs during embryogenesis

Abstract

Abstract Tissue resident macrophages develop during embryogenesis, are maintained independently of hematopoietic stem cells during adulthood, and display tissue-specific functions and phenotypes. To understand the genetic program that drives macrophage differentiation from distinct progenitors and their tissue-specific identity, we performed a systematic spatio-temporal analysis of macrophage development in mice. Transcriptional and in situ analyses revealed that a core macrophage program is established very early and within a short time window and is conserved throughout fetal development and in adult macrophages. A new genetic mouse model supports the transcriptional data as it allows to specifically label differentiating macrophages, and therefore targets adult macrophages in all tissues. Interestingly, immediately after colonization of the target tissue, we could identify tissue-specific macrophage programs that are maintained until adulthood. Additionally, we identified a novel transcriptional regulator, which is expressed in early fetal liver macrophages, and whose inactivation results in an impaired Kupffer cell development. In summary, we present a macrophage developmental atlas, identify novel tissue-specific markers and transcriptional regulators, and show that tissue specialization is mainly influenced by ontogenetic gene expression programs.