Specification of tissue-resident macrophages during organogenesis

TLDR

Tissue‑resident macrophages are essential for embryonic development, tissue homeostasis, and repair, yet the mechanisms governing their differentiation remain unclear. The study proposes that macrophage differentiation is integral to organogenesis, with embryonic colonization by premacrophages leading to tissue‑specific macrophage specification and diversity. Erythro‑myeloid progenitors generate premacrophages that colonize the embryo from E9.5 via chemokine‑receptor signaling, rapidly diversify into tissue‑specific macrophages, and Id3 loss disrupts liver macrophage development, leading to adult Kupffer cell deficiency.

Abstract

Tissue-resident macrophages support embryonic development and tissue homeostasis and repair. The mechanisms that control their differentiation remain unclear. We report here that erythro-myeloid progenitors in mice generate premacrophages (pMacs) that simultaneously colonize the whole embryo from embryonic day 9.5 in a chemokine-receptor-dependent manner. The core macrophage program initiated in pMacs is rapidly diversified as expression of transcriptional regulators becomes tissue-specific in early macrophages. This process appears essential for macrophage specification and maintenance, as inactivation of Id3 impairs the development of liver macrophages and results in selective Kupffer cell deficiency in adults. We propose that macrophage differentiation is an integral part of organogenesis, as colonization of organ anlagen by pMacs is followed by their specification into tissue macrophages, hereby generating the macrophage diversity observed in postnatal tissues.