Adult Langerhans cells derive predominantly from embryonic fetal liver monocytes with a minor contribution of yolk sac–derived macrophages

TLDR

Langerhans cells are epidermal dendritic cells that arise from hematopoietic precursors seeding the skin before birth, yet their embryonic origin remains unclear. The study aims to trace the lineage of Langerhans cell precursors to identify their embryonic source. In vivo lineage tracing uncovered a first wave of yolk sac–derived primitive myeloid progenitors that migrate to the embryo, giving rise to LC precursors in the skin and microglia in the brain. Adult Langerhans cells are predominantly derived from fetal liver monocytes, with only a minor contribution from yolk sac–derived cells, revealing a dual embryonic and late fetal origin.

Abstract

Langerhans cells (LCs) are the dendritic cells (DCs) of the epidermis, forming one of the first hematopoietic lines of defense against skin pathogens. In contrast to other DCs, LCs arise from hematopoietic precursors that seed the skin before birth. However, the origin of these embryonic precursors remains unclear. Using in vivo lineage tracing, we identify a first wave of yolk sac (YS)-derived primitive myeloid progenitors that seed the skin before the onset of fetal liver hematopoiesis. YS progenitors migrate to the embryo proper, including the prospective skin, where they give rise to LC precursors, and the brain rudiment, where they give rise to microglial cells. However, in contrast to microglia, which remain of YS origin throughout life, YS-derived LC precursors are largely replaced by fetal liver monocytes during late embryogenesis. Consequently, adult LCs derive predominantly from fetal liver monocyte-derived cells with a minor contribution of YS-derived cells. Altogether, we establish that adult LCs have a dual origin, bridging early embryonic and late fetal myeloid development.