Abstract
The origin of Langerhans cells (LCs), which are skin epidermis-resident macrophages, remains unclear. Current lineage tracing of LCs largely relies on the promoter-Cre-LoxP system, which often gives rise to contradictory conclusions with different promoters. Thus, reinvestigation with an improved tracing method is necessary. Here, using a laser-mediated temporal-spatial resolved cell labeling method, we demonstrated that most adult LCs originated from the ventral wall of the dorsal aorta (VDA), an equivalent to the mouse aorta, gonads, and mesonephros (AGM), where both hematopoietic stem cells (HSCs) and non-HSC progenitors are generated. Further fine-fate mapping analysis revealed that the appearance of LCs in adult zebrafish was correlated with the development of HSCs, but not T cell progenitors. Finally, we showed that the appearance of tissue-resident macrophages in the brain, liver, heart, and gut of adult zebrafish was also correlated with HSCs. Thus, the results of our study challenged the EMP-origin theory for LCs.
Highlights
Langerhans cells (LCs) are resident macrophages in skin epidermis, where they have immune-stimulatory capacities
The rostral blood island (RBI) region was labeled at 14–16 hpf when embryonic myelopoiesis begins (Ciau-Uitz et al, 2014), the ventral wall of the dorsal aorta (VDA) region was labeled at 28 hpf when the endothelial hematopoietic transition (EHT) occurs (Kissa and Herbomel, 2010), and the posterior blood island (PBI) region was heat-shocked at 20 hpf to prevent contamination of the RBI- and VDA-derived cells by the circulation which begins at ~25 hpf (Figure 1—figure supplement 1C and D) (Ciau-Uitz et al, 2014)
The RBI was the primary source for LCs at early embryonic stages, most (~80% LCs are GFP+) LCs in the adult zebrafish (3 months old) were of a VDA origin and only limited numbers of adult LCs were derived from the RBI and PBI, compared with non-heatshocked control fish (Figure 1B–D, Figure 1—source data 1)
Summary
Langerhans cells (LCs) are resident macrophages in skin epidermis, where they have immune-stimulatory capacities. Several studies have suggested that LCs confer immune tolerance of the skin (Bobr et al, 2010; Chopin and Nutt, 2015; Kaplan et al, 2005; Merad et al, 2008; Romani et al, 2012; Shklovskaya et al, 2011; van der Aar et al, 2013). The biological significance of the opposing roles of LCs remains unclear, but it is thought that LCs dampen the immune response under steady-state conditions, but activate the response upon challenge (Seneschal et al, 2012)
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