Fetal and neonatal murine skin harbors Langerhans cell precursors

Abstract

Resident epidermal Langerhans cells (LC) in adult mice express ADPase, major histocompatibility complex (MHC) class II, and CD205 and CD207 molecules, while the first dendritic leukocytes that colonize the fetal and newborn epidermis are only ADPase(+). In this study, we tested whether dendritic epidermal leukocytes (DEL) are end-stage cells or represent LC precursors. In epidermal sheets of fetal and neonatal mice, we found no apoptotic leukocytes, suggesting that these cells do not die in situ. To address whether DEL can give rise to LC, sorted DEL from murine newborn skin were cultured with cytokines used to generate LC from human CD34(+) precursors. After 7-14 days, DEL proliferated and acquired the morphology and phenotype of cells reminiscent of LC. In concordance with this finding, we show that neonatal epidermis harbors 10-20 times the number of cycling MHC class II(+) leukocytes as adult tissue. To test whether LC can differentiate from skin precursors in vivo, we developed a transplantation model. As it was impossible to transplant fetal epidermis, whole fetal skin was grafted onto adult severe combined immunodeficient mice. As opposed to the uniform absence of donor LC at the time of transplantation, examination of the epidermis from the grafts after 2-4 weeks revealed MHC class II(+) donor cells, which had acquired CD205 and CD207, thus qualifying them as LC. Finally, we present evidence that endogenous LC persist in skin grafts for the observation period of 45 days. These studies show that hematopoietic precursors seed the skin during embryonic life and can give rise to LC.

Flk2+ myeloid progenitors are the main source of Langerhans cells

“…30 Unfortunately, the capacity of DELs to generate LCs in vivo was not evaluated in this study. 30 Whether such skin-resident LC precursors originate from CLPs or CMPs during inflammation, or represent an independent source of LCs, remains unanswered.…”

“…30 Unfortunately, the capacity of DELs to generate LCs in vivo was not evaluated in this study. 30 Whether such skin-resident LC precursors originate from CLPs or CMPs during inflammation, or represent an independent source of LCs, remains unanswered. Our observation that progenitor-derived LCs typically appeared in clusters suggests that CMP-and CLP-derived progenitors may continue to proliferate after they are recruited to the skin.…”

The late endosomal adaptor molecule p14 (LAMTOR2) represents a novel regulator of Langerhans cell homeostasis

“…25,26 Hence, we asked whether p14 deletion in LCs affects this early wave of proliferation. To this end, we assessed LC mitosis in situ using phospho-histone H3 expression as a specific marker.…”

“…It is, however, extremely difficult to isolate sufficient amounts of highly purified LCs from the skin of newborn mice, 25 particularly from the declining LC pool in CD11c-p14 del mice. Therefore, we turned to BM-derived DCs (BMDCs) obtained from CD11c-p14 del and control mice ( Figure 7A).…”

Abnormalities of dendritic cell precursors in the pancreas of the NOD mouse model of diabetes

“…In organs, such as the skin and brain, local precursors for macrophages and Langerhans cells have been detected [9][10][11]. We earlier described the presence of local precursors for macrophages in the fetal pancreas of C57BL/6 mice [12].…”