Abstract: In this study, we show that during digit development, the embryonic limb contains an abundant and widespread population of "resident macrophages" that precede the onset of interdigital cell death responsible for the separation of digit primordia. The use of cultures of interdigital mesoderm at different remodeling stages, and GFP+ transgenic embryos in which the distal part of the autopodium has been surgically replaced by a fragment with identical characteristics from wild-type embryos, indicate that transient macrophages" are also recruited at the beginning of interdigital death. The expression of the Pu.1 gene in coincidence with the onset of interdigital death suggests that primary yolk-sac macrophages are later complemented by macrophages of hematopoietic origin. Q-PCR analysis revealed a predominant M2/anti-inflammatory gene signature in the interdigits during the whole remodeling process that correlated with an interdigital transcriptome including Csf1, Il-34, Igf1, Igfbp5, Tgfbeta4 (Tgfbeta1 in mammals), P75NTR/ Tnfrsf16, Hgf, Vegfa, that presumably stabilizes the macrophage M2 phenotype. However, M1-proinflammatory genes, including Tnfalfa and Tlr4, are expressed at very low levels prior to the onset of cell death but become up-regulated at the end of tissue remodeling. Together, our findings support the existence of "Tissue-Resident" and "Passenger/Transitory" macrophage populations of distinct origin and molecular profile participating in tissue remodeling processes associated with embryonic morphogenesis.

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