Macrophages restrict the nephrogenic field and promote endothelial connections during kidney development

Abstract

The origins and functions of kidney macrophages in the adult have been explored, but their roles during development remain largely unknown. Here we characterise macrophage arrival, localisation, heterogeneity, and functions during kidney organogenesis. Using genetic approaches to ablate macrophages, we identify a role for macrophages in nephron progenitor cell clearance as mouse kidney development begins. Throughout renal organogenesis, most kidney macrophages are perivascular and express F4/80 and CD206. These macrophages are enriched for mRNAs linked to developmental processes, such as blood vessel morphogenesis. Using antibody-mediated macrophage-depletion, we show macrophages support vascular anastomoses in cultured kidney explants. We also characterise a subpopulation of galectin-3+ (Gal3+) myeloid cells within the developing kidney. Our findings may stimulate research into macrophage-based therapies for renal developmental abnormalities and have implications for the generation of bioengineered kidney tissues.

Yolk-Sac-Derived Macrophages Progressively Expand in the Mouse Kidney with Age

“…These partly overlapping populations appear in the yolk-sac around E8.5. Subsequently, from E9.0 until E14.5, they proliferate, migrate, and colonize the embryo through the vascular system [9, 18]. To lineage-label these cells, we exposed Csf1r-Mer-iCre-Mer ; Rosa26-tdTomato and Cx3Cr1-CreER ; Rosa26-tdTomato embryos to 4-hydroxytamoxifen (4-OHT) at E8.5 and E9.5, respectively (Fig.…”

“…Renal macrophages are found in an intricate network surrounding the renal tubular epithelium [15-17] and have mixed origins from both yolk-sac and HSC [3, 6, 8, 18]. They exert unique functions depending on their anatomical locations; monitoring and clearing immune complexes is a function of cortical macrophages while bacterial immunity is the responsibility of medullary macrophages [15, 16].…”

Kidney organoids: accurate models or fortunate accidents

“…Six2 + Cited1 + nephron progenitor cells give rise to all segments of the epithelial nephrons (Boyle et al 2008;Kobayashi et al 2008), the entire ureteric epithelium derives from Ret+ ureteric tip cells (Chi et al 2009), and Foxd1 + stromal progenitors give rise to the majority of renal stromal cell types (Kobayashi et al 2014), complemented by Tbx18-derived stromal cells (Bohnenpoll et al 2013), which arise as the ureteric bud grows into the metanephric mesenchyme. Other major cell types in the developing kidney include macrophages (Rae et al 2007;Munro et al 2019), vasculature (Munro et al 2017;Daniel et al 2018), and nerves (Sariola et al 1988). The extent to which these latter cell types influence organogenesis is still emerging.…”

The cell biology of inflammation: From common traits to remarkable immunological adaptations

“…Macrophages are voracious phagocytes; Metchnikoff described seeing them "literally crammed full of foreign particles." Phagocytosis occurs not only at sites of tissue damage and infection but also during developmental sculpting of many body tissues (Weavers et al, 2016a;Munro et al, 2019) and during normal tissue homeostasis (Arandjelovic and Ravichandran, 2015), whenever large numbers of unwanted or spent cells must be cleared (Morioka et al, 2019).…”