Abstract
The renal endothelium has been debated as arising from resident hemangioblast precursors that transdifferentiate from the nephrogenic mesenchyme (vasculogenesis) and/or from invading vessels (angiogenesis). While the Foxd1-positive renal cortical stroma has been shown to differentiate into cells that support the vasculature in the kidney (including vascular smooth muscle and pericytes) it has not been considered as a source of endothelial cell progenitors. In addition, it is unclear if Foxd1-positive mesenchymal cells in other organs such as the lung have the potential to form endothelium. This study examines the potential for Foxd1-positive cells of the kidney and lung to give rise to endothelial progenitors. We utilized immunofluorescence (IF) and fluorescence-activated cell sorting (FACS) to co-label Foxd1-expressing cells (including permanently lineage-tagged cells) with endothelial markers in embryonic and postnatal mice. We also cultured FACsorted Foxd1-positive cells, performed in vitro endothelial cell tubulogenesis assays and examined for endocytosis of acetylated low-density lipoprotein (Ac-LDL), a functional assay for endothelial cells. Immunofluorescence and FACS revealed that a subset of Foxd1-positive cells from kidney and lung co-expressed endothelial cell markers throughout embryogenesis. In vitro, cultured embryonic Foxd1-positive cells were able to differentiate into tubular networks that expressed endothelial cell markers and were able to endocytose Ac-LDL. IF and FACS in both the kidney and lung revealed that lineage-tagged Foxd1-positive cells gave rise to a significant portion of the endothelium in postnatal mice. In the kidney, the stromal-derived cells gave rise to a portion of the peritubular capillary endothelium, but not of the glomerular or large vessel endothelium. These findings reveal the heterogeneity of endothelial cell lineages; moreover, Foxd1-positive mesenchymal cells of the developing kidney and lung are a source of endothelial progenitors that are likely critical to patterning the vasculature.
Highlights
The renal endothelium has been largely debated as arising from trans-differentiating resident hemangioblast precursors [1] and/or from invading vessels [2,3,4]
Since some Flk1-expressing cells outside of the kidney have been shown to differentiate into non-endothelial cells [13], we performed fluorescence-activated cell sorting (FACS) analysis in E13.5, E15.5, and E18.5 kidneys with Flk1 and with a smooth muscle actin or CD73; at no time point was there overlapping expression of Flk1 and aSMA or CD73 (Figure S1 and not shown)
While the origin of the endothelium of the kidney has been a subject of debate, it has long been thought that an endogenous progenitor cell likely existed
Summary
The renal endothelium has been largely debated as arising from trans-differentiating resident hemangioblast precursors (vasculogenesis) [1] and/or from invading vessels (angiogenesis) [2,3,4]. The renal stroma, characterized by expression of Foxd, has been shown to give rise to many different cell types including mesangial cells of the glomerulus as well as many other vascular supportive cells including fibroblasts, pericytes, vascular smooth muscle cells and renin cell precursors [5,6]; it has not been reported to give rise to endothelial cells. Endothelial cell precursors are thought to arise from the pulmonary mesenchyme via the process of vasculogenesis [7]. As is true in the kidney, there is a Foxd positive subpopulation in the developing pulmonary mesenchyme that has not been well characterized. There are no reports of endothelial cell progenitors arising from Foxd1-positive mesenchymal cells in the lung
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