Abstract
We have recently shown that kidney-derived stem cells (KSCs) isolated from the mouse newborn kidney differentiate into a range of kidney-specific cell types. However, the functionality and integration capacity of these mouse KSCs remain unknown. Therefore, the main objectives of this study were (1) to determine if proximal tubule-like cells, generated in vitro from KSCs, displayed absorptive function typical of proximal tubule cells in vivo, and (2) to establish whether the ability of KSCs to integrate into developing nephrons was comparable with that of metanephric mesenchyme (MM), a transient population of progenitor cells that gives rise to the nephrons during kidney organogenesis. We found that proximal tubule-like cells generated in vitro from mouse KSCs displayed megalin-dependent absorptive function. Subsequently, we used a chimeric kidney rudiment culture system to show that the KSCs could generate proximal tubule cells and podocytes that were appropriately located within the developing nephrons. Finally, we compared the ability of KSCs to integrate into developing kidneys ex vivo with that of metanephric mesenchyme cells. We found that KSCs integrated into nascent nephrons to a similar extent as metanephric mesenchyme cells while both were excluded from ureteric bud branches. Our analysis of the behavior of the two cell types shows that some, but not all KSC characteristics are similar to those of the MM.
Highlights
In mammals, the permanent kidney is derived from two mesodermal cell populations: the ureteric bud (UB) that gives rise to the collecting ducts and ureters, and the metanephric mesenchyme (MM) that generates the nephrons
Previous studies have shown that stem/progenitor cells derived from mouse and human kidney can generate cells that express markers of proximal tubule cells [25,26,34] including megalin (Figure 1A), an endocytic receptor that plays a key role in mediating the reabsorption of proteins from the glomerular filtrate [38]
In this study we have shown that mouse neonatal kidney-derived stem cells (KSCs) can generate proximal tubule-like cells in vitro that display megalindependent absorptive function
Summary
The permanent kidney is derived from two mesodermal cell populations: the ureteric bud (UB) that gives rise to the collecting ducts and ureters, and the metanephric mesenchyme (MM) that generates the nephrons. Nephron development begins when signals from the UB induce the MM to condense around the UB tips. The MM cells undergo mesenchymal-to-epithelial transition (MET) to form the renal vesicle, which elongates to form the nephron tubule, comprising the glomerulus, proximal and distal tubules [1]. As the renal vesicle elongates, Wt1 becomes highly expressed in the nascent podocytes of the glomeruli, but is downregulated in all other cell types within the developing nephron [5]. Pax is rapidly downregulated in the nascent podocytes, but continues to be expressed by the remaining cells of the nephron tubule and UB until kidney development is complete [6]
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