Defining and redefining the nephron progenitor population

Abstract

It has long been appreciated that the mammalian kidney arises via reciprocal interactions between an epithelial ureteric epithelium and the surrounding metanephric mesenchyme. More recently, lineage tracing has confirmed that the portion of the metanephric mesenchyme closest to the advancing ureteric tips, the cap mesenchyme, represents the progenitor population for the nephron epithelia. This Six2(+)Cited1(+) population undergoes self-renewal throughout nephrogenesis while retaining the potential to epithelialize. In contrast, the Foxd1(+) portion of the metanephric mesenchyme shows no epithelial potential, developing instead into the interstitial, perivascular, and possibly endothelial elements of the kidney. The cap mesenchyme rests within a nephrogenic niche, surrounded by the stroma and the ureteric tip. While the role of Wnt signaling in nephron induction is known, there remains a lack of clarity over the intrinsic and extrinsic regulation of cap mesenchyme specification, self-renewal, and nephron potential. It is also not known what regulates cessation of nephrogenesis, but there is no nephron generation in response to injury during the postnatal period. In this review, we will examine what is and is not known about this nephron progenitor population and discuss how an increased understanding of the regulation of this population may better explain the observed variation in final nephron number and potentially facilitate the reinitiation or prolongation of nephron formation.

Fig. 1

The progenitor niche within the nephrogenic zone of the developing mammalian kidney. A Diagrammatic representation of a section through a developing kidney showing the peripheral nephrogenic zone containing terminal tips of the branching ureteric tree (blue) surrounded by cap mesenchyme (red). B Progenitor niche comprising one branching tip (blue) surrounded by cap mesenchyme (CM; red) and Foxd1+ stroma. The location of Wnt9b and Wnt11 expression within the ureteric tip is indicated. Differentiation occurs in the ‘armpit’ of the branching ureteric tip, forming a pretublar aggregate and the epithelializing to form a renal vesicle. PA pre-tubular aggregate; RV renal vesicle. Key genes expressed in CM, PA, and RV are listed. Note the persistence of Six2 in the pretubular aggregate but not the RV. The first evidence of epithelialization is the expression of cadherins 4 and then 6. E-cadherin is not expressed in the RV (3)

Fig. 2

Lineage relationships during kidney development. The mammalian kidney is derived from the intermediate mesoderm (IM), which gives rise to the nephric duct (ND), and the metanephric mesenchyme (MM). The ND gives rise to the collecting duct system, which is composed of two key cell types, principal cells, and intercalated cells. The MM specifies the cap mesenchyme (CM) and also gives rise to the stroma. The CM is the nephron progenitor population and differentiates in the renal vesicle via a mesenchyme-to-epithelial transition. This structure immediately becomes patterned into distal and proximal RV, with the distal RV forming the connecting cells between nephron and collecting duct and the distal cell types of the nephron (distal tubules) and the proximal RV giving rise to the glomeruli and proximal tubules. The stroma is thought to give rise to the interstitial cells of the kidney, including the pericytes and possibly also the endothelial cells. However, there is also likely to be angiogenic ingrowth of endothelial cells. Neurons and macrophages are thought to migrate into the kidney from around embryonic day 12 in the mouse [90]

Fig. 3

Temporospatial representations of cap mesenchyme specification, differentiation and the effect of niche architecture on growth factor gradients and gene expression. A Temporal representation of commitment of MM to CM and stroma, followed by CM differentiation and exhaustion of the CM at the end of nephrogenesis. B Diagram of the cap mesenchyme nephron progenitor population as it is aligned within the nephrogenic zone (left) and then linearized from distal tip CM to renal vesicle to illustrate the differences in concentration of two secreted morphogens, Wnt9b and Wnt11. C Section in situ hybridization of the developing mouse kidney at E15.5 and postnatal day 2 showing the heterogeneity of gene expression within the cap mesenchyme for Six2 and Cited1. D Immunohistochemistry for Bcl2 in the kidney shows specific protein staining within the cap mesenchyme (images courtesy of E. Wainwright)

Fig. 4

Model of approaches for the generation of nephron progenitors. This may include the directed differentiation of human pluripotent stem cells (embryonic stem cells or induced pluripotent cells) so as to recapitulate the differentiative steps normally taken to reach cap mesenchyme. Alternatively, reprogramming of differentiated adult cells may be achieved via the enforced re-expression of lineage-instructive transcription factors