Recreating kidney progenitors from pluripotent cells

Abstract

Access to human pluripotent cells theoretically provides a renewable source of cells that can give rise to any required cell type for use in cellular therapy or bioengineering. However, successfully directing this differentiation remains challenging for most desired endpoints cell type, including renal cells. This challenge is compounded by the difficulty in identifying the required cell type in vitro and the multitude of renal cell types required to build a kidney. Here we review our understanding of how the embryo goes about specifying the cells of the kidney and the progress to date in adapting this knowledge for the recreation of nephron progenitors and their mature derivatives from pluripotent cells.

Figure 1.. Possible renal options for directed differentiation of pluripotent cells.

This schematic demonstrates the derivation of iPSC from adult somatic fibroblasts followed by the directed differentiation to mature kidney cells. The resulting cells might be useful for nephrotoxicity screening, disease modelling in vitro, or the generation of renal cells for use in bioengineering or cellular therapy. Gene editing to correct inherited mutations may allow the reintroduction of autologous normal cells to the original cell donor.

Figure 2.. Embryonic differentiation from inner cell mass to kidney.

Illustrated are the developmental decisions required during embryonic differentiation to both nephron progenitor and ureteric bud progenitor states (left) together with marker genes that would assist in the identification of intermediate endpoints (right). ICM, inner cell mass; Mesen, mesendoderm; Mes, mesoderm; Endo, endoderm; IM, intermediate mesoderm; LPM, laternal plate mesoderm; PM, paraxial mesoderm; MM, metanephric mesenchyme; NP, nephron progenitor / cap mesenchyme; WD, Wolffian duct; UB, ureteric bud.

Figure 3.. Temporal gene expression patterns during renal development from posterior primitive streak to mature renal cell types.

This framework illustrates the steps involved in forming renal cell types from the IM stage illustrating gene expression by compartment / cell type across development, as well as the interplay between the UB and NP populations that allows nephron formation via a mesenchyme to epithelial (Mes to Epith) transition. It also shows the spectrum of different mature epithelial cell types generated from the renal vesicle or from the UB after this event and illustrates markers used to identify stages of differentiation as well as mature cell types. IM, intermediate mesoderm; ND, nephric duct; UB, ureteric bud; UTip, ureteric tip; U Stalk, ureteric stalk / branch; PC, Principal cell; IC, intercalated cell; MM, metanephric mesenchyme; CM, cap mesenchyme (nephron progenitor); RV, renal vesicle (Stage 1 nephron); DT, distal tubule; PT, proximal tubule; POD, podocyte. Note that many of the genes involved in MET in the mesonephros are shared with that of the metanephros, however no CM or UB form (84). The mesonephric mesenchyme is also lacking expression of Hoxa11/d11.