Nephron reconstitution from pluripotent stem cells

Abstract

It has been a challenge in developmental biology and regenerative medicine to generate nephron progenitors that reconstitute the three-dimensional (3D) nephron structure in vitro. Many studies have tried to induce nephron progenitors from pluripotent stem cells by mimicking the developmental processes in vivo. However, the current developmental model does not precisely address the spatiotemporal origin of nephron progenitors, hampering our understanding of cell fate decisions in the kidney. Here, we present a revised model of early-stage kidney specification, suggesting distinct origins of the two major kidney components: the ureteric bud and metanephric mesenchyme. This model enables the induction of metanephric nephron progenitors from both mouse and human pluripotent stem cells. The induced cells self-organize in the presence of Wnt signaling and reconstitute 3D nephron structures including both nephric tubules with a clear lumina and glomeruli with podocytes. The engrafted kidney tissue develops vascularized glomeruli and nephric tubules, but it does not produce urine, suggesting the requirement for further maturation. Nevertheless, the generation of nephron components from human-induced pluripotent stem cells will be useful for future application in regenerative therapy and modeling of congenital kidney diseases in vitro. This review discusses the possibility of de novo organogenesis of a functional kidney from pluripotent stem cells and the future direction toward clinical applications.

Generation of nephron progenitor cells and kidney organoids from human pluripotent stem cells

“…Our protocols yield NPCs, with much higher induction efficiency, from both hESCs and hiPSCs when compared to previous studies, including our own 3,4,13,14,23 . High induction efficiency at each step of differentiation, simultaneously, indicates high specificity of kidney induction.…”

Development of the Mammalian Kidney

“…Depending on the induction conditions, cultures can self organize to generate kidney-like organoids with both ureteric-like and nephron progenitor-like cell types (Takasato et al, 2014). In other procedures, isolated progenitors can be generated independently for each of these lineages (Taguchi et al, 2014; Xia et al, 2014), and nephron progenitor-like cells differentiated into distinct nephron fates (Taguchi et al, 2015). Further, differentiated nephron types can be reprogrammed to earlier nephron progenitor–like states through the ectopic action of a small number of transcriptional regulators associated with normal progenitor programs (Hendry et al, 2013).…”

“…Strikingly, all of these advances come from a rigorous application of knowledge gained from studying kidney development in model systems (Takasato and Little, 2015; Taguchi and Nishinakamura, 2015; Vanslambrouck and Little, 2015). While there is room for methodological improvements and a firmer grasp on the cell types generated in these procedures, applied developmental biology has opened the door for regenerative approaches to treat human kidney disease (Little and Takasato, 2015).…”

Concise Review: Understanding the Renal Progenitor Cell Niche In Vivo to Recapitulate Nephrogenesis In Vitro

“…On the addition of these factors to embryoid bodies, expression of intermediate mesoderm markers such as Pax2 and Wt1 increases, and on stimulation of metanephric mesenchyme with embryonic spinal cord, expression of renal epithelial makers was observed, suggesting that these factors can promote nephron differentiation [91]. Other groups have reported similar approaches for differentiation of murine embryonic stem cells, also confirming their capacity to undergo tubulogenesis and form glomeruli when grafted in vivo [93–96].…”