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.