Cellular and Molecular Mechanisms of Kidney Development: From the Embryo to the Kidney Organoid

Abstract

Development of the metanephric kidney is strongly dependent on complex signaling pathways and cell-cell communication between at least four major progenitor cell populations (ureteric bud, nephron, stromal, and endothelial progenitors) in the nephrogenic zone. In recent years, the improvement of human-PSC-derived kidney organoids has opened new avenues of research on kidney development, physiology, and diseases. Moreover, the kidney organoids provide a three-dimensional (3D) in vitro model for the study of cell-cell and cell-matrix interactions in the developing kidney. In vitro recreation of a higher-order and vascularized kidney with all of its complexity is a challenging issue; however, some progress has been made in the past decade. This review focuses on major signaling pathways and transcription factors that have been identified which coordinate cell fate determination required for kidney development. We discuss how an extensive knowledge of these complex biological mechanisms translated into the dish, thus allowed the establishment of 3D human-PSC-derived kidney organoids.

Promoting Maturation of Human Pluripotent Stem Cell-Derived Renal Microtissue by Incorporation of Endothelial and Mesenchymal Cells

“…Furthermore, in vitro-generated human pluripotent stem cell (hPSC)-derived kidney cells provide a suitable platform for studying kidney development, physiology, disease modeling, and drug screening. Although hPSCsderived kidney organoids express some markers of fully differentiated kidney tissues, they have relatively immature characteristics [2]. Several strategies have been reported to improve the maturity of in vitro-differentiated kidney structures.…”

“…Embryological studies demonstrated that spatiotemporal cell-cell communication and signals from the complex microenvironment during development have important roles in the proper maintenance and differentiation of renal cells. PSC-derived renal cells can be generated following the same developmental events that occur during the embryonic period [2]. In recent years, multistep protocols have been used for differentiation of hPSCs into the renal lineage by recapitulating stages of in vivo kidney development.…”

“…Nephrogenic IM includes four major progenitor cell populations: ureteric-bud progenitor cells, nephron progenitor cells (NPCs), stromal progenitors, and endothelial progenitor cells (EPCs). The mature kidney consists of various types of specialized cells such as different nephron segments, collecting duct, interstitial stromal and endothelial cells (ECs) [2]. Kidney development depends on the migration of endothelial and stromal cells from other embryonic tissues into the developing kidney [12,14,15].…”

“…Kidney development depends on the migration of endothelial and stromal cells from other embryonic tissues into the developing kidney [12,14,15]. ECs play a principal role in delivery of oxygen and micronutrients to the developing kidney, and paracrine factors secreted from ECs have a key role in proper differentiation and maturation of renal progenitors [2,16]. On the contrary, several renal cell types have been shown to promote survival, migration, and tube formation of ECs, as well as the proper spatial distribution of renal vessels during kidney development [2].…”

3D kidney organoids for bench-to-bedside translation

“…With regard to the kidney, more than a dozen distinct cell types contribute to the structure and function of the nephron in vivo. The reconstitution of a nephron would necessitate direct reprogramming to a common ancestor of all contributing cell types, namely, nephron progenitor cells, endothelial progenitor cells, and stromal progenitor cells [19]. The required approach to developing tissue akin to the native kidney is directed differentiation, a method predicated upon profound knowledge of kidney development.…”