A Modular Differentiation System Maps Multiple Human Kidney Lineages from Pluripotent Stem Cells

Abstract

Summary: Recent studies using human pluripotent stem cells (hPSCs) have developed protocols to induce kidney-lineage cells and reconstruct kidney organoids. However, the separate generation of metanephric nephron progenitors (NPs), mesonephric NPs, and ureteric bud (UB) cells, which constitute embryonic kidneys, in in vitro differentiation culture systems has not been fully investigated. Here, we create a culture system in which these mesoderm-like cell types and paraxial and lateral plate mesoderm-like cells are separately generated from hPSCs. We recapitulate nephrogenic niches from separately induced metanephric NP-like and UB-like cells, which are subsequently differentiated into glomeruli, renal tubules, and collecting ducts in vitro and further vascularized in vivo. Our selective differentiation protocols should contribute to understanding the mechanisms underlying human kidney development and disease and also supply cell sources for regenerative therapies. : Tsujimoto et al. establish a differentiation system that separately generates multiple mesoderm lineages from hiPSCs. Three kidney progenitors, metanephric nephron progenitors (NPs), mesonephric NP-like cells, and the ureteric bud (UB), are further induced. They also generate interconnected kidney organoids from separately induced metanephric NPs and UB. Keywords: induced pluripotent stem cells, kidney, differentiation, mesonephros, metanephros, ureteric bud, collecting duct, nephrogenesis, single-cell analysis, organoid