A comparative transcriptomic framework across kidney organoid, assembloid, and transplantation models

Abstract

Human kidney organoids recapitulate key aspects of renal development and have emerged as valuable platforms for disease modeling, nephrotoxicity screening, and therapeutic development. The field now includes a wide range of emerging protocols with distinct cellular compositions and maturation states, which complicates systematic comparison and model selection. Here, we integrated single-cell and single-nucleus transcriptomes from 11 studies spanning kidney organoid and assembloids, both in vitro and following transplantation, benchmarked against fetal and adult kidney references. Transcriptional maturation toward adult identity is compartment specific and does not correlate with protocol complexity. Assembloid protocols show the most adult-like podocyte and distal nephron signatures, transplantation is associated with enhanced tubular oxidative metabolic features, only protocols incorporating ureteric progenitors reliably generate collecting-duct lineages, and no protocol achieves mature adult proximal tubule identity. Annotating against either fetal or adult kidney reference alone leads to misassignment, because early fetal nephron epithelium transcriptionally resembles injury-dedifferentiated adult proximal tubule cells. Assembloid and transplantation models share elevated mechanosensing pathway expression independently of vascularization. Together, these findings provide a framework for kidney organoid model selection.