Toward Physiologically Relevant Organoid Models of PKD through Microenvironment Reconstruction

Abstract The tissue microenvironment plays a pivotal role in polycystic kidney disease (PKD) progression, orchestrating cyst initiation and expansion through dynamic interactions among kidney epithelial, stromal, and immune cells, alongside systemic factors. Accurately reconstructing this complex in vivo milieu is essential to elucidate the mechanisms of PKD pathogenesis and to develop effective therapeutics. Human pluripotent stem cell–derived kidney organoids and patient-specific tubuloids have emerged as powerful platforms for modeling PKD within defined genetic contexts, faithfully recapitulating key pathological features of tubular cystogenesis. However, current organoid culture systems remain limited in their ability to replicate the full complexities of the native disease niche. Integrating bioengineering with developmental and biological insights will be essential to recreating physiologically relevant microenvironments. Such innovations will enhance the fidelity, predictive power, and translational utility of PKD organoid models, ultimately enabling more accurate drug testing and personalized therapeutics.