A Tissue-Bioengineering Strategy for Modeling Rare Human Kidney Diseases In Vivo

Our recent publication in Nature Communications showcases a bioengineering approach to model renal diseases associated with Tuberous Sclerosis Complex, using transplanted human iPSC-derived renal organoids. Renal manifestations occur in over 80% of TSC patients, with renal angiomyolipoma and cystic disease representing the most frequent renal lesions. The findings represent the first experimental model of renal angiomyolipoma (AML), a tumor with potential lethality whose mechanisms remain obscure due to the previous lack of appropriate models. We show that AML organoids mimicking kidney AML anatomically and transcriptionally, can be generated from iPSCs derived from a patient, after introduction of a loss-of-function mutation in the TSC2 gene. Using these AML organoids, we further identify a molecular mechanism of tumor resistance previously unknown in these tumors. Key to the entire concept is the use of AML organoid xenografts with which we tested local delivery of rapamycin-loaded nanoparticles as a therapeutic approach to rapidly ablate AMLs without affecting neighboring healthy tissues. Overall the work represents the first iPSC-based bioengineering approach to model rare kidney disease in vivo for therapeutic research purposes.