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Abstract: SA-OR13

A Novel Vascularized Human Kidney Organoid to Study Podocyte and Endothelial Health and Disease

Session Information

Category: Bioengineering

  • 400 Bioengineering

Authors

  • Maggiore, Joseph C., University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
  • Ebrahimkhani, Mo R., University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
  • Hukriede, Neil A., University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
Background

Recapitulating vasculature in in vitro kidney systems is critical for mechanistic studies due to its important role in health and disease. Many methods for vascularizing have been taken, however, few have been robust, reliable, high-throughput, and can be used to study podocyte/endothelial morphology and morphological changes in injury settings.

Methods

Here, we generate vascularized human kidney organoids by mixing an inducible ETS translocation variant 2 (ETV2) human induced pluripotent stem cell line (iETV2-hiPSC), which directs endothelial fate, with a non-transgenic iPSC line in suspension organoid culture.

Results

We demonstrate that the addition of iETV2-hiPSCs to an established kidney organoid protocol generates a vascularized human kidney organoid with a ~10-fold increase in endothelial cells and a 60% increase in organoid diameter. Podocyte clusters were consistently encased in a network of endothelial cells with invagination. On snRNAseq we found vascularized podocytes exhibit enhanced VEGF signaling, basement membrane maturation, and endothelial differentiation markers. Additionally, we demonstrate that vascularization of human kidney organoids enables the formation of a functional interstitium with drug responsive renin+ cells. These renin cells existed within podocyte clusters of vascularized organoids only. Finally, we show that iETV2-hiPSCs undergo co-development with kidney organoid parenchymal tissue, thus generating mature fenestrated kidney-specific endothelial networks.

Conclusion

We generated a vascularized human kidney organoid with increased maturation of nephron structures including more mature podocytes with improved foot process interdigitation, a fenestrated endothelium, and the presence of renin+ cells. This represents the first demonstration of renin+ cells in a kidney organoid without the use of exogenous stimulation. The creation of an engineered vascular niche capable of improving kidney organoid maturation and cell type complexity is a significant step forward in the path to clinical translation.

Funding

  • NIDDK Support