Investigating Vascular Patterning and Regression in Kidney Development and Organoids

Chronic kidney disease (CKD) and end stage renal disease (ESRD) are increasingly frequent and devastating conditions that have driven a surge in the need for kidney transplantation. A stark shortage of organs has fueled interest in generating viable replacement tissues ex vivo for transplantation. One promising approach has been self-organizing organoids, which mimic developmental processes and yield multicellular, organ-specific tissues. However, a recognized roadblock to this approach is that many organoid cell types fail to acquire full maturity and function. I comprehensively assessed the vasculature in two distinct kidney organoid models as well as in explanted embryonic kidneys. Using a variety of methods, my work shows that while organoids can develop a wide range of kidney cell types, as previously shown, endothelial cells (ECs) initially arise but then rapidly regress overtime in culture. Vasculature of cultured embryonic kidneys exhibit similar regression. By contrast, engraftment of kidney organoids under the kidney capsule results in the formation of a stable, perfused vasculature that integrates into the organoid. This work demonstrates that kidney organoids offer a promising model system to define the complexities of vascular-nephron interactions, but the establishment and maintenance of a vascular network present unique challenges when grown ex vivo. The future of the field necessitates the inclusion of flow and perhaps additional factors into in vitro culture methods. Future studies investigating endothelial heterogeneity in the developing kidney will aid in forwarding our mission of creating a functional organoid vasculature.