Vascular deficiencies in renal organoids and ex vivo kidney organogenesis

• Published in: Developmental biology 2021-09, Vol.477, p.98-116
• Main Authors: Ryan, Anne R., England, Alicia R., Chaney, Christopher P., Cowdin, Mitzy A., Hiltabidle, Max, Daniel, Edward, Gupta, Ashwani Kumar, Oxburgh, Leif, Carroll, Thomas J., Cleaver, Ondine
• Format: Article
• Language: English
• Subjects: Angioblast; Animals; Blood vessel; Cells, Cultured; Cord; Endothelial cell; Endothelial Cells; Endothelium, Vascular - cytology; Endothelium, Vascular - embryology; Female; Humans; Kidney; Kidney - blood supply; Kidney - cytology; Kidney - embryology; Male; Mice; Organogenesis; Organoid; Organoids - embryology; Organoids - transplantation; RNA-Seq; RNAseq; Tissue Culture Techniques
• ISSN: 0012-1606; 1095-564X; 1095-564X
• DOI: 10.1016/j.ydbio.2021.04.009

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. Here, we comprehensively assess the vasculature in two distinct kidney organoid models as well as in explanted embryonic kidneys. Using a variety of methods, we show that while organoids can develop a wide range of kidney cell types, as previously shown, endothelial cells (ECs) initially arise but then rapidly regress over time 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. [Display omitted] •HESC-derived renal organoids develop sparse and transient vascular structures.•Blood vessels in kidney organoids (hESC and NZC derived) largely lack lumens and patterning.•Vasculature in ex vivo kidneys regresses in culture.•Implantation of kidney organoids ensures organoid vascularization due to invasion of perfused host blood vessels.•ScRNA-seq analysis reveals that cultured organoid ECs are similar to embryonic ECs but diverge over time.