Renal Subcapsular Transplantation of PSC-Derived Kidney Organoids Induces Neo-vasculogenesis and Significant Glomerular and Tubular Maturation In Vivo

• Published in: Stem cell reports Vol. 10; no. 3; pp. 751 - 765
• Main Authors: van den Berg, Cathelijne W., Ritsma, Laila, Avramut, M. Cristina, Wiersma, Loes E., van den Berg, Bernard M., Leuning, Daniëlle G., Lievers, Ellen, Koning, Marije, Vanslambrouck, Jessica M., Koster, Abraham J., Howden, Sara E., Takasato, Minoru, Little, Melissa H., Rabelink, Ton J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 13.03.2018; Elsevier
• Subjects: Animals; Cell Differentiation - physiology; directed differentiation; Endothelial Cells - physiology; human pluripotent stem cells; Humans; intravital microscopy; Kidney Glomerulus - physiology; kidney organoids; Kidney Transplantation - methods; Kidney Tubules - physiology; maturation; Mice; Morphogenesis - physiology; Organoids - physiology; Pluripotent Stem Cells - physiology; Podocytes - physiology; transplantation; vascularization; directed differentiation; maturation; intravital microscopy; transplantation; kidney organoids; vascularization; human pluripotent stem cells
• ISSN: 2213-6711; 2213-6711
• DOI: 10.1016/j.stemcr.2018.01.041

Human pluripotent stem cell (hPSC)-derived kidney organoids may facilitate disease modeling and the generation of tissue for renal replacement. Long-term application, however, will require transferability between hPSC lines and significant improvements in organ maturation. A key question is whether time or a patent vasculature is required for ongoing morphogenesis. Here, we show that hPSC-derived kidney organoids, derived in fully defined medium conditions and in the absence of any exogenous vascular endothelial growth factor, develop host-derived vascularization. In vivo imaging of organoids under the kidney capsule confirms functional glomerular perfusion as well as connection to pre-existing vascular networks in the organoids. Wide-field electron microscopy demonstrates that transplantation results in formation of a glomerular basement membrane, fenestrated endothelial cells, and podocyte foot processes. Furthermore, compared with non-transplanted organoids, polarization and segmental specialization of tubular epithelium are observed. These data demonstrate that functional vascularization is required for progressive morphogenesis of human kidney organoids. [Display omitted] •PSC-derived kidney organoids remain disorganized and immature upon prolonged culture•Renal subcapsular transplantation in mice induces vascularization of kidney organoids•Intravital imaging shows perfusion of glomeruli and pre-existing vascular networks•Subcapsular transplantation results in progressive maturation of nephron structures In this article, Van den Berg and colleagues show that PSC-derived kidney organoids contain nephron structures but remain disorganized and immature after prolonged culture. Upon transplantation, the organoids develop host-derived vascularization, functional glomerular perfusion, and connection to pre-existing vascular networks. The authors conclude that patent vasculature is required for ongoing morphogenesis and maturation of these kidney organoids.