Adult Stem Cell-Derived Kidney Organoids to Model Tissue Physiology and Disease

Frans Schutgens

Research output: PhD ThesisPhD thesis

Abstract

“Organoid” is defined as a 3D structure grown from stem cells and consisting of organ-specific cell types that self-organizes through cell sorting and spatially restricted lineage commitment. Organoids can be derived from either adult stem cells (ASCs) or pluripotent stem cells (PSCs). The development of ASC-derived organoid cultures for other organs than the kidney is described and it is explained why organoids are a valuable tool for biology and medicine. In addition, we address the state-of-the-art of ASC cultures and how the field of nephrology may benefit from ASC-derived organoid cultures. An adequate ASC-derived kidney organoid culture system does not exist, although in theory such system would have useful applications. The other cell source for establishing organoid cultures are PSCs, either embryonic or induced. For the kidney, organoid cultures derived from PSCs have been well-established. In order to gain insight into growth conditions that allow expansion and differentiation of kidney cells, published protocols to differentiate PSCs into kidney organoids are reviewed. Furthermore, the development of an ASC-derived kidney organoid culture is described. Cultures can be established from mouse and human kidney tissue, as well as from human urine. Organoids can be expanded for 6 months while remaining genetically stable and can be used to model infectious and malignant disease. Kidney organoids derived from the urine of cystic fibrosis patients can be used to predict treatment efficacy ex vivo. In addition, a living organoid biobank of pediatric kidney tumors is established. This biobank contains the most common types of pediatric kidney tumors, such as Wilms tumor, malignant rhabdoid tumor of the kidney and renal cell carcinoma. Organoid lines from tumor and matching normal tissue can be efficiently established and reflect the primary tissue on histology. Organoid-derived cells are also integrated with an organ-on-a-chip platform, to allow high-throughput transporter and toxicity studies, and with a hollow fiber platform, to create 'living membranes.' Organoids may function as an autologous cell source for these technologies, thereby broadening the scope of applications of the culture system. Finally, a population of murine kidney cells with increased organoid-forming capacity is described. In vivo tracing of these cells yields mono-clonal expansions during kidney development, adult homeostasis and repair.
Original languageEnglish
QualificationDoctor (dr.)
Awarding Institution
Supervisors/Advisors
  • Clevers, Hans, Promotor
Award date21 Nov 2017
Publisher
Publication statusPublished - 21 Nov 2017

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