Abstract: PO0613
Human Induced Pluripotent Stem Cell-Derived Kidney Micro-Organoids for High Throughput Disease Modeling in Drug Discovery
Session Information
- CKD Mechanisms - 1
October 22, 2020 | Location: On-Demand
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2103 CKD (Non-Dialysis): Mechanisms
Authors
- Kumar, Santhosh V, Bioscience Renal, Research and Early Development Cardiovascular, Renal and Metabolism (CVRM) BioPharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom
- Jonebring, Anna, Translational Genomics, Discovery Sciences, R&D, AstraZeneca, Gothenburg, Sweden
- Laerkegaard Hansen, Pernille B., Bioscience Renal, Research and Early Development Cardiovascular, Renal and Metabolism (CVRM) BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
- Hicks, Ryan, Translational Genomics, Discovery Sciences, R&D, AstraZeneca, Gothenburg, Sweden
- Woollard, Kevin, Bioscience Renal, Research and Early Development Cardiovascular, Renal and Metabolism (CVRM) BioPharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom
Group or Team Name
- AZ Kidney-organoids
Background
Human kidney contains around 1 million nephrons, more than 2 dozen different cell types. Reproducing physiological kidney cell types in-vitro is limited. Recent advancements in human iPSCs differentiation provide an opportunity to culture and utilize multicellular kidney structures “kidney-organoids”. We have employed a kidney micro-organoid in suspension culture this method eventually accelerates kidney organoids to the industrial scale and differentiates from traditional low throughput trans-well organoids. This method involves differentiation of iPSCs to intermediate mesoderm using CHIR and FGF9 and spontaneous aggregation in the swirler culture leads to mature to kidney organoids, this can be used to study kidney disease in a high-throughput manner.
Methods
We aimed to model human kidney inflammatory and genetic disease in-vitro using kidney micro-organoids, treatment with different insults to reproduce CKD microenvironment eg. IL-1b, TGFb, Angiotensin-II and protamine sulphate.
Results
After 24h of stimulation, we noted significant upregulation of kidney injury biomarkers including KIM1 and inflammatory cytokines. Reproducing genetic diseases like PKD is very challenging in-vitro, we show treatment of cultured micro-organoids with forskolin (to elevate intracellular cAMP) altered the transportation of ciliary proteins and promoted cyst formation, resembling human PKD. These observations clearly demonstrate the use of micro-kidney organoids to study renal diseases in-vitro for drug discovery applications with human translatable functional biomarkers.
Conclusion
Impact statement: Kidney micro-organoids provide a platform for high throughput modeling of human kidney diseases related fibrosis, inflammation and genetic disease like polycystic kidney disease with human translatable biomarkers in drug discovery.