Abstract: TH-OR65
Organoid Xenograft Model of Polycystic Kidney Disease Reveals Context-Dependent Cross-Talk Between Primary Cilium and Autophagy in Cystogenesis
Session Information
- Investigations in Polycystic and Tubulointerstitial Kidney Diseases
November 02, 2023 | Location: Room 105, Pennsylvania Convention Center
Abstract Time: 05:06 PM - 05:15 PM
Category: Genetic Diseases of the Kidneys
- 1201 Genetic Diseases of the Kidneys: Cystic
Authors
- Xia, Yun, Nanyang Technological University, Singapore, Singapore, Singapore
- Liu, Meng, Nanyang Technological University, Singapore, Singapore, Singapore
- Cardilla, Angelysia, Nanyang Technological University, Singapore, Singapore, Singapore
- Zhang, Tian, Nanyang Technological University, Singapore, Singapore, Singapore
- Naik, Mihir Yogesh, Nanyang Technological University, Singapore, Singapore, Singapore
Background
In the past few years, organoid models have been developed to study polycystic kidney disease (PKD), including those derived from human pluripotent stem cells (PSC) and adult kidney tissue. Despite successful recapitulation of tubular cyst formation in vitro, most organoid models of PKD rely on stress stimulation to demonstrate disease phenotypes, possibly due to the lack of native tissue microenvironment. Novel organoid models of PKD need to be developed to reveal the pathogenetic underpinnings for human PKD.
Methods
We generated kidney organoids from PKD patient induced PSCs (iPSC) and gene-corrected iPSCs, followed by engrafting these kidney organoids into the sub-renal capsule space of immunocompromised mice. Genetic editing was performed in PKD patient iPSCs to modulate primary cilium-autophagy signaling axis, followed by organoid generation and xenotransplantation. The organoid xenografts were recovered four weeks post engraftment for phenotypic assessment and single cell transcriptomic analysis.
Results
PKD patient iPSCs-derived kidney organoids spontaneously developed tubular cysts in vivo, whereas gene-corrected organoid xenografts showed an absence of cystogenesis. PKD organoid xenografts showed a myriad of structural and functional abnormalities reminiscent of human PKD. In particular, cellular autophagy was significantly compromised in PKD organoid xenografts. Primary cilium ablation in PKD organoid xenografts inhibited cystogenesis, alongside an upregulation of autophagy. On the contrary, primary cilium ablation in the gene-corrected organoid xenografts induced cystogenesis, in parallel with a significant downregulation of autophagy. Employing the organoid xenograft model of PKD, we evaluated the effect of an FDA-approved drug on cystogenesis in vivo.
Conclusion
The organoid xenograft model of PKD recapitulates spontaneous cyst formation in vivo, representing a more sophisticated system for revealing novel therapeutic targets and for evaluating the clinical potential of candidate drugs.
Funding
- Government Support – Non-U.S.