Kidney organoid models reveal cilium-autophagy metabolic axis as a therapeutic target for PKD both in vitro and in vivo

  • Cell Stem Cell. 2024 Jan 4;31(1):52-70.e8. doi: 10.1016/j.stem.2023.12.003.
Meng Liu  1 ,  Chao Zhang  1 ,  Ximing Gong  1 ,  Tian Zhang  1 ,  Michelle Mulan Lian  2 ,  Elaine Guo Yan Chew  2 ,  Angelysia Cardilla  1 ,  Keiichiro Suzuki  3 ,  Huamin Wang  1 ,  Yuan Yuan  4 ,  Yan Li  1 ,  Mihir Yogesh Naik  1 ,  Yixuan Wang  1 ,  Bingrui Zhou  1 ,  Wei Ze Soon  1 ,  Emi Aizawa  5 ,  Pin Li  1 ,  Jian Hui Low  1 ,  Moses Tandiono  2 ,  Enrique Montagud  6 ,  Daniel Moya-Rull  7 ,  Concepcion Rodriguez Esteban  8 ,  Yosu Luque  6 ,  Mingliang Fang  9 ,  Chiea Chuen Khor  10 ,  Nuria Montserrat  11 ,  Josep M Campistol  6 ,  Juan Carlos Izpisua Belmonte  12 ,  Jia Nee Foo  13 ,  Yun Xia  14
Affiliations
  • 1. Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, 11 Mandalay Road, Singapore 308232, Singapore.
  • 2. Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, 11 Mandalay Road, Singapore 308232, Singapore; Human Genetics, Genome Institute of Singapore, Agency for Science, Technology and Research, A∗STAR, Singapore 138672, Singapore.
  • 3. Institute for Advanced Co-Creation Studies, Osaka University, Toyonaka 560-8531, Osaka, Japan; Graduate School of Engineering Science, Osaka University, Toyonaka 560-8531, Osaka, Japan; Graduate School of Frontier Bioscience, Osaka University, Suita 560-8531, Osaka, Japan.
  • 4. Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, 11 Mandalay Road, Singapore 308232, Singapore; Institute of Special Environmental Medicine, Nantong University, Nantong 226019, Jiangsu, China.
  • 5. Graduate School of Engineering Science, Osaka University, Toyonaka 560-8531, Osaka, Japan.
  • 6. Hospital Clinic of Barcelona, Career Villarroel, 170, 08036 Barcelona, Spain.
  • 7. Pluripotency for Organ Regeneration (PR Lab), Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology (BIST), 08028 Barcelona, Spain.
  • 8. Altos Labs, 5510 Morehouse Drive, Suite 300, San Diego, CA 92121, USA.
  • 9. Department of Environmental Science and Engineering, Fudan University, Shanghai 200433, China.
  • 10. Human Genetics, Genome Institute of Singapore, Agency for Science, Technology and Research, A∗STAR, Singapore 138672, Singapore; Duke-National University of Singapore Medical School, 8 College Road, Singapore 169857, Singapore; Singapore Eye Research Institute, 20 College Road Discovery Tower, Level 6 The Academia, Singapore 169856, Singapore.
  • 11. Pluripotency for Organ Regeneration (PR Lab), Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology (BIST), 08028 Barcelona, Spain; University of Barcelona, Barcelona, Spain; Institució Catalana de Recerca i Estudis Avançats (ICREA), Passeig de Lluís Companys, 23, 08010 Barcelona, Spain; Networking Biomedical Research Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Madrid, Spain.
  • 12. Altos Labs, 5510 Morehouse Drive, Suite 300, San Diego, CA 92121, USA. Electronic address: [email protected].
  • 13. Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, 11 Mandalay Road, Singapore 308232, Singapore; Human Genetics, Genome Institute of Singapore, Agency for Science, Technology and Research, A∗STAR, Singapore 138672, Singapore. Electronic address: [email protected].
  • 14. Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, 11 Mandalay Road, Singapore 308232, Singapore. Electronic address: [email protected].
PMID: 38181751 DOI: 10.1016/j.stem.2023.12.003
Abstract

Human pluripotent stem cell-derived kidney organoids offer unprecedented opportunities for studying polycystic kidney disease (PKD), which still has no effective cure. Here, we developed both in vitro and in vivo Organoid models of PKD that manifested tubular injury and aberrant upregulation of renin-angiotensin aldosterone system. Single-cell analysis revealed that a myriad of metabolic changes occurred during cystogenesis, including defective Autophagy. Experimental activation of Autophagy via ATG5 overexpression or primary cilia ablation significantly inhibited cystogenesis in PKD kidney organoids. Employing the Organoid xenograft model of PKD, which spontaneously developed tubular cysts, we demonstrate that minoxidil, a potent Autophagy activator and an FDA-approved drug, effectively attenuated cyst formation in vivo. This in vivo Organoid model of PKD will enhance our capability to discover novel disease mechanisms and validate candidate drugs for clinical translation.

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