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

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

Cell Stem Cell

10.1016/j.stem.2023.12.003

https://doi.org/10.1016/j.stem.2023.12.003

MENG LIU, Chao Zhang, Ximing Gong, Tian Zhang, Michelle Mulan Lian, Elaine Guo Yan Chew, Angelysia Cardilla, Keiichiro Suzuki, Huamin Wang, Yuan Yuan, Yan Li, Mihir Yogesh Naik, Yixuan Wang, Bingrui Zhou, Wei Ze Soon, Emi Aizawa, Pin Li, Jian Hui Low, Moses Tandiono, Enrique Montagud, Daniel Moya–Rull, Concepcion Rodriguez Esteban, Yosu Luque, Mingliang Fang, Chiea Chuen Khor, Nuria Montserrat, Josep M. Campistol, Juan Carlos Izpisua Belmonte, Jia Nee Foo, Yun Xia

04 January 2024

Liu, M., Zhang, C., Gong, X., Zhang, T., Lian, M. M., Chew, E. G. Y., Cardilla, A., Suzuki, K., Wang, H., Yuan, Y., Li, Y., Naik, M. Y., Wang, Y., Zhou, B., Soon, W. Z., Aizawa, E., Li, P., Low, J. H., Tandiono, M., … Xia, Y. (2024). Kidney organoid models reveal cilium-autophagy metabolic axis as a therapeutic target for PKD both in vitro and in vivo. Cell Stem Cell, 31(1), 52-70.e8. https://doi.org/10.1016/j.stem.2023.12.003

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.

Publisher Copyright

Y.X. is supported by Singapore Ministry of Education Academic Research Fund Tier 2 and Tier 3 (MOE-MOET32020-0004, MOE2019-T2-1-072, MOE-TEP30220-0008), Singapore Ministry of Health’s National Medical Research Council Open Fund Large Collaborative Grant (MOH-001214, OFLCG22may-0011), and Nanyang Assistant Professorship. J.N.F is supported by Ministry of Education Singapore Academic Research Fund Tier 2 and Tier 3 (MOE-T2EP30220-0005, MOE-MOET32020-0004) and National Medical Research Council Singapore (MOH-000559). C.C.K. is supported by National Research Foundation of Singapore, NRF Investigatorship (NRF-NRFI2018-01).

https://oar.a-star.edu.sg/communities-collections/articles/22597

1934-5909

Genome Institute of Singapore