Spatially patterned kidney assembloids recapitulate progenitor self-assembly and enable high-fidelity in vivo disease modeling

Biao Huang¹, Pedro Medina¹, Jincan He², Zipeng Zeng¹, Sunghyun Kim³, Janet Romo³, Kari Koppitch³, Chennan C Zhang¹, Georgina Gyarmati⁴, Yohan Park⁵, Ruslan Bohovyk⁶, Pierre-Emmanuel Yoann N'Guetta⁷, Jinjin Guo³, Tianyi Ma¹, Megan E Schreiber¹, Cong Xu¹, Jessica Pham⁸, Riana K Parvez³, Jackson Su¹, Mateo W Xia¹, Zhenqing Liu⁹, Laura Perin¹⁰, Danny El-Nachef³, Charles E Murry³, Sanjeev Kumar¹¹, Lori O'Brien⁷, Kurt A Zimmerman⁵, Justin Ichida³, Nils O Lindström³, Nuria M Pastor-Soler⁸, Kenneth R Hallows⁸, Alexander Staruschenko⁶, Janos Peti-Peterdi⁴, Cizhong Jiang², Andrew P McMahon³, Zhongwei Li¹²

Affiliations

¹ Vito M. Campese MD/UKRO Kidney Research Center, Division of Nephrology and Hypertension, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA; Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
² Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Orthopaedic Department of Tongji Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200065, China.
³ Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
⁴ Department of Physiology and Neuroscience and Department of Medicine, Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, CA 90033, USA.
⁵ Department of Internal Medicine, Division of Nephrology and Hypertension, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73034, USA.
⁶ Department of Molecular Pharmacology and Physiology, University of South Florida, Tampa, FL 33602, USA.
⁷ Department of Cell Biology and Physiology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
⁸ Vito M. Campese MD/UKRO Kidney Research Center, Division of Nephrology and Hypertension, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
⁹ Department of Neurodegenerative Diseases, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA.
¹⁰ GOFARR Laboratory, Division of Urology, Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, CA 90027, USA.
¹¹ Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
¹² Vito M. Campese MD/UKRO Kidney Research Center, Division of Nephrology and Hypertension, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA; Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA. Electronic address: zhongwei.li@med.usc.edu.

PMID: 40967224
DOI: 10.1016/j.stem.2025.08.013

Spatially patterned kidney assembloids recapitulate progenitor self-assembly and enable high-fidelity in vivo disease modeling

Biao Huang et al. Cell Stem Cell. 2025.

. 2025 Oct 2;32(10):1614-1633.e13.

doi: 10.1016/j.stem.2025.08.013. Epub 2025 Sep 17.

Authors

Affiliations

¹ Vito M. Campese MD/UKRO Kidney Research Center, Division of Nephrology and Hypertension, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA; Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
² Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Orthopaedic Department of Tongji Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200065, China.
³ Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
⁴ Department of Physiology and Neuroscience and Department of Medicine, Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, CA 90033, USA.
⁵ Department of Internal Medicine, Division of Nephrology and Hypertension, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73034, USA.
⁶ Department of Molecular Pharmacology and Physiology, University of South Florida, Tampa, FL 33602, USA.
⁷ Department of Cell Biology and Physiology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
⁸ Vito M. Campese MD/UKRO Kidney Research Center, Division of Nephrology and Hypertension, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
⁹ Department of Neurodegenerative Diseases, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA.
¹⁰ GOFARR Laboratory, Division of Urology, Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, CA 90027, USA.
¹¹ Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
¹² Vito M. Campese MD/UKRO Kidney Research Center, Division of Nephrology and Hypertension, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA; Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA. Electronic address: zhongwei.li@med.usc.edu.

PMID: 40967224
DOI: 10.1016/j.stem.2025.08.013

Abstract

Current kidney organoids do not recapitulate the kidney's complex spatial patterning and function, limiting their applications. The human kidney comprises one million nephrons, derived from nephron progenitor cells, that connect to an arborized ureteric progenitor cell-derived collecting system. Here, we develop spatially organized mouse and human kidney progenitor assembloid (KPA) models in which the nephrons undergo extensive development and fuse to a centrally located collecting system, recapitulating kidney progenitor self-assembly processes observed in vivo. KPAs show dramatically improved cellular complexity and maturity and exhibit several aspects of major kidney functions in vitro and in vivo. Modeling human autosomal dominant polycystic kidney disease (ADPKD) with genome-edited, in vivo-grown human KPAs recapitulated the cystic phenotype and the molecular and cellular hallmarks of the disease and highlighted the crosstalk among cyst epithelium, stroma, and macrophages. The KPA platform opens new avenues for high-fidelity disease modeling and lays a strong foundation for kidney regenerative medicine.

Keywords: collecting duct; functional maturation; kidney organoid; nephron; nephron patterning; nephron progenitor cell; pluripotent stem cell; polycystic kidney disease; progenitor plasticity; ureteric progenitor cell.

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Conflict of interest statement

Declaration of interests A.P.M. is a scientific advisor or consultant for eGENESIS, Trestle Biotherapeutics, GentiBio, and IVIVA Medical. J.P.-P. and G.G. are co-founders of Macula Densa Cell LLC, a biotechnology company that develops therapeutics to target macula densa cells for a regenerative treatment for chronic kidney disease. Macula Densa Cell LLC has a patent entitled “Targeting macula densa cells as a new therapeutic approach for kidney disease” (US patents 10,828,374 and 11,318,209). Z. Li, B.H., P.M., Z.Z., and A.P.M. have applied for intellectual property protection on technologies discussed here.

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Spatially patterned kidney assembloids recapitulate progenitor self-assembly and enable high-fidelity in vivo disease modeling

Affiliations

Spatially patterned kidney assembloids recapitulate progenitor self-assembly and enable high-fidelity in vivo disease modeling

Authors

Affiliations

Abstract

Conflict of interest statement

MeSH terms

LinkOut - more resources

Full Text Sources

Medical

Molecular Biology Databases