Afrin Humayra, Qamar Usama, Robichaud Jielu Hao, Ellabbad Mohammad, Harris Peter C, Gupta Navin
Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, United States.
Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota, United States.
Am J Physiol Renal Physiol. 2025 Jul 1;329(1):F143-F159. doi: 10.1152/ajprenal.00116.2025. Epub 2025 Jun 11.
Kidney organoids are an increasingly established model of polycystic kidney disease (PKD). Derived from human pluripotent stem cells (hPSCs), organoids may be generated from induced pluripotent stem cells (iPSCs) of patients that bear naturally occurring mutations or from CRISPR mutant hPSCs by virtue of their genetic tractability. PKD is the leading inheritable cause of kidney failure (KF), accounting for ∼5%-10% of the kidney transplant and dialysis needs worldwide. PKD is a disorder of considerable genetic heterogeneity, composed of typical adult-onset autosomal dominant (ADPKD) and fetal-onset autosomal recessive (ARPKD) forms, which share pathomechanisms. Despite advances in our understanding of the genetic and molecular underpinnings of PKD, the limited clinical treatment options have raised concerns regarding the faithfulness of preclinical models. Kidney organoids have emerged as a promising platform to study PKD by mimicking human-specific responses, enabling personalized medicine, and supporting high-throughput screens. Yet, valid criticisms have related to the relative immaturity of kidney organoids for modeling adult-onset forms of PKD, the faithfulness of organoids in modeling the cystic distribution of afflicted patients, and their batch-to-batch variability limiting experimental reproducibility. Here, we summarize a decade of kidney organoid models of PKD, emphasizing their role in advancing translational and therapeutic applications while addressing their limitations and future potential.
肾类器官是一种越来越成熟的多囊肾病（PKD）模型。类器官源自人类多能干细胞（hPSC），可从携带自然发生突变的患者的诱导多能干细胞（iPSC）或通过基因可操作性从CRISPR突变hPSC中生成。PKD是肾衰竭（KF）的主要遗传性病因，占全球肾脏移植和透析需求的5%-10%。PKD是一种具有显著遗传异质性的疾病，由典型的成人发病常染色体显性（ADPKD）和胎儿发病常染色体隐性（ARPKD）形式组成，它们具有共同的病理机制。尽管我们对PKD的遗传和分子基础的理解取得了进展，但有限的临床治疗选择引发了对临床前模型可靠性的担忧。肾类器官已成为一个有前景的平台，用于通过模拟人类特异性反应、实现个性化医疗和支持高通量筛选来研究PKD。然而，合理的批评涉及肾类器官在模拟成人发病形式的PKD方面相对不成熟、类器官在模拟患病患者囊性分布方面的可靠性，以及它们批次间的变异性限制了实验的可重复性。在这里，我们总结了十年的PKD肾类器官模型，强调它们在推进转化和治疗应用方面的作用，同时解决它们的局限性和未来潜力。
