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Updated: May 20, 2025
Implementing Patch Clamp and Live Fluorescence Microscopy to Monitor Functional Properties of Freshly Isolated PKD Epithelium
Published on: September 1, 2015
PKD1 mutation perturbs morphogenesis in tubular epithelial organoids derived from human pluripotent stem cells
Alexandru Scarlat1, Piera Trionfini1, Paola Rizzo1
1Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy.
Abstract:
Autosomal dominant polycystic kidney disease (ADPKD) is the most common renal genetic disease, with most patients carrying mutations in PKD1. The main feature is the formation of bilateral renal cysts, leading to end stage renal failure in a significant proportion of those affected. Despite recent advances made in understanding ADPKD, there are currently no effective curative therapies. The emergence of human induced pluripotent stem cell (hiPSC)-derived kidney disease models has led to renewed hope that more physiological systems will allow for the development of novel treatments. hiPSC-derived organoid models have been used to recapitulate ADPKD, however they present numerous limitations which remain to be addressed. In the present study, we report an efficient method for generating organoids containing a network of polarised and ciliated epithelial tubules. PKD1 null (PKD1-/-) organoids spontaneously develop dilated tubules, recapitulating early ADPKD cystogenesis. Furthermore, PKD1-/- tubules present primary cilia defects when dilated. Our model could therefore serve as a valuable tool to study early ADPKD cystogenesis and to develop novel therapies.
Insights
Researchers developed a new organoid model for Autosomal dominant polycystic kidney disease (ADPKD). This model effectively replicates early cyst formation and primary cilia defects, offering a promising avenue for novel therapeutic development.
Area of Science:
- Nephrology
- Stem Cell Biology
- Genetics
Background:
- Autosomal dominant polycystic kidney disease (ADPKD) is the most prevalent inherited renal disorder.
- Mutations in the PKD1 gene are the primary cause of ADPKD, leading to renal cyst formation and eventual end-stage renal failure.
- Current therapeutic options for ADPKD are limited, highlighting the need for advanced disease models.
Purpose of the Study:
- To develop an efficient method for generating human induced pluripotent stem cell (hiPSC)-derived organoids that model ADPKD.
- To investigate the early cystogenesis and associated cellular defects in ADPKD using these novel organoids.
- To establish a platform for screening potential therapeutic interventions for ADPKD.
Main Methods:
- Generation of hiPSC-derived kidney organoids.
- Utilizing CRISPR/Cas9 technology to create PKD1-null organoids.
- Characterization of organoid structure, tubule polarization, and primary cilia function.
Main Results:
- The developed organoids successfully formed polarized, ciliated epithelial tubules.
- PKD1-null organoids exhibited spontaneous development of dilated tubules, mimicking early ADPKD cystogenesis.
- Defects in primary cilia were observed in dilated tubules of PKD1-null organoids.
Conclusions:
- The novel hiPSC-derived organoid model efficiently recapitulates key features of early ADPKD.
- This model provides a valuable tool for studying ADPKD pathogenesis, particularly cystogenesis and cilia dysfunction.
- The model holds potential for the development and testing of innovative ADPKD therapies.
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