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Human Organoids as Drug Development Tools for Polycystic Kidney Disease
Hongxia Fu1,2,3,4,5, Benjamin S Freedman6,7,8,9,10
1Department of Medicine, Department of Bioengineering, Institute for Stem Cell and Regenerative Medicine, and PKD In Vitro Center, University of Washington, Seattle, Washington, USA.
Background:
Polycystic kidney disease (PKD) is commonly inherited as a loss-of-function mutation in PC1 (polycystin-1) or PC2. The molecular functions of polycystins remain uncertain, and therapeutics remain limited for millions of patients. One major roadblock has been the scarcity of assays that re-create PKD-specific cystogenesis in vitro, to complement mouse models.
Summary:
Over the past decade, a human organoid model of PKD has emerged that promises to bridge this gap. Human kidney organoids derived from PKD1-/- or PKD2-/- pluripotent stem cells recapitulate the pathognomonic cystic phenotype in a PKD-specific manner. Here we review important achievements, current limitations, and future strategies, with a focus on translational "bench to bedside" potential of PKD organoids as drug development tools.
Key Messages:
Human PKD organoids reveal that PKD cystogenesis is a cell intrinsic process that can be re-created in vitro. These systems have revealed unexpected mechanisms for PKD cystogenesis and have been utilized to blueprint new therapeutic strategies, but their potential is not yet fully realized. The complexity and cost of organoids remain significant barriers to entry, and dedicated technology development is required to improve their physiological relevance.
Insights
Human kidney organoids model polycystic kidney disease (PKD) cystogenesis in vitro. This breakthrough allows studying PKD mechanisms and developing new therapies for this inherited kidney disorder.
Area of Science:
- Nephrology
- Stem Cell Biology
- Genetics
Background:
- Polycystic kidney disease (PKD) is a common inherited disorder caused by mutations in PC1 or PC2.
- Limited therapeutic options exist for PKD, partly due to a lack of effective in vitro models.
- Current research faces challenges in replicating PKD cystogenesis outside of animal models.
Purpose of the Study:
- To review the achievements and limitations of human kidney organoids in modeling PKD.
- To explore the potential of PKD organoids as drug development tools.
- To discuss future strategies for advancing PKD organoid technology.
Main Methods:
- Utilizing human pluripotent stem cells to generate kidney organoids from PKD1-/- or PKD2-/- cell lines.
- Characterizing the recapitulation of PKD-specific cystic phenotypes in vitro.
- Analyzing the cell-intrinsic nature of PKD cystogenesis.
Main Results:
- Human PKD organoids successfully replicate the characteristic cystic phenotype of PKD.
- The organoid system demonstrates that PKD cystogenesis is a cell-intrinsic process.
- PKD organoids have unveiled novel mechanisms underlying cyst formation and aided in designing therapeutic strategies.
Conclusions:
- Human kidney organoids represent a significant advancement for studying PKD in vitro.
- Despite current limitations in complexity and cost, PKD organoids hold great promise for drug discovery.
- Further technological development is crucial to enhance the physiological relevance and translational potential of PKD organoids.
