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Updated: May 22, 2025
In Vivo Biosensor Tracks Non-apoptotic Caspase Activity in Drosophila
Published on: November 27, 2016
Caspase 9-induced apoptosis enables efficient fetal cell ablation and disease modeling
Kenji Matsui1, Masahito Watanabe2,3, Shutaro Yamamoto1,4
1Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan.
Abstract:
Fetal cell ablation models are crucial for studying congenital diseases, organ regeneration, and xenotransplantation. However, conventional knockout models offer limited control over disease severity, while conditional ablation models often require fetus-harming inducers. In the present study, we demonstrate that the inducible caspase 9 system enables precise targeting of fetal nephron progenitor cells in mice through the intrinsic apoptotic pathway. Using a safe, placenta-permeable inducer, this system facilitates specific, rapid, and efficient cell ablation. The system's temporal control allows precise adjustment of disease severity, generating reproducible models ranging from congenital kidney deficiency to severe chronic kidney disease. Cells with low expression levels of inducible caspase 9 and those in solid organs are less susceptible to apoptosis. However, this limitation can be overcome by inhibiting the X-linked inhibitor of apoptosis protein, thereby expanding the system's applicability. Additionally, this model provides a developmental environment suitable for chimeric kidney regeneration. This system advances understanding of induced cell death mechanisms, enhances pathological research tools, and supports therapeutic development in kidney disease and xenotransplantation applications.
Insights
This study introduces an inducible caspase 9 system for precise fetal cell ablation in mice, creating advanced models for congenital kidney diseases and organ regeneration research.
Area of Science:
- Developmental biology
- Molecular biology
- Genetics
Background:
- Fetal cell ablation models are essential for studying congenital diseases, organ regeneration, and xenotransplantation.
- Existing models like knockout and conditional ablation have limitations in controlling disease severity and require harmful inducers.
Purpose of the Study:
- To develop a precise and controllable fetal cell ablation system using the inducible caspase 9 (iCasp9) system in mice.
- To establish reproducible models for congenital kidney diseases and explore applications in organ regeneration and xenotransplantation.
Main Methods:
- Utilized the inducible caspase 9 system for targeted ablation of fetal nephron progenitor cells in mice.
- Employed a safe, placenta-permeable inducer for specific and efficient cell apoptosis.
- Investigated methods to overcome limitations in cell susceptibility, including inhibiting the X-linked inhibitor of apoptosis protein (XIAP).
Main Results:
- Achieved precise, rapid, and efficient ablation of fetal cells via the intrinsic apoptotic pathway.
- Demonstrated temporal control over cell ablation, enabling adjustable disease severity from mild to severe chronic kidney disease.
- Showcased the model's suitability for studying chimeric kidney regeneration and overcoming apoptosis resistance in certain cell types.
Conclusions:
- The iCasp9 system offers a powerful, controllable tool for fetal cell ablation, advancing research in kidney development and disease.
- This model enhances the study of induced cell death mechanisms and pathological processes.
- The system holds significant potential for therapeutic development in kidney disease and xenotransplantation research.
