Caspase 9-induced apoptosis enables efficient fetal cell ablation and disease modeling

Kenji Matsui, Masahito Watanabe, Shutaro Yamamoto, Shiho Kawagoe, Takumi Ikeda, Hinari Ohashi, Takafumi Kuroda, Nagisa Koda, Keita Morimoto, Yoshitaka Kinoshita, Yuka Inage, Yatsumu Saito, Shohei Fukunaga, Toshinari Fujimoto, Susumu Tajiri, Kei Matsumoto, Eiji Kobayashi, Takashi Yokoo () and Shuichiro Yamanaka ()
Additional contact information
Kenji Matsui: The Jikei University School of Medicine
Masahito Watanabe: Meiji University International Institute for Bio-Resource Research
Shutaro Yamamoto: The Jikei University School of Medicine
Shiho Kawagoe: The Jikei University School of Medicine
Takumi Ikeda: The Jikei University School of Medicine
Hinari Ohashi: The Jikei University School of Medicine
Takafumi Kuroda: The Jikei University School of Medicine
Nagisa Koda: The Jikei University School of Medicine
Keita Morimoto: The Jikei University School of Medicine
Yoshitaka Kinoshita: The Jikei University School of Medicine
Yuka Inage: The Jikei University School of Medicine
Yatsumu Saito: The Jikei University School of Medicine
Shohei Fukunaga: The Jikei University School of Medicine
Toshinari Fujimoto: The Jikei University School of Medicine
Susumu Tajiri: The Jikei University School of Medicine
Kei Matsumoto: The Jikei University School of Medicine
Eiji Kobayashi: The Jikei University School of Medicine
Takashi Yokoo: The Jikei University School of Medicine
Shuichiro Yamanaka: The Jikei University School of Medicine

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-57795-6

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