Introduction: We are developing a renal failure therapy based on xeno-regenerative medicine, in which human iPS cell–derived nephron progenitor cells (NPCs) are combined with porcine fetal kidneys to generate chimera kidneys. To establish a chassis for chimera kidney generation, a cell-ablation system targeting NPCs is required to create a vacant nephrogenic niche. Several such systems have been developed in mouse models (1). Furthermore, using an anephric rat model, we demonstrated prolonged survival after transplantation of allogeneic fetal kidneys (2). That model demands sophisticated microsurgery techniques—creation of a integrated metanephros-bladder composite and anastomosis via a stepwise peristaltic ureter system connecting the fetal bladder to the native ureter. Translating these techniques to the mouse scale is technically challenging; thus, developing a cell-ablation system in a rat model promises to accelerate these studies.
Methods: We generated a “Six2-ATTAC9” BAC transgenic rat expressing FK506-inducible iCaspase9 under the control of the Six2 promoter. Fetal kidneys were harvested and treated with a chemical inducer of dimerization (CID) to ablate NPCs and thereby form a nephrogenic niche. These niche-prepared fetal kidneys were then repopulated in vitro by isolating and transplanting exogenous mouse NPCs, and the resulting chimera fetal kidneys were cultured on Transwell inserts.
Results: Fetal kidneys cultured on Transwell membranes with CID showed effective NPC depletion and successful formation of a nephrogenic niche. After transplanting mouse progenitor cells into these kidneys and culturing for four days, immunostaining revealed integration of donor mouse cells with rat ureteric buds and the formation of chimeric nephrons (Figure 1).

Conclusion: We have successfully up-scaled our microsurgical platform to a rat model compatible with cell ablation. This advance enables functional evaluation of chimera fetal kidneys and assessment of survival benefit in vivo, moving us closer to clinical application. ​

References
(1) Matsui K, Watanabe M, Yamamoto S, et al. Caspase 9–induced apoptosis enables efficient fetal cell ablation and disease modeling. Nat Commun. 2025;16:2572. doi:10.1038/s41467-025-57795-6
(2) Kinoshita Y, Kobayashi E, Matsui K, et al. Life-supporting functional kidney replacement by integration of embryonic metanephros–bladder composite tissue transplants. Kidney Int. 2025 Mar 21. doi:10.1016/j.kint.2025.02.024