Generation of Human Renal Vesicles in Mouse Organ Niche Using Nephron Progenitor Cell Replacement System

Highlights

• Development of a tamoxifen-inducible NPC ablation system for human cells

• Regeneration of interspecies nephrons from rat NPCs via an NPC replacement system

• Regenerated interspecies nephrons exhibit urine production abilities

• Transplanted human induced NPCs differentiate and connect to host tissue

Summary

Animal fetuses may be used for the regeneration of human organs. We have previously generated a transgenic mouse model that allows diphtheria toxin (DT)-induced ablation of Six2-positive nephron progenitor cells (NPCs). Elimination of existing native host NPCs enables their replacement with donor NPCs, which can generate neo-nephrons. However, this system cannot be applied to human NPCs, because DT induces apoptosis in human cells. Therefore, the present study presents a transgenic mouse model for the ablation of NPCs using tamoxifen, which does not affect human cells. Using this system, we successfully regenerate interspecies neo-nephrons, which exhibit urine-producing abilities, from transplanted rat NPCs in a mouse host. Transplantation of human induced pluripotent stem cell (iPSC)-derived NPCs results in differentiation into renal vesicles, which connect to the ureteric bud of the host. Thus, we demonstrate the possibility of the regeneration of human kidneys derived from human iPSC-derived NPCs via NPC replacement.