Animal fetuses and embryos may have applications in the generation of human organs. Progenitor cells may be an appropriate cell source for regenerative organs because of their safety and availability. However, regenerative organs derived from exogenous lineage progenitors in developing animal fetuses have not yet been obtained. Here, we established a combination system through which donor cells could be precisely injected into the nephrogenic zone and native nephron progenitor cells (NPCs) could be eliminated in a time- and tissue-specific manner. We successfully achieved removal of Six2+ NPCs within the nephrogenic niche and complete replacement of transplanted NPCs with donor cells. These NPCs developed into mature glomeruli and renal tubules, and blood flow was observed following transplantation in vivo. Furthermore, this artificial nephron could be obtained using NPCs from different species. Thus, this technique enables in vivo differentiation from progenitor cells into nephrons, providing insights into nephrogenesis and organ regeneration.

Kidney regeneration is expected to be a new alternative treatment to the currently limited treatments for chronic kidney disease. By transplanting exogeneous nephron progenitor cells (NPCs) into the metanephric mesenchyme of a xenogeneic foetus, we aimed to regenerate neo-kidneys that originate from transplanted NPCs. Previously, we generated a transgenic mouse model enabling drug-induced ablation of NPCs (the Six2-iDTR mouse). We demonstrated that eliminating existing native host NPCs allowed their 100% replacement with donor mouse or rat NPCs, which could generate neo-nephrons on a culture dish. To apply this method to humans in the future, we examined the possibility of the in vivo regeneration of nephrons between different species via NPC replacement. We injected NPCs-containing rat renal progenitor cells and diphtheria toxin below the renal capsule of E13.5 metanephroi (MNs) of Six2-iDTR mice; the injected MNs were then transplanted into recipient rats treated with immunosuppressants. Consequently, we successfully regenerated rat/mouse chimeric kidneys in recipient rats receiving the optimal immunosuppressive therapy. We revealed a functional connection between the neo-glomeruli and host vessels and proper neo-glomeruli filtration. In conclusion, we successfully regenerated interspecies kidneys in vivo that acquired a vascular system. This novel strategy may represent an effective method for human kidney regeneration.

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We have previously reported that a major quantitative trait locus (QTL) responsible for susceptibility to salt-induced stroke in the stroke-prone spontaneously hypertensive rat (SHRSP) is located in a 3-Mbp region on chromosome 1 covered by SHRSP.SHR-( D1Rat23 - D1Rat213 )/Izm (termed Pr1.31), a congenic strain with segments from SHRSP/Izm introduced into the stroke-resistant SHR/Izm. Here, we attempted to narrow down the candidate region on chromosome 1 further through analyses of subcongenic strains constructed for the target region. Simultaneously, salt-induced kidney injury was evaluated through the measurement of urinary albumin and the gene expression of renal tubular injury markers ( Kim-1 and Clu ) to explore a possible mechanism leading to the onset of stroke. All subcongenic strains examined in this study showed lower susceptibility to salt-induced stroke than SHRSP. Interestingly, Pr1.31 had the lowest stroke susceptibility when compared with newly constructed subcongenic strains harboring fragments of the congenic sequence in Pr1.31. Although Kim-1 and Clu expression after 1 week of salt loading in Pr1.31 did not differ significantly from those in SHRSP, the urinary albumin level of Pr1.31 was significantly lower than those of the other subcongenic strains and that of SHRSP. The present results indicated that, although the congenic fragment in Pr1.31 harbored the gene(s) related to salt-induced organ damages, further genetic dissection of the candidate region was difficult due to multiple QTLs suggested in this region. Further analysis using Pr1.31 will unveil genetic and pathophysiological mechanisms underlying salt-induced end organ damages in SHRSP.