Generation of pluripotent stem cell-derived mouse kidneys in Sall1-targeted anephric rats

Teppei Goto,Hiromitsu Nakauchi,Hideki Masaki,Toshihiro Kobayashi,Makoto Sanbo,Tomoyuki Yamaguchi,Shinichi Hochi,Hiromasa Hara,Masumi Hirabayashi,Hideyuki Sato

doi:10.1038/s41467-019-08394-9

Abstract

Regeneration of human kidneys in animal models would help combat the severe shortage of donors in transplantation therapy. Previously, we demonstrated by interspecific blastocyst complementation between mouse and rats, generation of pluripotent stem cell (PSC)-derived functional pancreas, in apancreatic Pdx1 mutant mice. We, however, were unable to obtain rat PSC-derived kidneys in anephric Sall1 mutant mice, likely due to the poor contribution of rat PSCs to the mouse metanephric mesenchyme, a nephron progenitor. Here, conversely, we show that mouse PSCs can efficiently differentiate into the metanephric mesenchyme in rat, allowing the generation of mouse PSC-derived kidney in anephric Sall1 mutant rat. Glomerular epithelium and renal tubules in the kidneys are entirely composed of mouse PSC-derived cells expressing key functional markers. Importantly, the ureter-bladder junction is normally formed. These data provide proof-of-principle for interspecific blastocyst complementation as a viable approach for kidney generation.

Highlights

Regeneration of human kidneys in animal models would help combat the severe shortage of donors in transplantation therapy
We first attempted to understand the causes behind the failure of interspecific blastocyst complementation, for kidney generation, when rat pluripotent stem cell (PSC) were injected into Sall1mut/mut mouse blastocysts
Since, during allogenic blastocyst complementation, wildtype PSC-derived cells could replace mutant cells in the metanephric mesenchyme[12], we reasoned that a required level of PSC contribution to the metanephric mesenchyme, is essential for the successful generation of the PSC-derived kidney

Summary

Introduction

Regeneration of human kidneys in animal models would help combat the severe shortage of donors in transplantation therapy. We demonstrated by interspecific blastocyst complementation between mouse and rats, generation of pluripotent stem cell (PSC)-derived functional pancreas, in apancreatic Pdx[1] mutant mice. We were unable to obtain rat PSC-derived kidneys in anephric Sall[1] mutant mice, likely due to the poor contribution of rat PSCs to the mouse metanephric mesenchyme, a nephron progenitor. These data provide proof-of-principle for interspecific blastocyst complementation as a viable approach for kidney generation. Organ transplantation is among the most effective treatments to improve quality-of-life (QOL) in patients with end-stage renal disease (ESRD). A chronic shortage of donor kidneys leaves many patients with ESRD no choice, but to undergo continued dialysis treatment, associated with poor QOL, high medical costs and risk of complications. Use of apancreatic Pdx1mut/mut mouse host blastocysts allows the generation of PSC-

Methods

Results

Conclusion