Center for Genetic Analysis of Behavior, National Institute for Physiological Sciences, Okazaki, 444-8787, Aichi, Japan.
Center for Molecular Medicine, Jichi Medical University, Shimotsuke, 329-0498, Tochigi, Japan.
Nat Commun. 2019 Feb 5;10(1):451. doi: 10.1038/s41467-019-08394-9.
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.
在动物模型中实现人类肾脏的再生将有助于解决移植治疗中严重的供体短缺问题。此前，我们通过鼠和大鼠之间的种间胚泡互补，在胰腺 Pdx1 突变小鼠中生成了多能干细胞 (PSC) 衍生的功能性胰腺，证明了这一点。然而，我们无法在无肾 Sall1 突变小鼠中获得大鼠 PSC 衍生的肾脏，这可能是由于大鼠 PSCs 对小鼠后肾间充质（肾单位祖细胞）的贡献较差。在这里，相反，我们表明，小鼠 PSCs 可以在大鼠中有效地分化为后肾间充质，从而允许在无肾 Sall1 突变大鼠中生成小鼠 PSC 衍生的肾脏。肾脏中的肾小球上皮和肾小管完全由表达关键功能标记物的小鼠 PSC 衍生细胞组成。重要的是，输尿管膀胱连接正常形成。这些数据为种间胚泡互补作为一种可行的肾脏生成方法提供了原理证明。
