Generation of Kidney from Pluripotent Stem Cells via Blastocyst Complementation
Generation of Kidney from Pluripotent Stem Cells via Blastocyst Complementation
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DOI：
10.1016/j.ajpath.2012.03.007
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发表时间：
2012-06-01
影响因子：
6
通讯作者：
Nakauchi, Hiromitsu
中科院分区：
文献类型：
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作者：
Usui, Jo-ichi;Kobayashi, Toshihiro;Nakauchi, Hiromitsu
由于供体器官的短缺一直是器官移植计划扩展的主要障碍，因此可移植器官的产生是再生医学的最终目标之一。然而，器官发生所需的组织之间和组织内的复杂细胞相互作用难以在体外重现。作为替代方案，我们使用胚泡互补在体内产生多能干细胞（PSC）衍生的供体器官。我们假设，如果我们将PSC注射到从突变小鼠中获得的囊胚中，其中特定器官的发育被遗传操作排除，从而为器官发育留下一个小生境，PSC衍生的细胞将发育补偿缺陷并形成缺失的器官。在我们之前的工作中，我们通过将PSC注射到胰腺缺陷的Pdx 1（-/-）小鼠囊胚中，证明了胰腺生成的原理性发现。在这项研究中，我们已经将这种技术扩展到使用Sall 1（-/-）小鼠囊胚的肾脏生成。结果，有缺陷的细胞被完全取代，肾脏完全由注射的小鼠PSC衍生细胞形成，除了不受Sal 1表达影响的结构（即集合管和微血管）。这些发现表明，胚泡互补可以扩展到产生PSC衍生的肾脏。因此，该系统可以提供新的见解肾器官发生。(Am J Pathol 2012，180：2417-2424 http：//dx·doi·org/10·1016/j·ajpath·2012·03·007）
Because a shortage of donor organs has been a major obstacle to the expansion of organ transplantation programs, the generation of transplantable organs is among the ultimate goals of regenerative medicine. However, the complex cellular interactions among and within tissues that are required for organogenesis are difficult to recapitulate in vitro. As an alternative, we used blastocyst complementation to generate pluripotent stem cell (PSC)-derived donor organs in Vivo. We hypothesized that if we injected PSCs into blastocysts obtained from mutant mice in which the development of a certain organ was precluded by genetic manipulation, thereby leaving a niche for organ development, the PSC-derived cells would developmentally compensate for the defect and form the missing organ. In our previous work, we showed proof-of-principle findings of pancreas generation by injection of PSCs into pancreas-deficient Pdx1(-/-) mouse blastocysts. In this study, we have extended this technique to kidney generation using Sall1(-/-) mouse blastocysts. As a result, the defective cells were totally replaced, and the kidneys were entirely formed by the injected mouse PSC-derived cells, except for structures not under the influence of Sal1 expression (ie, collecting ducts and microvasculature). These findings indicate that blastocyst complementation can be extended to generate PSC-derived kidneys. This system may therefore provide novel insights into renal organogenesis. (Am J Pathol 2012, 180:2417-2424 http://dx.doi.org/10.1016/j.ajpath.2012.03.007)