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Reconstruction of the Human Colon Epithelium In Vivo.
Cell Stem Cell ( IF 23.9 ) Pub Date : 2018-Feb-01 , DOI: 10.1016/j.stem.2017.11.012
Shinya Sugimoto , Yuki Ohta , Masayuki Fujii , Mami Matano , Mariko Shimokawa , Kosaku Nanki , Shoichi Date , Shingo Nishikori , Yoshihiro Nakazato , Tetsuya Nakamura , Takanori Kanai , Toshiro Sato

Genetic lineage tracing has revealed that Lgr5+ murine colon stem cells (CoSCs) rapidly proliferate at the crypt bottom. However, the spatiotemporal dynamics of human CoSCs in vivo have remained experimentally intractable. Here we established an orthotopic xenograft system for normal human colon organoids, enabling stable reconstruction of the human colon epithelium in vivo. Xenografted organoids were prone to displacement by the remaining murine crypts, and this could be overcome by complete removal of the mouse epithelium. Xenografted organoids formed crypt structures distinctively different from surrounding mouse crypts, reflecting their human origin. Lineage tracing using CRISPR-Cas9 to engineer an LGR5-CreER knockin allele demonstrated self-renewal and multipotency of LGR5+ CoSCs. In contrast to the rapidly cycling properties of mouse Lgr5+ CoSCs, human LGR5+ CoSCs were slow-cycling in vivo. This organoid-based orthotopic xenograft model enables investigation of the functional behaviors of human CoSCs in vivo, with potential therapeutic applications in regenerative medicine.

中文翻译:

体内人结肠上皮的重建。

遗传谱系追踪表明,Lgr5 +鼠结肠干细胞(CoSCs)在隐窝底部迅速增殖。但是,人类CoSCs在体内的时空动态在实验上仍然难以解决。在这里,我们建立了正常人结肠类器官的原位异种移植系统,从而能够在体内稳定重建人结肠上皮。异种移植的类器官易于被剩余的鼠隐窝置换,这可以通过完全去除小鼠上皮来克服。异种移植的类器官形成的隐窝结构与周围的小鼠隐窝明显不同,反映了它们的起源。使用CRISPR-Cas9进行沿袭追踪以设计LGR5-CreER敲入等位基因证明了LGR5 +的自我更新和多能性CoSC。与小鼠Lgr5 + CoSCs的快速循环特性相反,人LGR5 + CoSCs在体内的循环较慢。这种基于类器官的原位异种移植模型能够研究人CoSC在体内的功能行为,并在再生医学中具有潜在的治疗应用。
更新日期:2017-12-31
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