Reconstruction of the Human Colon Epithelium In Vivo

Shinya Sugimoto, Yuki Ohta, Masayuki Fujii, Mami Matano, Mariko Shimokawa, Kosaku Nanki, Shoichi Date, Shingo Nishikori, Yoshihiro Nakazato, Tetsuya Nakamura, Takanori Kanai, Toshiro Sato

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

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. Sugimoto et al. established an orthotopic xenotransplantation system for human normal colon organoids. Using LGR5-CreER knockin organoids for genetic lineage tracing, they demonstrated the self-renewal and multipotency of LGR5+ colon stem cells in mouse colon. Interestingly, human LGR5+ colon stem cells showed slower cycling than those of mice in vivo.

Original languageEnglish
Pages (from-to)171-176.e5
JournalCell Stem Cell
Volume22
Issue number2
DOIs
Publication statusPublished - 2018 Feb 1

Keywords

  • colon stem cells
  • lineage tracing
  • organoids
  • stem cell niche

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Cell Biology

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  • Cite this

    Sugimoto, S., Ohta, Y., Fujii, M., Matano, M., Shimokawa, M., Nanki, K., Date, S., Nishikori, S., Nakazato, Y., Nakamura, T., Kanai, T., & Sato, T. (2018). Reconstruction of the Human Colon Epithelium In Vivo. Cell Stem Cell, 22(2), 171-176.e5. https://doi.org/10.1016/j.stem.2017.11.012