Reconstruction of the Human Colon Epithelium In Vivo

doi:10.1016/j.stem.2017.11.012

. 2018 Feb 1;22(2):171-176.e5.

doi: 10.1016/j.stem.2017.11.012. Epub 2017 Dec 28.

Reconstruction of the Human Colon Epithelium In Vivo

Affiliations

¹ Department of Gastroenterology, Keio University School of Medicine, Tokyo 160-8582, Japan.
² Department of Gastroenterology, Keio University School of Medicine, Tokyo 160-8582, Japan; Fujii Memorial Research Institute, Otsuka Pharmaceutical Company, Limited, Shiga 520-0106, Japan.
³ Department of Advanced Therapeutics for GI Diseases, Tokyo Medical and Dental University, Tokyo 113-8510, Japan.
⁴ Department of Gastroenterology, Keio University School of Medicine, Tokyo 160-8582, Japan. Electronic address: t.sato@keio.jp.

PMID: 29290616
DOI: 10.1016/j.stem.2017.11.012

Free article

Reconstruction of the Human Colon Epithelium In Vivo

Shinya Sugimoto et al. Cell Stem Cell. 2018.

Free article

. 2018 Feb 1;22(2):171-176.e5.

doi: 10.1016/j.stem.2017.11.012. Epub 2017 Dec 28.

Affiliations

¹ Department of Gastroenterology, Keio University School of Medicine, Tokyo 160-8582, Japan.
² Department of Gastroenterology, Keio University School of Medicine, Tokyo 160-8582, Japan; Fujii Memorial Research Institute, Otsuka Pharmaceutical Company, Limited, Shiga 520-0106, Japan.
³ Department of Advanced Therapeutics for GI Diseases, Tokyo Medical and Dental University, Tokyo 113-8510, Japan.
⁴ Department of Gastroenterology, Keio University School of Medicine, Tokyo 160-8582, Japan. Electronic address: t.sato@keio.jp.

PMID: 29290616
DOI: 10.1016/j.stem.2017.11.012

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.

Keywords: colon stem cells; lineage tracing; organoids; stem cell niche.

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Reconstruction of the Human Colon Epithelium In Vivo

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Reconstruction of the Human Colon Epithelium In Vivo

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