Functional engraftment of colon epithelium expanded in vitro from a single adult Lgr5+ stem cell
Abstract
Adult stem-cell therapy holds promise for the treatment of gastrointestinal diseases. Here we describe methods for long-term expansion of colonic stem cells positive for leucine-rich repeat containing G protein-coupled receptor 5 (Lgr5(+) cells) in culture. To test the transplantability of these cells, we reintroduced cultured GFP(+) colon organoids into superficially damaged mouse colon. The transplanted donor cells readily integrated into the mouse colon, covering the area that lacked epithelium as a result of the introduced damage in recipient mice. At 4 weeks after transplantation, the donor-derived cells constituted a single-layered epithelium, which formed self-renewing crypts that were functionally and histologically normal. Moreover, we observed long-term (>6 months) engraftment with transplantation of organoids derived from a single Lgr5(+) colon stem cell after extensive in vitro expansion. These data show the feasibility of colon stem-cell therapy based on the in vitro expansion of a single adult colonic stem cell.
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Tissues including small intestine, colon, stomach, esophagus, tongue, liver, lung, pancreas, heart, ear, and skin have been obtained from iPSCs, adult or fetal cells, either stem/progenitor cells or differentiated cells.
“Under defined physicochemical conditions, tissues such as small intestine7, colon30,31, stomach32,33, esophagus30, tongue34, liver35–38, lung15, pancreas39–41, heart42, ear43, and skin44 have been obtained from iPSCs, adult or fetal cells, either stem/progenitor cells or differentiated cells.”
From Organoids (2022) · cites this paper as [30]
Organoids can arise either from round colonies generated by single cells or from initial multicellular structures such as intestinal crypts, cell aggregates, or micropatterned cells.
“Organoids can arise either from round colonies generated by single cells7,35 or, from initial multicellular structures such as intestinal crypts30,63, cell aggregates24 or micropatterned cells26.”
From Organoids (2022) · cites this paper as [30]
Intestinal organoids were one of the earliest organoid types to be successfully cultured in vitro.
“Intestinal organoids are among the first organoid types successfully established in vitro7,30.”
From Organoids (2022) · cites this paper as [30]
Embedding intact murine colonic crypts and isolated Lgr5+ progenitor cells in collagen I with hepatocyte growth factor, R-spondin 1, EGF, and Noggin generated organoids that were able to engraft onto damaged mouse intestinal epithelia upon transplantation.
“Yui and colleagues showed that embedding intact murine colonic crypts and isolated Lgr5+ progenitor cells in collagen I with hepatocyte growth factor, R-spondin 1, EGF, and Noggin generated organoids that were able to engraft onto damaged mouse intestinal epithelia upon transplantation.”
From Towards organoid culture without Matrigel (2021) · cites this paper as [89]
Ex vivo cultured colon organoids were successfully transplanted into mice colons and formed functionally and histologically normal crypts.
“The clinical translatability of this study gets support from previous study 34 in which ex vivo cultured colon organoids were successfully transplanted into mice colons and formed functionally and histologically normal crypts.”
From CRISPR-Cas9: a new and promising player in gene therapy (2015) · cites this paper as [34]
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Self-citation
- Authors
- Yui, S., Nakamura, T., Sato, T., Nemoto, Y., Mizutani, T., Zheng, X., Ichinose, S., Nagaishi, T., Okamoto, R., Tsuchiya, K., Clevers, H., & Watanabe, M.
- Affiliations
- Tokyo Medical and Dental University (JP)
- Keio University (JP)
- University Medical Center Utrecht (NL)
- Corresponding author
- Clevers, Hans
- Watanabe, Mamoru
- ORCID
- Venue
- Nature Medicine
- Published
- 2012-03-11
- Volume
- 18
- Issue
- 4
- Pages
- 618-623
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- OpenAlex
- W2143149122
- Cited by
- 805
- References
- 34
- Citations by year
- 2026: 35 · 2025: 47 · 2024: 54 · 2023: 43 · 2022: 67 · 2021: 57 · 2020: 57 · 2019: 57 · 2018: 56 · 2017: 100 · 2016: 58 · 2015: 58 · 2014: 44 · 2013: 50 · 2012: 21
- FWCI
- 27.36
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- KNAW Research Portal (The Royal Netherlands Academy of Arts and Sciences) (publishedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Funders
- Japan Society for the Promotion of Science (24590937, 22590694, 22590696, 21590805, 21590806, 23659394, 24590936, 24390186, 21590803, 23790777, 23590934, 23890204, 24790684, 22590695, 22229005)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Health Sciences › Medicine › Surgery › Tissue Engineering and Regenerative Medicine
- Keywords
- Lgr5+ stem cells, colonic stem cells, colon organoids, stem cell therapy, in vitro expansion, DSS-induced colitis, acute colitis, epithelial repair, gastrointestinal diseases
- MeSH terms
- Animals, Body Weight, Cells, Cultured, Colon, DNA-Binding Proteins, Epithelium, Membrane Proteins, Mice, Transgenic, Organoids, Rhodamines, Time Factors, Ki-67 Antigen, Transplants, Receptors, G-Protein-Coupled, Green Fluorescent Proteins, Mice, Cyclooxygenase 1, Chromogranin A, Adult Stem Cells, In Vitro Techniques
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