Curated Papers > High-impact authoritative literature on "organoids"

Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche.

Literature Information

DOI	10.1038/nature07935
PMID	19329995
Journal	Nature
Impact Factor	48.5
JCR Quartile	Q1
Publication Year	2009
Times Cited	3690
Keywords	Lgr5 stem cells, intestinal epithelium, organoid structures
Literature Type	Journal Article
ISSN	0028-0836
Pages	262-5
Issue	459(7244)
Authors	Toshiro Sato, Robert G Vries, Hugo J Snippert, Marc van de Wetering, Nick Barker, Daniel E Stange, Johan H van Es, Arie Abo, Pekka Kujala, Peter J Peters, Hans Clevers

TL;DR

This study investigates the self-renewing capabilities of Lgr5(+) stem cells in the intestinal epithelium by establishing long-term culture conditions that allow single crypts to form multiple crypt fissions and villus-like structures containing all differentiated cell types. The findings highlight that these intestinal crypt-villus units can self-organize from a single stem cell without the need for a non-epithelial niche, providing insights into stem cell biology and potential applications in regenerative medicine.

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Lgr5 stem cells · intestinal epithelium · organoid structures

Abstract

The intestinal epithelium is the most rapidly self-renewing tissue in adult mammals. We have recently demonstrated the presence of about six cycling Lgr5(+) stem cells at the bottoms of small-intestinal crypts. Here we describe the establishment of long-term culture conditions under which single crypts undergo multiple crypt fission events, while simultanously generating villus-like epithelial domains in which all differentiated cell types are present. Single sorted Lgr5(+) stem cells can also initiate these cryptvillus organoids. Tracing experiments indicate that the Lgr5(+) stem-cell hierarchy is maintained in organoids. We conclude that intestinal cryptvillus units are self-organizing structures, which can be built from a single stem cell in the absence of a non-epithelial cellular niche.

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Primary Questions Addressed

1. What are the implications of Lgr5(+) stem cells being able to self-organize into crypt-villus structures without a mesenchymal niche?
2. How do the long-term culture conditions affect the differentiation and function of the organoids derived from single Lgr5(+) stem cells?
3. What specific signaling pathways are involved in the maintenance of the Lgr5(+) stem-cell hierarchy within these organoids?
4. In what ways might the findings regarding Lgr5(+) stem cells contribute to regenerative medicine or treatments for intestinal disorders?
5. How does the absence of a mesenchymal niche influence the cellular interactions and microenvironment of the crypt-villus structures formed in vitro?

Key Findings

Key Insights

1. Research Background and Objectives: The intestinal epithelium is characterized by its rapid turnover and regenerative capacity, primarily due to the activity of Lgr5(+) stem cells located at the base of the intestinal crypts. Understanding the mechanisms behind the self-renewal and organization of these stem cells is crucial for insights into gut biology and potential therapeutic applications. The objective of this study was to establish long-term culture conditions that allow single Lgr5(+) stem cells to self-organize into functional intestinal structures, specifically crypt-villus units, without the presence of a mesenchymal niche.

2. Key Methods and Findings: The researchers developed a culture system that supports the long-term growth of intestinal crypts derived from single Lgr5(+) stem cells. They observed that these single crypts undergo multiple fission events, leading to the formation of villus-like structures that encompass all differentiated cell types found in the intestinal epithelium. Notably, tracing experiments demonstrated that the hierarchical organization of Lgr5(+) stem cells is preserved within the resulting organoids. This indicates that the self-assembly of intestinal structures can occur autonomously from a single stem cell, highlighting the intrinsic capabilities of these cells.

3. Core Conclusions: The study concludes that intestinal crypt-villus units can be constructed from individual Lgr5(+) stem cells without requiring a supportive mesenchymal niche. This finding underscores the self-organizing properties of the intestinal epithelium, suggesting that the crypt-villus architecture is a result of intrinsic stem cell behavior rather than dependence on surrounding tissues. The maintenance of the stem cell hierarchy within organoids further emphasizes the potential of Lgr5(+) cells to regenerate complex intestinal structures.

4. Research Significance and Impact: This research holds significant implications for regenerative medicine and tissue engineering, particularly in developing strategies for intestinal repair and the treatment of disorders such as inflammatory bowel disease. By demonstrating that single stem cells can autonomously form complex tissue structures, this study paves the way for future investigations into the mechanisms of stem cell differentiation and organization. Additionally, the ability to culture these organoids long-term could facilitate drug testing and disease modeling, offering a novel platform for understanding intestinal biology and the pathogenesis of gastrointestinal diseases. The findings may also inspire new approaches to harness stem cells for therapeutic purposes in regenerative therapies.

References

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Literatures Citing This Work

1. The tortoise and the hair: slow-cycling cells in the stem cell race. - Elaine Fuchs - Cell (2009)
2. Stem cells and solid cancers. - Stuart A C McDonald;Trevor A Graham;Stefanie Schier;Nicholas A Wright;Malcolm R Alison - Virchows Archiv : an international journal of pathology (2009)
3. Telomeres and disease. - Peter M Lansdorp - The EMBO journal (2009)
4. Colon cancer stem cells. - Lucia Ricci-Vitiani;Eros Fabrizi;Elisabetta Palio;Ruggero De Maria - Journal of molecular medicine (Berlin, Germany) (2009)
5. The stem cells of small intestinal crypts: where are they? - C S Potten;R Gandara;Y R Mahida;M Loeffler;N A Wright - Cell proliferation (2009)
6. Tumour-initiating cells: challenges and opportunities for anticancer drug discovery. - Bin-Bing S Zhou;Haiying Zhang;Marc Damelin;Kenneth G Geles;Justin C Grindley;Peter B Dirks - Nature reviews. Drug discovery (2009)
7. Stable expression of neurogenin 1 induces LGR5, a novel stem cell marker, in an immortalized human neural stem cell line HB1.F3. - Jun-ichi Satoh;Shinya Obayashi;Hiroko Tabunoki;Taeko Wakana;Seung U Kim - Cellular and molecular neurobiology (2010)
8. Stem cells in gastroenterology and hepatology. - Michael Quante;Timothy C Wang - Nature reviews. Gastroenterology & hepatology (2009)
9. Bronchiolar progenitor cells. - Huaiyong Chen;Keitaro Matsumoto;Barry R Stripp - Proceedings of the American Thoracic Society (2009)
10. Quantitative proteomics by metabolic labeling of model organisms. - Joost W Gouw;Jeroen Krijgsveld;Albert J R Heck - Molecular & cellular proteomics : MCP (2010)

... (3680 more literatures)

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