MaltSci 麦伴科研

Appearance

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

Paneth cells constitute the niche for Lgr5 stem cells in intestinal crypts. ​

Literature Information ​

DOI10.1038/nature09637
PMID21113151
JournalNature
Impact Factor48.5
JCR QuartileQ1
Publication Year2011
Times Cited1353
KeywordsLgr5 stem cells, Paneth cells, intestinal crypts, cell signaling, organoid
Literature TypeJournal Article
ISSN0028-0836
Pages415-8
Issue469(7330)
AuthorsToshiro Sato, Johan H van Es, Hugo J Snippert, Daniel E Stange, Robert G Vries, Maaike van den Born, Nick Barker, Noah F Shroyer, Marc van de Wetering, Hans Clevers

TL;DR ​

This study investigates the relationship between Lgr5 stem cells and Paneth cells in the small intestine, revealing that Paneth cells provide critical niche signals that support the maintenance and proliferation of Lgr5 stem cells. The findings highlight the importance of this interaction in organoid formation and suggest that Paneth cells play a crucial role in the homeostasis of intestinal crypts, which has implications for understanding stem cell regulation and intestinal health.

Search for more papers on MaltSci.com ​

Lgr5 stem cells · Paneth cells · intestinal crypts · cell signaling · organoid

Abstract ​

Homeostasis of self-renewing small intestinal crypts results from neutral competition between Lgr5 stem cells, which are small cycling cells located at crypt bottoms. Lgr5 stem cells are interspersed between terminally differentiated Paneth cells that are known to produce bactericidal products such as lysozyme and cryptdins/defensins. Single Lgr5-expressing stem cells can be cultured to form long-lived, self-organizing crypt-villus organoids in the absence of non-epithelial niche cells. Here we find a close physical association of Lgr5 stem cells with Paneth cells in mice, both in vivo and in vitro. CD24(+) Paneth cells express EGF, TGF-α, Wnt3 and the Notch ligand Dll4, all essential signals for stem-cell maintenance in culture. Co-culturing of sorted stem cells with Paneth cells markedly improves organoid formation. This Paneth cell requirement can be substituted by a pulse of exogenous Wnt. Genetic removal of Paneth cells in vivo results in the concomitant loss of Lgr5 stem cells. In colon crypts, CD24(+) cells residing between Lgr5 stem cells may represent the Paneth cell equivalents. We conclude that Lgr5 stem cells compete for essential niche signals provided by a specialized daughter cell, the Paneth cell.

MaltSci.com AI Research Service ​

Intelligent ReadingAnswer any question about the paper and explain complex charts and formulas
Locate StatementsFind traces of a specific claim within the paper
Add to KBasePerform data extraction, report drafting, and advanced knowledge mining

Primary Questions Addressed ​

  1. What are the specific mechanisms by which Paneth cells support the maintenance and function of Lgr5 stem cells in the intestinal crypts?
  2. How does the interaction between Paneth cells and Lgr5 stem cells influence the overall homeostasis of the intestinal epithelium?
  3. What are the implications of the loss of Paneth cells on the regenerative capacity of the intestinal crypts and potential disease states?
  4. How do different signaling molecules produced by Paneth cells affect the differentiation pathways of Lgr5 stem cells?
  5. Are there alternative niche cells in other regions of the intestine that play similar roles to Paneth cells in supporting stem cell populations?

Key Findings ​

Research Background and Objective ​

The study investigates the role of Paneth cells in supporting Lgr5 intestinal stem cells within the small intestinal crypts. It aims to elucidate how Paneth cells contribute to the maintenance and proliferation of Lgr5 stem cells, thereby influencing intestinal homeostasis and regeneration.

Main Methods/Materials/Experimental Design ​

The research employs a combination of in vivo and in vitro techniques to analyze the interactions between Lgr5 stem cells and Paneth cells.

  1. Cell Isolation and Culture: Lgr5-EGFP-ires-creERT2 mice were used to isolate Lgr5 stem cells, and Paneth cells were sorted based on CD24 expression. The cells were cultured in a Matrigel-based system supplemented with EGF, R-spondin 1, and noggin.

  2. Co-culture Experiments: Sorted Lgr5 stem cells were co-cultured with Paneth cells to assess the effects on organoid formation.

  3. Gene Expression Profiling: Comparative gene expression analysis was performed to identify markers specific to Lgr5 stem cells and Paneth cells.

  4. In Vivo Models: Genetic mouse models with mutations affecting Paneth cell populations were utilized to assess the consequences on Lgr5 stem cell numbers.

Mermaid diagram

Key Results and Findings ​

  • Physical Association: Lgr5 stem cells are closely associated with Paneth cells, which provide essential niche signals for stem cell maintenance.
  • Enhanced Organoid Formation: Co-culturing Lgr5 stem cells with Paneth cells significantly enhances the formation of organoids, indicating a crucial supportive role of Paneth cells.
  • Gene Expression: Paneth cells express critical factors such as EGF, Wnt3, and Notch ligands that are vital for the maintenance of Lgr5 stem cells.
  • In Vivo Observations: Genetic depletion of Paneth cells leads to a corresponding decrease in Lgr5 stem cell numbers, confirming their dependence on Paneth cells for survival and proliferation.

Main Conclusions/Significance/Innovation ​

The study concludes that Paneth cells serve as essential niche providers for Lgr5 stem cells in the intestinal crypts. This relationship highlights a novel aspect of stem cell biology where differentiated cells (Paneth cells) actively support stem cell function. The findings contribute to a better understanding of intestinal homeostasis and regeneration, with potential implications for regenerative medicine and cancer research.

Research Limitations and Future Directions ​

  • Limitations: The study primarily focuses on murine models, which may not fully translate to human biology. The exact mechanisms by which Paneth cells regulate stem cell behavior require further exploration.
  • Future Directions: Further research could investigate the signaling pathways involved in the Paneth-Lgr5 interaction and explore therapeutic strategies targeting these pathways in intestinal diseases and cancers. Additionally, studying the role of Paneth cells in human intestinal biology would provide valuable insights.

References ​

  1. Intestinal stem cells lacking the Math1 tumour suppressor are refractory to Notch inhibitors. - Johan H van Es;Natalie de Geest;Maaike van de Born;Hans Clevers;Bassem A Hassan - Nature communications (2010)
  2. Stem cells and niches: mechanisms that promote stem cell maintenance throughout life. - Sean J Morrison;Allan C Spradling - Cell (2008)
  3. Transcription factor achaete scute-like 2 controls intestinal stem cell fate. - Laurens G van der Flier;Marielle E van Gijn;Pantelis Hatzis;Pekka Kujala;Andrea Haegebarth;Daniel E Stange;Harry Begthel;Maaike van den Born;Victor Guryev;Irma Oving;Johan H van Es;Nick Barker;Peter J Peters;Marc van de Wetering;Hans Clevers - Cell (2009)
  4. Intestinal crypt homeostasis results from neutral competition between symmetrically dividing Lgr5 stem cells. - Hugo J Snippert;Laurens G van der Flier;Toshiro Sato;Johan H van Es;Maaike van den Born;Carla Kroon-Veenboer;Nick Barker;Allon M Klein;Jacco van Rheenen;Benjamin D Simons;Hans Clevers - Cell (2010)
  5. The beta-catenin/TCF-4 complex imposes a crypt progenitor phenotype on colorectal cancer cells. - Marc van de Wetering;Elena Sancho;Cornelis Verweij;Wim de Lau;Irma Oving;Adam Hurlstone;Karin van der Horn;Eduard Batlle;Damien Coudreuse;Anna Pavlina Haramis;Menno Tjon-Pon-Fong;Petra Moerer;Maaike van den Born;Gwen Soete;Steven Pals;Martin Eilers;Rene Medema;Hans Clevers - Cell (2002)
  6. Morphological observations on mucus-secreting nongoblet cells in the deep crypts of the rat ascending colon. - G G Altmann - The American journal of anatomy (1983)
  7. The stem-cell zone of the small intestinal epithelium. I. Evidence from Paneth cells in the adult mouse. - M Bjerknes;H Cheng - The American journal of anatomy (1981)
  8. Cellular inheritance of a Cre-activated reporter gene to determine Paneth cell longevity in the murine small intestine. - Heather Ireland;Carol Houghton;Louise Howard;Douglas J Winton - Developmental dynamics : an official publication of the American Association of Anatomists (2005)
  9. Inducible Cre-mediated control of gene expression in the murine gastrointestinal tract: effect of loss of beta-catenin. - Heather Ireland;Richard Kemp;Carol Houghton;Louise Howard;Alan R Clarke;Owen J Sansom;Douglas J Winton - Gastroenterology (2004)
  10. Multipotent somatic stem cells contribute to the stem cell niche in the Drosophila testis. - Justin Voog;Cecilia D'Alterio;D Leanne Jones - Nature (2008)

Literatures Citing This Work ​

  1. Stem cells: Self-sufficient. - Nicola McCarthy - Nature reviews. Cancer (2011)
  2. Tracking adult stem cells. - Hugo J Snippert;Hans Clevers - EMBO reports (2011)
  3. Lgr5 intestinal stem cells have high telomerase activity and randomly segregate their chromosomes. - Arnout G Schepers;Robert Vries;Maaike van den Born;Marc van de Wetering;Hans Clevers - The EMBO journal (2011)
  4. Biomimetic platforms for human stem cell research. - Gordana Vunjak-Novakovic;David T Scadden - Cell stem cell (2011)
  5. Distinct ATOH1 and Neurog3 requirements define tuft cells as a new secretory cell type in the intestinal epithelium. - François Gerbe;Johan H van Es;Leila Makrini;Bénédicte Brulin;Georg Mellitzer;Sylvie Robine;Béatrice Romagnolo;Noah F Shroyer;Jean-François Bourgaux;Christine Pignodel;Hans Clevers;Philippe Jay - The Journal of cell biology (2011)
  6. Investigating monogenic and complex diseases with pluripotent stem cells. - Hao Zhu;M William Lensch;Patrick Cahan;George Q Daley - Nature reviews. Genetics (2011)
  7. Fibroblast growth factor receptor-3 (FGFR-3) regulates expression of paneth cell lineage-specific genes in intestinal epithelial cells through both TCF4/beta-catenin-dependent and -independent signaling pathways. - Brooks Brodrick;Alda Vidrich;Edith Porter;Leigh Bradley;Jenny M Buzan;Steven M Cohn - The Journal of biological chemistry (2011)
  8. TRAPping telomerase within the intestinal stem cell niche. - Matthew F Pech;Steven E Artandi - The EMBO journal (2011)
  9. Paneth cells, antimicrobial peptides and maintenance of intestinal homeostasis. - Charles L Bevins;Nita H Salzman - Nature reviews. Microbiology (2011)
  10. lines and bowl affect the specification of cyst stem cells and niche cells in the Drosophila testis. - Stephen Dinardo;Tishina Okegbe;Lindsey Wingert;Sarah Freilich;Natalie Terry - Development (Cambridge, England) (2011)

... (1343 more literatures)

© 2025 MaltSci - We reshape scientific research with AI technology