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Cell fate specification and differentiation in the adult mammalian intestine. ​

Literature Information ​

DOI10.1038/s41580-020-0278-0
PMID32958874
JournalNature reviews. Molecular cell biology
Impact Factor90.2
JCR QuartileQ1
Publication Year2021
Times Cited291
Keywordsintestinal stem cells, cell fate specification, tissue repair, single-cell transcriptomics, organoid models
Literature TypeJournal Article, Review
ISSN1471-0072
Pages39-53
Issue22(1)
AuthorsJoep Beumer, Hans Clevers

TL;DR ​

This study explores the role of intestinal stem cells in tissue renewal and repair, highlighting how lineage plasticity and niche signals enable efficient regeneration of the intestinal epithelium. The findings, derived from advanced techniques like single-cell transcriptomics and organoid models, offer valuable insights into stem cell regulation that could inform therapeutic strategies aimed at enhancing gut regeneration and functionality.

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intestinal stem cells · cell fate specification · tissue repair · single-cell transcriptomics · organoid models

Abstract ​

Intestinal stem cells at the bottom of crypts fuel the rapid renewal of the different cell types that constitute a multitasking tissue. The intestinal epithelium facilitates selective uptake of nutrients while acting as a barrier for hostile luminal contents. Recent discoveries have revealed that the lineage plasticity of committed cells - combined with redundant sources of niche signals - enables the epithelium to efficiently repair tissue damage. New approaches such as single-cell transcriptomics and the use of organoid models have led to the identification of the signals that guide fate specification of stem cell progeny into the six intestinal cell lineages. These cell types display context-dependent functionality and can adapt to different requirements over their lifetime, as dictated by their microenvironment. These new insights into stem cell regulation and fate specification could aid the development of therapies that exploit the regenerative capacity and functionality of the gut.

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Primary Questions Addressed ​

  1. What are the key signals that influence the fate specification of intestinal stem cells in the adult mammalian intestine?
  2. How does lineage plasticity in committed intestinal cells contribute to tissue repair mechanisms in the gut?
  3. What role do microenvironmental factors play in the differentiation of intestinal cell types throughout their lifespan?
  4. How can advancements in single-cell transcriptomics enhance our understanding of intestinal stem cell regulation?
  5. In what ways might therapies targeting gut regenerative capacity differ from traditional approaches to treating intestinal diseases?

Key Findings ​

1. Research Background and Objective: The adult mammalian intestine is a complex and dynamic tissue that relies on intestinal stem cells located at the base of crypts for the continuous renewal of its diverse cell types. These cells play crucial roles in both nutrient absorption and maintaining a barrier against harmful substances in the gut lumen. Given the high turnover rate and the tissue's vulnerability to damage, understanding how intestinal stem cells differentiate and specify their fates is essential. The objective of this research is to elucidate the mechanisms underlying cell fate specification and differentiation in the intestinal epithelium, particularly focusing on the role of niche signals and lineage plasticity in tissue repair and regeneration.

2. Key Methods and Findings: The study employs advanced techniques such as single-cell transcriptomics and organoid models to dissect the cellular and molecular dynamics within the intestinal epithelium. These methodologies enable researchers to map the fate specification pathways of stem cell progeny, revealing the intricate signaling networks that guide their differentiation into the six distinct intestinal cell lineages. Notably, it was discovered that committed intestinal cells exhibit lineage plasticity, allowing them to adapt their functions based on the local microenvironment and changing physiological demands. This adaptability is supported by redundant niche signals that facilitate efficient tissue repair following injury.

3. Core Conclusions: The research concludes that the intestinal epithelium's ability to repair itself is underpinned by the plasticity of its committed cells and the presence of multiple niche signals. These insights indicate that intestinal stem cells can dynamically respond to their environment, altering their differentiation pathways as required. This flexibility is crucial for maintaining intestinal homeostasis and function, especially in the face of damage or stress.

4. Research Significance and Impact: The findings have significant implications for the field of regenerative medicine and therapeutic development. By deepening our understanding of stem cell regulation and differentiation in the gut, this research opens avenues for developing novel therapies aimed at enhancing gut regeneration and treating various intestinal disorders. The insights into the plasticity of intestinal cells could lead to innovative strategies that harness the regenerative capabilities of the gut, ultimately improving patient outcomes in conditions characterized by intestinal injury or dysfunction. This work highlights the potential of manipulating stem cell behavior in therapeutic contexts, promising to advance our capabilities in tissue engineering and regenerative therapies.

References ​

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  2. The role of enterocytes in the intestinal barrier function and antigen uptake. - Veerle Snoeck;Bruno Goddeeris;Eric Cox - Microbes and infection (2005)
  3. A single-cell survey of the small intestinal epithelium. - Adam L Haber;Moshe Biton;Noga Rogel;Rebecca H Herbst;Karthik Shekhar;Christopher Smillie;Grace Burgin;Toni M Delorey;Michael R Howitt;Yarden Katz;Itay Tirosh;Semir Beyaz;Danielle Dionne;Mei Zhang;Raktima Raychowdhury;Wendy S Garrett;Orit Rozenblatt-Rosen;Hai Ning Shi;Omer Yilmaz;Ramnik J Xavier;Aviv Regev - Nature (2017)
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  6. Clonal analysis of mouse intestinal epithelial progenitors. - M Bjerknes;H Cheng - Gastroenterology (1999)
  7. A clonal marker induced by mutation in mouse intestinal epithelium. - D J Winton;M A Blount;B A Ponder - Nature (1988)
  8. Identification of stem cells in small intestine and colon by marker gene Lgr5. - Nick Barker;Johan H van Es;Jeroen Kuipers;Pekka Kujala;Maaike van den Born;Miranda Cozijnsen;Andrea Haegebarth;Jeroen Korving;Harry Begthel;Peter J Peters;Hans Clevers - Nature (2007)
  9. 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)
  10. Peyer's patch M cells derived from Lgr5(+) stem cells require SpiB and are induced by RankL in cultured "miniguts". - Wim de Lau;Pekka Kujala;Kerstin Schneeberger;Sabine Middendorp;Vivian S W Li;Nick Barker;Anton Martens;Frans Hofhuis;Rodney P DeKoter;Peter J Peters;Edward Nieuwenhuis;Hans Clevers - Molecular and cellular biology (2012)

Literatures Citing This Work ​

  1. Organoid-based modeling of intestinal development, regeneration, and repair. - Joep Sprangers;Irene C Zaalberg;Madelon M Maurice - Cell death and differentiation (2021)
  2. The Hippo-YAP Signaling as Guardian in the Pool of Intestinal Stem Cells. - Yoojin Seo;So-Yeon Park;Hyung-Sik Kim;Jeong-Seok Nam - Biomedicines (2020)
  3. The 3D Pattern of the Rainbow Trout (Oncorhynchus mykiss) Enterocytes and Intestinal Stem Cells. - Nicole Verdile;Rolando Pasquariello;Tiziana A L Brevini;Fulvio Gandolfi - International journal of molecular sciences (2020)
  4. A bioengineering perspective on modelling the intestinal epithelial physiology in vitro. - Maria Antfolk;Kim B Jensen - Nature communications (2020)
  5. Cytoskeletal Control and Wnt Signaling-APC's Dual Contributions in Stem Cell Division and Colorectal Cancer. - M Angeles Juanes - Cancers (2020)
  6. Spatiotemporal analysis of human intestinal development at single-cell resolution. - David Fawkner-Corbett;Agne Antanaviciute;Kaushal Parikh;Marta Jagielowicz;Ana Sousa Gerós;Tarun Gupta;Neil Ashley;Doran Khamis;Darren Fowler;Edward Morrissey;Chris Cunningham;Paul R V Johnson;Hashem Koohy;Alison Simmons - Cell (2021)
  7. A centric view of JAK/STAT5 in intestinal homeostasis, infection, and inflammation. - Marta Surbek;William Tse;Richard Moriggl;Xiaonan Han - Cytokine (2021)
  8. Transit-Amplifying Cells Coordinate Changes in Intestinal Epithelial Cell-Type Composition. - Laura E Sanman;Ina W Chen;Jake M Bieber;Veronica Steri;Coralie Trentesaux;Byron Hann;Ophir D Klein;Lani F Wu;Steven J Altschuler - Developmental cell (2021)
  9. JAK-STAT Pathway Inhibition Partially Restores Intestinal Homeostasis in Hdac1- and Hdac2-Intestinal Epithelial Cell-Deficient Mice. - Alexis Gonneaud;Naomie Turgeon;Francois-Michel Boisvert;Francois Boudreau;Claude Asselin - Cells (2021)
  10. Subversion of Niche-Signalling Pathways in Colorectal Cancer: What Makes and Breaks the Intestinal Stem Cell. - Nathalie Sphyris;Michael C Hodder;Owen J Sansom - Cancers (2021)

... (281 more literatures)

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