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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The authors thank J. Puschhof for critical reading of the manuscript.
H.C. is the inventor on several patents related to organoid technology; his full disclosure is given at https://www.uu.nl/staff/JCClevers/. H.C. is the founder of OrganoidZ, which uses organoids for drug development. J.B. declares no competing interests.
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- Genetic lineage tracing
Developmental tool to identify the progeny of a single cell through the introduction of a genetic marker in an individual (stem) cell.
- Chemical mutagenesis labelling
Marking random cells through chemical induction of mutations in a traceable locus to study stem cell dynamics and clonal succession. All intestinal epithelial cells are stained by the Dolichos biflorus agglutinin lectin, but this is lost by random mutations in the Dlb1 (also known as B4galnt2) locus, allowing the study of clonal dynamics.
Ribonucleoprotein and reverse transcriptase that can add telomere repeat sequences to the end of telomeres.
Secreted enhancer of the WNT signalling pathway acting through cognate leucine-rich repeat-containing G protein-coupled receptor 4 (LGR4), LGR5 and LGR6.
- Stem cell factors
Instructive signals that dictate stem cell proliferation and the balance between multipotency and lineage commitment.
- Neutral drift
Model in which equipotent stem cells neutrally compete for niche space, which over time results in clonal crypts.
ErbB family members are tyrosine kinase receptors that dimerize on ligand (such as epidermal growth factor (EGF)) engagement, activating downstream signalling. EGF–ErbB signalling is a main player in the control of intestinal proliferation.
Precursor that is processed to epithelial growth factor (EGF) through proteolytic cleavage.
Inflammation of the intestine causing epithelial damage often with a strong autoimmune component.
A parasitic worm that can infect the intestinal tract, a condition called ‘helminthiasis’.
- Granulomatous infiltrates
A histological pattern of infection containing circular granulomas harbouring different immune cells. In the context of helminth infection, these can develop to control parasite spreading.
Three-dimensional culture of a homogeneous cell population (typically from a cell line). When the 3D structures harbour different organ-specific cell types, these are generally referred to as ‘organoids’.
The process of programmed cell death that occurs when epithelial cells lose contact with the surrounding extracellular matrix.
- Neural crest
Group of cells emanating from the embryonic neurectoderm during development that develop through complex migration patterns into a wide variety of cell types, including melanocytes, smooth muscle and the enteric nervous system.
- Piezo channels
Class of mechanosensitive ion channels that acts as gates depending on mechanical stimuli on the cell membrane.
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Beumer, J., Clevers, H. Cell fate specification and differentiation in the adult mammalian intestine. Nat Rev Mol Cell Biol (2020). https://doi.org/10.1038/s41580-020-0278-0