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. 2013 Apr 1;1(2):e24965.
doi: 10.4161/tisb.24965.

Understanding Epithelial Homeostasis in the Intestine: An Old Battlefield of Ideas, Recent Breakthroughs and Remaining Controversies

Free PMC article

Understanding Epithelial Homeostasis in the Intestine: An Old Battlefield of Ideas, Recent Breakthroughs and Remaining Controversies

Jan R De Mey et al. Tissue Barriers. .
Free PMC article


The intestinal epithelium constitutes the barrier between the gut lumen and the rest of the body and a very actively renewing cell population. The crypt/villus and crypt/cuff units of the mouse small intestine and colon are its basic functional units. The field is confronted with competing concepts with regard to the nature of the cells that are responsible for all the day-to day cell replacement and those that act to regenerate the tissue upon injury and with two diametrically opposed models for lineage specification. The review revisits groundbreaking pioneering studies to provide non expert readers and crypt watchers with a factual analysis of the origins of the current models deduced from the latest spectacular advances. It also discusses recent progress made by addressing these issues in the crypts of the colon, which need to be better understood, since they are the preferred sites of major pathologies.

Keywords: Delta-Notch signaling; Wnt signaling; asymmetric division; cell stemness; intestinal epithelium; intestinal stem cells; lineage specification; planar cell polarity; stem cell maintenance; tissue homeostasis.


Figure 1. Topological organization of epithelial cells near the crypt bottom of crypts. (A) In the SI, the CBC/PC zone contains Paneth cells interspersed with actively proliferating CBC SCs. The latter divide symmetrically to yield two CBC cells. In positions around +4, more quiescent SCs are found. The light green cells are Mix progenitors which are CBC cells that have lost contact with the signals maintaining stemness. The dividing Mix cell displays anisotropic movement of the upper daughter. It also displays asymmetric distribution of a cluster of mNumb vesicles located in the daughter that has maintained a basal process with the extracellular matrix. (B) In the descending colon, actively proliferating SCs (vacuolated cells), quiescent Lrig1(+) SCs, crypt base Goblet-like cells, Mix and early C1 and M1 progenitors are all intermingled in the SC/GLC zone. The dividing dark green SC is represents the proposed mechanism by which anisotropic movement of the upper daughter places it outside the reach of the GLC its mother was contacting. This daughter will give rise to a Mix progenitor. This mechanism may also be used by CBC cells at the border between the CBC/PC zone and the OCD in the SI crypt. The dividing Mix progenitor near the crypt bottom is another example of the asymmetric distribution of transient mNumb clusters near the cleavage furrow that may initiate the symmetry breaking leading to lateral Delta-Notch inhibition between sister cells.
Figure 3. Topological properties of intestinal epithelial cells. (A) Bent shape of the interphase cells lining the crypts. (B) The bent cell shape is lost in the apparently normal intestinal epithelium of Apc+/Δ14 mice. (C) Computer-based representation of a dividing cell in telophase in the SC compartment. The dotted line denotes the cleavage plane between the two daughter cells. In this cell, the BP that connects the cell body to the basal lamina asymmetrically segregates in one daughter cell (left daughter) and this daughter also exhibits asymmetric distribution of mNumb (green spot). The nuclei are in blue and the centrosomes labeled for γ-Tubulin in red.
Figure 2. Two competing models for lineage specification in crypts of the SI. (A) According to Simons and Clevers, CBC SCs divide symmetrically to yield two CBC cells and self-produce a niche with one of their immediate progeny, the PCs. Shown here is the proposal of De Mey, Freund and coll. that the anisotropic movement of one daughter cell at the border between the CBC/PC zone and the OCD generates early TA cells that continue dividing symmetrically. Stochastic Delta-Notch signaling between progeny that are not necessarily siblings and additional gene network expression generate progenitors of each of the differentiated cell types. The dark yellow cell is a quiescent Paneth cell precursor that will give rise to PC-like cells. These can be reprogrammed into CBC cells upon tissue injury. This was interpreted as meaning that these LRCs are the same cells as the quiescent +4 SCs described by others. (B) According to Bjerknes and Cheng, CBC SCs that leave the CBC/PC zone become committed Mix progenitors. Divisions asymmetric with respect to cell fate generate DOMNotch and DOMDelta daughters that set up between them Delta/Notch lateral inhibition. Added here is the suggested possibility that asymmetric mNumb distribution initiates this process. To the right is shown a yellow cell that stands for all the proposed types of quiescent SCs found in the undulating +4 annulus. These cells may display their own hierarchy that is not shown here. Also shown are C0 and M0 long-lived and quiescent progenitors which can be reprogrammed to become either +4SCs or CBC cells. Shown here is the possibility that this involves passage through a Mix progenitor, but no evidence for this exists.

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