Figure 1.
The paradigm of epithelium renewal in the intestine.
(A) Cell proliferation and apoptosis in the intestine of zebrafish. Left panel: Cell proliferation assay with proliferating cells stained dark brown. Middle panel: Cell apoptosis assay with apoptotic cells stained green. Right panel: Compartmentalization of epithelium into stem cells, transit amplifying cells, differentiated cells and apoptotic cells. (B) The intestinal epithelium is divided into four components while constructing the model, based on the analogous paradigm of epithelium renewal across teleost, murine and human species. Stem cells maintain their own population through self-renewal, and in the mean time, they produce progenies that will differentiate later on. Transit amplifying cells are directly derived from stem cells and go through rapid expansion. Then they go for cell differentiation and finally apoptosis. Denotation: - population of stem cells;
- population of transit amplifying cells;
- population of differentiated cells. Note that all populations are normalized against their homeostatic populations in the model.
Figure 2.
Schematic illustration of the STORM model.
The model takes experimental measurement of transit amplifying and differentiated cell populations as input information. By optimizing the turnover dynamics, it yields the number of stem cells required on each section of pocket or crypt of the intestine. It also provides information on epithelium turnover changes, for example, extended turnover cycles due to a reduction in the transit amplifying cells.
Figure 3.
General relationships between ,
and
.
(A) In general, is positively correlated with
. For teleosts where
is smaller,
is lower; For humans where
is bigger,
is higher. (B) The epithelium renewal cycle is also correlated to the value of
. Bigger value of
means longer renewal cycle. Cycles are normalized to be dimensionless.
: dividing frequency
stem population/transit amplifying population;
: intestinal epithelium renewal cycle;
: ratio of differentiated epithelium population/transit amplifying population.
Table 1.
Stem cell number in the small intestine of different species as suggested by STORM model.
Figure 4.
Adaptive changes in the intestinal stem cell number.
(A) Intestine of zebrafish. (B) Small intestine of mouse. (C) Duodenum of human. Upper and lower limits of the division frequency of stem cells in vivo (once to twice per day) define a range of the number of stem cells required to be present on each section of inter-villi pocket in zebrafish intestine. Reduction in cell proliferation would result in a bigger value of and thus a prolonged epithelium renewal cycle. That would be accompanied by less number of stem cells around. On the other hand, enhanced cell proliferation would result in a smaller value of
and thus an accelerated epithelium renewal process, accompanied by an increase in stem cell population. That would be the case where hyperplasia or adenoma starts to develop.
Figure 5.
Comparison of epithelium renewal dynamics in different species.
(A) The transit amplifying-to-stem cell ratio is the highest in teleost but the lowest in human during normal homeostasis. (B) The differentiated-to-transit amplifying cell ratio is the lowest in teleost but the highest in human during normal homeostasis. (C) As a strategy of efficient tissue restitution, there will be a transient expansion of the transit amplifying population by 10–15% in these species. This value does not vary much as long as the lesion ranges below ∼95% of the epithelium tissue. (D) Recovery time varies in these species. In teleost, epithelium can be restituted in a shorter period of time, but this is achieved by allowing a bigger transient expansion in the transit amplifying population. In human, it takes longer time to complete epithelium restitution, but this is achieved with a tighter mediation over the expansion of the transit amplifying population. These data suggest that these species employ different strategies in maintenance of homeostasis. Compared with intestines of other species, human intestine harbors minimum number of stem cells to support a larger villus size and restitutes epithelium through tightly mediated proliferation to maintain genome integrity and minimize the possibility of carcinogenic transformations.
Figure 6.
Changes in cell populations during epithelium restitution.
The transit amplifying population will transiently expand during epithelium restitution. In the case of extreme tissue lesion where more than 90% tissue is damaged, there will be an overwhelming response of the crypt-villus system and the transit amplifying population will expand in an uncontrolled manner, producing intestinal hyperplasia or adenoma in the teleost and murine intestines, though it seems less likely in human intestine. Denotation: ▾ for zebrafish; • for mouse; ▪ for human.