Abstract
BackgroundThe small intestinal epithelium is a dynamic system with specialized cell types. The various cell populations of this tissue are continually renewed and replenished from stem cells that reside in the small intestinal crypt. The cell types and their locations in the crypt and villus are well known, but the details of the kinetics of stem cell division, and precursor cell proliferation and differentiation into mature enterocytes and secretory cells are still being studied. These proliferation and differentiation events have been extensively modeled with a variety of computational approaches in the past.MethodsA compartmental population kinetics model, incorporating experimentally measured proliferation rates for various intestinal epithelial cell types, is implemented for a previously reported scheme for the intestinal cell dynamics. A sensitivity analysis is performed to determine the effect that varying the model parameters has upon the model outputs, the steady-state cell populations.ResultsThe model is unable to reproduce the experimentally known timescale of renewal of the intestinal epithelium if literature values for the proliferation rates of stem cells and transit amplifying cells are employed. Unphysically large rates of proliferation result when these parameters are allowed to vary to reproduce this timescale and the steady-state populations of terminally differentiated intestinal epithelial cells. Sensitivity analysis reveals that the strongest contributor to the steady-state populations is the transit amplifying cell proliferation rate when literature values are used, but that the differentiation rate of transit amplifying cells to secretory progenitor cells dominates when all parameters are allowed to vary.ConclusionsA compartmental population kinetics model of proliferation and differentiation of cells of the intestinal epithelium can provide a simplifying means of understanding a complicated multistep process. However, when literature values for proliferation rates of the crypt based columnar and transit amplifying cell populations are employed in the model, it cannot reproduce the experimentally known timescale of intestinal epithelial renewal. Nevertheless, it remains a valuable conceptual tool, and its sensitivity analysis provides important clues for which events in the process are the most important in controlling the steady-state populations of specialized intestinal epithelial cells.
Highlights
The small intestinal epithelium is a dynamic system with specialized cell types
It has been demonstrated by the Clevers group that the intestinal stem cell is the crypt based columnar (CBC) cell that resides between Paneth cells at the crypt base and expresses the marker Lgr5 [1]
The signaling mechanisms governing the fate of transit amplifying cells to enterocytes or one of the secretory cell types are complex and under active study, but broadly include the Wnt pathway, which regulates proliferation in the crypt base, and Notch signaling, which determines whether transit amplifying cells and other intermediate cell populations will go down the absorptive or secretory pathways [12]
Summary
The small intestinal epithelium is a dynamic system with specialized cell types. The various cell populations of this tissue are continually renewed and replenished from stem cells that reside in the small intestinal crypt. It has been demonstrated by the Clevers group that the intestinal stem cell is the crypt based columnar (CBC) cell that resides between Paneth cells at the crypt base and expresses the marker Lgr5 [1] These stem cells divide both to maintain their own population and remain at the base of the crypt, and to produce proliferative transit amplifying cells that migrate up the crypt [2, 3], and further divide and differentiate into terminally differentiated cell populations of the intestinal epithelium: the absorptive enterocytes; and the secretory goblet cells [4]; enteroendocrine cells [5, 6]; and Paneth cells [7,8,9]. The signaling mechanisms governing the fate of transit amplifying cells to enterocytes or one of the secretory cell types are complex and under active study, but broadly include the Wnt pathway, which regulates proliferation in the crypt base, and Notch signaling, which determines whether transit amplifying cells and other intermediate cell populations will go down the absorptive or secretory pathways [12]
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