Cell migration and organization in the intestinal crypt using a lattice-free model.

We present a novel class of spatial models of cell movement and arrangement applied to the two-dimensional cellular organization of the intestinal crypt. The model differs from earlier approaches in using a dynamic movement on a lattice-free cylindrical surface. Cell movement is a consequence of mitotic activity. Cells interact by viscoelastic forces. Voronoi tessellation permits simulations of individual cell boundaries. Simulations can be compared with experimental data obtained from cell scoring in sections. Simulation studies show that the model is consistent with the experimental results for the spatial distribution of labelling indices, mitotic indices and other observed phenomena using a fixed number of stem cells and a fixed number of transit cell divisions.

A continuum model to analyse spatial cell fluxes from positional labelling data applied to cell migration in oral mucosa.

A novel method is presented which allows the estimation of the velocity of migrating cells from positional 3HTdR labelling data in spatially organized epithelial tissues. In a continuum approach, wave-like profiles of labelling index (LI) data, which travel away from the basal layer, are followed and compared with experimental LI profiles. The method yields estimates of migration velocity, cell flow, and turnover time. Results for the ventral tongue mucosa in a group of 55 BDF1 mice that were labelled at the same time of the day and culled at different time points within a 24-h period have been analysed. The results show a strong circadian rhythm in the migration velocity and the related parameters.

Cell kinetic studies in the murine ventral tongue epithelium: mucositis induced by radiation and its protection by pretreatment with keratinocyte growth factor (KGF).

Radiation kills or reduces reproductive capacity of proliferating cells, including stem cells. In the oral mucosae this can result in a decline in the number of cells in the tissue which, if severe enough, will result in the formation of an ulcer when the cellularity essentially reaches zero. We have used histometric measurements of cellularity following exposure to radiation in mouse ventral tongue epithelium as a model for oral mucositis (ulcer development). Here we provide further measurements of cellularity changes in the basal layer and in the epithelium as a whole at various times following 15, 20 or 25 Gy doses. The protective effects of prior treatment with keratinocyte growth factor (KGF) are also investigated. 20 Gy of 300 kV X-rays has become our standard reference dose and the changes in cellularity seen following this dose are highly reproducible, with minimum values being observed 6 days following irradiation. A higher dose results in a greater reduction of cellularity, although the minimum value also occurs at 6 days. A lower dose (15 Gy) results in a much shallower curve, with a minimum value being observed about 1 day earlier. These changes in cellularity can be related to the less sensitive index of mucositis, namely epithelial thickness. There is also a sharp peak in proliferation about 1 day after the minimum in cellularity, i.e. on day 7. The peak following a lower dose of radiation occurs a little earlier and, following the higher dose, the peak tends to be broader. Previous work and data presented in the preceding paper in this series has shown that KGF, given over a period of 3 days, results in a dramatic increase in epithelial thickness in oral mucosa, including the ventral tongue. As a result of the increased cellularity induced by KGF given before radiation, a delay in the fall in cellularity results, which is the consequence of the increased number of cells in the epithelium at the beginning of the study.

Cell kinetic studies in the murine ventral tongue epithelium: thymidine metabolism studies and circadian rhythm determination.

The oral mucosa is a rapidly replacing body tissue that has received relatively little attention in terms of defining its cell kinetics and cellular organization. The tissue is sensitive to the effects of cytotoxic agents, the consequence of which can be stem cell death with the subsequent development of ulcers and the symptoms of oral mucositis. There is considerable interest in designing strategies to protect oral stem cells and, hence, reduce the mucositis side-effects in cancer therapy patients. Here we present details of a new histometric approach designed to investigate the changing patterns in cellularity in the ventral tongue mucosa. This initial paper in a series of four papers presents observations on the changing patterns in the labelling index following tritiated thymidine administration, which suggest a delayed uptake of tritiated thymidine from a long-term intracellular thymidine pool, a phenomenon that will complicate cell kinetic interpretations in a variety of experimental situations. We also provide data on the changing pattern of mitotic activity through a 24-h period (circadian rhythms). Using vincristine-induced stathmokinesis, the data indicate that 54% of the basal cells divide each day and that there is a high degree of synchrony in mitotic activity with a mitotic peak occurring around 13.00 h. The mitotic circadian peak occurs 9-12 h after the circadian peak in DNA synthesis. The data presented here and in the subsequent papers could be interpreted to indicate that basal cells of BDF1 mice have an average turnover time of about 26-44 h with some cells cycling once a day and others with a 2- or 3-day cell cycle time.