Villus Epithelial Cell Migration is Delayed in Hypothyroid C.RF|[sol]|hyt Mice |[bull]| 579

The intestinal epithelium is established and maintained by continuous production of new cells, their migration along the villi and extrusion at the villus tip. In newborn mice replicating and differentiating cells are located throughout the intervillus epithelium, and mature cells slowly traverse the length of the villi. During the suckling period the proliferative epithelium becomes organized and confined to developing crypts. As crypts mature near weaning the replicating cell populations expand, and villus cell migration accelerates eventually reaching rates in adults that are 4-5X greater than in newborns. Glucocorticoid and thyroid hormones mediate changes in digestive enzyme expression during the suckling-weaning transition period, but mechanisms regulating epithelial renewal kinetics during development are not known. Our prior studies show glucocorticoids exert little effect on cell migration and epithelial renewal rates. This study examines thyroid hormone effects on villus epithelial cell migration in C.RF/hyt mice, a strain with primary hypothyroidism, undetectable serum T4 and normal corticosterone production. Proliferating cells were labeled with the thymidine analog, BrdUrd, on day of life 2, 5, 9, 14 or 18, or adults, and migration examined at intervals after labeling using immunohistochemical staining. Migration rates in C.RF/hyt and control euthyroid, Balb/cJ, mice are comparable in the first week of life when endogenous T4 levels are normally low. As T4 rises in the second week, migration rates accelerate rapidly in Balb/cJ mice. In contrast, migration rates in C.RF/hyt mice increase only gradually through weaning and remain delayed in adult animals. In all regions of the small bowel, villus epithelial cell migration rates in adult C.RF/hyt mice reach only 50% of the rates attained in adult euthyroid mice. Correction of hypothyroidism with dietary supplementation adequate to establish fertility and normal serum T4 results in more rapid epithelial cell migration and renewal rates approaching those observed in euthyroid mice. These studies show normal acceleration of villus epithelial cell migration rates during intestinal development are regulated by the physiologic rise in thyroid hormone levels during the suckling period.