Regulation of intestinal epithelial proliferation: a few answers, many questions

The epithelium of the gastrointestinal tract mucosa is a highly dynamic and diverse mixture of cell populations requiring exquisite integration of the processes of cellular proliferation, differentiation, and senescence. It is likely that the proliferative compartment of the intestinal epithelium encompasses a hierarchy of totipotent and pluripotent stem cells in a manner similar to that which generates diversity in hematopoietic cell populations. Identification and characterization of the stem cell and progenitor populations in the intestine has been limited by the absence of markers or culture systems to identify these cells. Regulation of the proliferative compartment may be accomplished through the combined integration of key peptide growth factors and constituents of the extracellular matrix. The relative contribution of the epithelial populations themselves and the contributions made by associated cell populations such as pericryptal fibroblasts remain unclear. Recent studies have suggested that the transforming growth factors-alpha and -beta, two structurally unrelated peptide growth factors, might serve to regulate the balanced proliferation and turnover of intestinal epithelial cells. The proproliferative effects of TGF-alpha may be counterbalanced by the proliferation-inhibiting TGF-beta. Recent studies have demonstrated close interregulation of these peptides, which act through autocrine and paracrine mechanisms in model intestinal epithelial cell lines.