Experimental evidence has shown that fetal gut mesenchymal cells can modulate epithelial cell differentiation. It is postulated that reciprocal stromal-epithelial interactions in the digestive tract are maintained beyond embryonic life. The mature colonic mucosa contains pericryptal fibroblasts (PCF), a stromal cell type exhibiting smooth muscle morphological features, which are thought to regulate the growth and differentiation of adjacent epithelial cells. Using an antibody directed at alpha-smooth muscle actin, which is constantly expressed in smooth muscle cells, we performed an immuno-histochemical study on human embryonic tissues to assess PCF differentiation during development. PCF expressing alpha-smooth muscle actin were first detected around the 21st week of gestation, at the bases of the crypts; the number of differentiated PCF increased then progressively, in synchrony with epithelial proliferation, to achieve at birth the characteristic distribution found in adults. We analyzed a series of non-malignant and malignant epithelial proliferative lesions of the adult colon by the same technique. Only sparse immunoreactive PCF were observed in 10/10 pure tubular adenomas, whereas in 11/11 villous adenomas immunoreactive PCF were consistently found bordering proliferative epithelia. Interestingly, 3/5 papillary adenomas, associated with areas of moderate to marked dysplasia, demonstrated foci of multilayered immunoreactive PCF. In 14/14 carcinomas examined, PCF were no longer recognizable; stromal cells expressing variable amounts of alpha-smooth muscle actin, constituting the desmoplastic reaction, were constantly present. These observations establish immunohistochemically a smooth muscle phenotypic feature of PCF, which is acquired at mid-gestation, and the ability of PCF to proliferate in conjunction with some epithelial neoplasias. These findings might help to clarify the histogenesis of PCF and to improve our understanding of the mesenchymal-epithelial interactions suspected to operate during organogenesis as well as benign and malignant neoplastic conditions.