Expression of TGF-β during in vitro differentiation of hamster tracheal epithelial cells

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Abstract
The control of growth and differentiation of tracheal epithelial cells is poorly understood. Retinoic acid seems to be essential for the growth and secretory cell differentiation of hamster tracheal epithelial (HTE) cells in culture. In this study, we tested the hypothesis that one way by which retinoic acid (RA) stimulates growth is by decreasing transforming growth factor beta (TGFβ) expression or activity or both. HTE cells were very sensitive to TGFβ-induced growth inhibition. TGFβ1 was more potent than TGFβ2 with 50% inhibition of growth achieved at a concentration less than 0.1 ng/ml. A single TGFβ1 transcript of 2.4 kb was expressed in HTE cells, and the amount increased by fourfold as cell proliferation decreased and differentiation increased. No TGFβ2 mRNA could be detected in proliferating undifferentiated HTE cells, but two distinct mRNAs (5.1 and 3.5 kb) were observed to be induced in a transient fashion in RA-treated cells which correlated with the onset of differentiation. The amount of biologically active TGFβ in conditioned media from HTE cells at different stages of growth and differentiation in primary culture was determined by the mink lung epithelial cell growth inhibition assay and the use of neutralizing antibodies. These assays indicated a large increase in the total amount of TGFβ at the time the cells slowed their growth and started to differentiate. The activity was due primarily to TGFβ1. Interestingly, cells treated with RA had a major component of “preactivated” (non-latent) TGFβ1 compared to control cells. Addition of TGFβ1 neutralizing antibodies directly to HTE cultures delayed the onset of both growth arrest and differentiation. These results do not support the hypothesis that RA stimulates HTE cell growth by decreasing TGFβ; rather they suggest that endogenously produced TGFβ may play a role in the initiation of growth arrest which precedes differentiation.

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