Cell-to-cell signaling in the regulation of procollagen expression in primary avian tendon cells.

High cell density is required for high procollagen expression (50% of total protein synthesis) in primary avian tendon (PAT) cells but the signaling mechanism that triggers this response has been difficult to decipher. By using a quantitative in situ hybridization assay for procollagen mRNA, cell density dependent changes in procollagen expression can be followed at the single cell level. PAT cells can then be shown to respond to the presence of their neighbors over approximately 1-mm distance. The cell density signal remains effective independent of the medium volume to cell ratio but becomes sensitive to dispersion and dilution when the medium is agitated. PAT cells respond to a reduction in cell density, when neighboring cells are scraped away, by outgrowth (approximately 1 mm) and reestablishment of a cell density gradient in cellular procollagen mRNA levels. However, removing neighboring cells while preventing migration off of their own extracellular matrix retards the drop in procollagen mRNA levels. The evidence, taken as a whole, is consistent with a model whereby the cell density signal is a loosely bound component of the cell layer thereby restricting its diffusion to two dimensions but making it susceptible to dispersion by medium agitation.