Regulation of the three-dimensional organization of thyroid epithelial cells into follicle structures by the matricellular protein, thrombospondin-1.

Thyroid epithelial cells in primary culture have the capacity to organize into thyroid-specific three-dimensional structures, the follicles, in response to TSH. We studied whether thrombospondin 1 (TSP1), which represents, besides thyroglobulin, the main protein secreted by thyroid cells, could play a role in the process of folliculogenesis. TSH promoted follicle formation and inhibited TSP1 production. On the contrary, the phorbol ester, 12-O-tetradecanoyl-phorbol 13-acetate (1-100 nM) prevented TSH-induced follicle formation and strongly increased the synthesis of TSP1. Activation of TSP1 synthesis was dependent upon messenger RNA synthesis. Transforming growth factor-beta, like 12-O-tetradecanoyl-phorbol 13-acetate, increased TSP1 synthesis and prevented TSH-induced follicle formation. Thus, signaling molecules that depressed or conversely activated TSP1 production, respectively promoted or prevented thyroid folliculogenesis. TSP1, purified from platelets, was devoid of effect on cell substratum attachment, but exerted a concentration-dependent inhibition of the TSH-activated reconstitution of thyroid follicles (half-inhibition at 40 microg/ml). TSP1 exhibited the same effect when added to thyroid cell aggregates representing primitive follicle structures. Our data suggest that the control of thyroid follicle formation may operate at least in part through regulation of the production of the matricellular protein TSP1, which acts as a negative modulator of the cell-cell adhesion process involved in thyroid follicle morphogenesis.