Submitted to: Circulation Research
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/5/2003
Publication Date: 9/5/2003
Citation: Hirschi, K., Burt, J.M., Hirschi, K., Dai, C. 2003. Gap junction communication mediates transforming growth factor-beta activation and endothelial-induced mural cell differentiation. Circulation Research. 93:429-437. Interpretive Summary: The ability for cells to communicate with one another is essential. The dynamics of cell to cell signaling is important for cell growth and for the formation of regenerative tissues following injury. In this manuscript we demonstrate that small pores or "junctions" between cells help in the formation of information transfer between cells. The junctions also help communicate to the cells the timing of differentiation. The knowledge gained from these studies has a profound effect on our ability to alter the speed and fidelity of tissue repair.
Technical Abstract: During blood vessel assembly, endothelial cells recruit mesenchymal progenitors and induce their differentiation into mural cells via contact-dependent transforming growth factor-ß (TGF-ß) activation. We investigated whether gap junction channels are formed between endothelial cells and recruited mesenchymal progenitors and whether intercellular communication is necessary for endothelial-induced mural cell differentiation. Mesenchymal progenitors from Cx43-/- murine embryos and Cx43+/+ littermates were cocultured with prelabeled endothelial cells. Intracellular dye injection and dual whole-cell voltage clamp revealed that endothelial cells formed gap junction channels with Cx43+/+ but not Cx43-/- progenitors. In coculture with endothelial cells, Cx43-/- progenitors did not undergo mural cell differentiation as did Cx43+/+ cells. Stable reexpression of Cx43 in Cx43-/- cells (reCx43) restored their ability to form gap junctions with endothelial cells and undergo endothelial-induced mural cell differentiation. Cocultures of endothelial cells and either Cx43+/+ or reCx43 mesenchymal cells produced activated TGF-ß; endothelial-Cx43-/- cocultures did not. However, Cx43-/- cells did produce latent TGF-ß and undergo mural cell differentiation in response to exogenous TGF-ß1. These studies indicate that gap junction communication between endothelial and mesenchymal cells mediates TGF-ß activation and subsequent mural cell differentiation.