Type III TGFβ receptor and Src direct hyaluronan-mediated invasive cell motility

Abstract

During embryogenesis, the epicardium undergoes proliferation, migration, and differentiation into several cardiac cell types which contribute to the coronary vessels. This process requires epithelial to mesenchymal transition (EMT) and directed cellular invasion. The Type III Transforming Growth Factor-beta Receptor (TGFβR3) is required for epicardial cell invasion and coronary vessel development. Using primary epicardial cells derived from Tgfbr3+/+ and Tgfbr3−/− mouse embryos, high-molecular weight hyaluronan (HMWHA) stimulated cellular invasion and filamentous (f-actin) polymerization are detected in Tgfbr3+/+ cells, but not in Tgfbr3−/− cells. Furthermore, HMWHA-stimulated cellular invasion and f-actin polymerization in Tgfbr3+/+ epicardial cells are dependent on Src kinase. Src activation in HMWHA-stimulated Tgfbr3−/− epicardial cells is not detected in response to HMWHA. RhoA and Rac1 also fail to activate in response to HMWHA in Tgfbr3−/− cells. These events coincide with defective f-actin formation and deficient cellular invasion. Finally, a T841A activating substitution in TGFβR3 drives ligand-independent Src activation. Collectively, these data define a TGFβR3–Src–RhoA/Rac1 pathway that is essential for hyaluronan-directed cell invasion in epicardial cells.

Transcriptional Profiling of Cultured, Embryonic Epicardial Cells Identifies Novel Genes and Signaling Pathways Regulated by TGFβR3 In Vitro

“…Invasion of epicardial cells is also defective in vivo and in vitro in cells lacking TGFβR3 [ 16 ]. Consistent with a defect in cell interaction with the ECM, we observe that epicardial cells in vitro fail to invade in response to high molecular weight HA [ 16 , 64 ], a major ECM component of the subepicardial space [ 65 ]. CD44 is the cell surface receptor which binds HA and this interaction is important for epicardial invasion [ 44 ].…”

Common pathways regulate Type III TGFβ receptor-dependent cell invasion in epicardial and endocardial cells

“…Therefore, these results are consistent with a model where TGFβR3-T841A activates or allows NF-κB activity to increase which results in invasion. Recent studies have shown that TGFβR3-dependent epicardial cell invasion stimulated by HMW-HA or the overexpression of TGFβR3-T841A is dependent on Src activation [47] which provides a well-described mechanism for the alteration of NF-κB activity [reviewed in [48]] that may support cell invasion.…”

Novel therapeutic strategies targeting fibroblasts and fibrosis in heart disease

“…These proteins affect pathways including canonical and non-canonical Wnt signalling and hedgehog and retinoic acid signalling, which have downstream effects on gene programmes that regulate intercellular interactions, actin dynamics and cell motility. Following invagination of mesenchyme from the embryonic epicardium into the myocardium, various signal transduction and regulatory molecules, including TGFβ, 54, 55 FGF, 56 platelet derived growth factor (PDGF), 57 proto-oncogene tyrosine-protein kinase, 55 rho kinase, 58 integrins, 59 popeye domain-containing genes such as Bves, 60, 61 serum response factor, 62 transcription factor 21 (Tcf21), 63, 64 and myocardin-related factors 65 govern the transition of epicardium derived cells (EPDCs) into cells with more mature fates, including fibroblasts. 5, 6 There is also evidence from studies in Xenopus laevis that Tcf21 functions as a transcriptional repressor to regulate proepicardial cell specification and the correct formation of a mature epithelial epicardium.…”