TGFβ2-mediated production of hyaluronan is important for the induction of epicardial cell differentiation and invasion

Abstract

In the developing heart, the epicardium is a major source of progenitor cells that contribute to the formation of the coronary vessel system. These epicardial progenitors give rise to the different cellular components of the coronary vasculature by undergoing a number of morphological and physiological changes collectively known as epithelial to mesenchymal transformation (EMT). However, the specific signaling mechanisms that regulate epicardial EMT are yet to be delineated. In this study we investigated the role of TGFβ2 and hyaluronan (HA) during epicardial EMT and how signals from these two molecules are integrated during this important process. Here we show that TGFβ2 induces MEKK3 activation, which in turn promotes ERK1/2 and ERK5 phosphorylation. TGFβ2 also increases Has2 expression and subsequent HA production. Nevertheless, inhibition of MEKK3 kinase activity, silencing of ERK5 or pharmacological disruption of ERK1/2 activation significantly abrogates this response. Thus, TGFβ2 promotes Has2 expression and HA production through a MEKK3/ERK1/2/5-dependent cascade. Furthermore, TGFβ2 is able to induce epicardial cell invasion and differentiation but not proliferation. However, inhibition of MEKK3-dependent pathways, degradation of HA by hyaluronidases or blockade of CD44, significantly impairs the biological response to TGFβ2. Taken together, these findings demonstrate that TGFβ2 activation of MEKK3/ERK1/2/5 signaling modulates Has2 expression and HA production leading to the induction of EMT events. This is an important and novel mechanism showing how TGFβ2 and HA signals are integrated to regulate changes in epicardial cell behavior.

BMP2 rescues deficient cell migration inTgfbr3−/−epicardial cells and requires Src kinase

“…Hyaluronan Synthase 2 (Has2) synthesizes the glycosaminoglycan hyaluronan (HA), an important component of the extracellular matrix required for cardiac development and epicardial migration and invasion. 29,30 mRNA expression of Has2 is 4.5-fold higher in Tgfbr3 . This further outlines TGFbR3 related compensation, as TGFbR3 is required for both TGFb2 and HMWHA stimulated epicardial cell invasion.…”

VEGF-A not Ang2 mediates endothelial-like differentiation of immature DCs by ERK1/2 signaling in the microenvironment of human colon adenocarcinoma

“…Many growth factors can lead to cell differentiation through cellular signal transduction (27). The ERK1/2 signaling plays a key role in mediating signals from membrane receptors to the nucleus, and is involved in the processes of cell growth, differentiation, proliferation and apoptosis (28,29).…”

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

“…Briefly, cells were fluorescently labeled with CalceinAM (BD Biosciences) and plated at 12,000 cells per well in 0.5% FBS/DMEM on collagen gels [27] in the top chamber. Epicardial cells were allowed to adhere overnight at 37 °C.…”