Transcription factor CCAAT enhancer-binding protein beta (C/EBPbeta) regulates the formation of a unique extracellular matrix that controls uterine stromal differentiation and embryo implantation.

ABSTRACT

During implantation, the uterine stromal cells undergo terminal differentiation into decidual cells, which support the proper progression of maternal-embryo interactions to successful establishment of pregnancy. The decidual cells synthesize extracellular matrix (ECM) components, such as laminins and collagens, which assemble into a unique basal lamina-like network that surrounds these cells. The functional significance of this matrix during implantation is unknown. We previously showed that the transcription factor CCAAT enhancer-binding protein ß (C/EBPß) critically regulates decidualization in the mouse. We now provide evidence that C/EBPß directly controls the Lamc1 gene, which encodes a predominant laminin constituent of the ECM produced by the decidual cells. Suppression of Lamc1 expression in mouse primary endometrial stromal cells prevented the assembly of this ECM and impaired stromal differentiation. Attenuation of expression of integrin ß1, a major constituent of the integrin receptors targeted by decidual laminins, also inhibited this differentiation process. Disruption of laminin-integrin interactions led to impaired activation of the focal adhesion kinase, an integrin-mediated regulator of cytoskeletal remodeling during decidualization. To further analyze the role of the decidual ECM in modulating maternal-embryo interactions, we monitored trophoblast invasion into differentiating uterine stromal monolayers, using a co-culture system. Silencing of stromal Lamc1 expression, which prevented formation of the basal lamina-like matrix, resulted in marked reduction in trophoblast outgrowth. Collectively, our findings identified C/EBPß as a critical regulator of the unique ECM that controls decidual cell architecture and differentiation, and it provided new insights into the mechanisms by which the uterine stromal microenvironment controls the progression of embryo implantation.