Abstract
BackgroundFusion of placental villous cytotrophoblasts with the overlying syncytiotrophoblast is essential for the maintenance of successful pregnancy, and disturbances in this process have been implicated in pathological conditions such as pre-eclampsia and intra-uterine growth retardation. Caveolin-1 has been shown to be expressed in human villous cytotrophoblast and to be downregulated during fusion into syncytiotrophoblast but it is unclear whether it plays a role in this process.Methodology/Principal FindingsWe used RNA interference to determine whether caveolin-1 plays a role in differentiation and fusion in the BeWo choriocarcinoma cell line, a model of villous cytotrophoblast fusion. Assessment of cell fusion by desmosomal protein immunostaining revealed that cells transfected with caveolin-1 siRNA showed significantly enhanced fusion in response to treatment with dibutyryl cyclic AMP compared with cells transfected with a non-silencing control. Furthermore, caveolin-1 knockdown alone was sufficient to promote spontaneous fusion. In addition, biochemical differentiation, assessed by expression of placental alkaline phosphatase, was upregulated in caveolin-1 siRNA-transfected cells, with or without dbcAMP treatment. Assessment of Akt phosphorylation showed that caveolin-1 knockdown resulted in a significant reduction in phosphorylation at Thr308.Conclusions/SignificanceTaken together, these results suggest that caveolin-1 regulates BeWo cell differentiation and fusion, possibly through a mechanism involving modulation of Akt activity.
Highlights
Fusion of proliferating villous cytotrophoblast stem cells is essential to form, grow and maintain the syncytiotrophoblast epithelium of the human placenta [1]
A number of proteins have been implicated in the fusion process, including envelope proteins derived from human endogenous retroviruses (HERVs) [6], caspase-8 [7], connexin 43 [8] and ADAM proteins [9]
BeWo cells were transfected with siRNA duplexes targeted to human caveolin-1 mRNA (Cav-1 siRNA) or a non-silencing control which has no homology to any known mammalian gene
Summary
Fusion of proliferating villous cytotrophoblast stem cells is essential to form, grow and maintain the syncytiotrophoblast epithelium of the human placenta [1]. Syncytiotrophoblast is in direct contact with maternal blood and serves key placental functions such as nutrient and gas exchange, and the synthesis of steroid and peptide hormones [2]. Disturbances in this process may be involved in pathological conditions such as pre-eclampsia and intra-uterine growth retardation [3,4]. Fusion of placental villous cytotrophoblasts with the overlying syncytiotrophoblast is essential for the maintenance of successful pregnancy, and disturbances in this process have been implicated in pathological conditions such as pre-eclampsia and intra-uterine growth retardation. Caveolin-1 has been shown to be expressed in human villous cytotrophoblast and to be downregulated during fusion into syncytiotrophoblast but it is unclear whether it plays a role in this process
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