Expression Pattern of Progranulin in the Human Placenta and Its Effect on Cell Proliferation in the Choriocarcinoma Cell Line BeWo

Abstract

Abstract. Expression of the glycoprotein progranulin has been recently identified in rodent trophoblast cells during early embryonic development. The aim of our study was to describe the expression pattern of progranulin in human placental tissue specimens by immunostaining. We further analyzed the influence of progranulin on invasion and migration of isolated first trimester villous trophoblast cells. The effect of progranulin on cell proliferation was investigated using the human choriocarcinoma derived cell lines BeWo and Jeg-3. Cells were tested with recombinant human progranulin at various concentrations (0.1, 0.2 and 1.0 μg/ml). The strongest expression of progranulin was observed in the villous trophoblast cells, particularly in the syncytiotrophoblast. The intensity of staining in these cells was higher in the first trimester than in the third trimester. In contrast, the staining of the extravillous trophoblast cells and of the villous and decidual stroma was only weak. Using an ELISA technique, we also detected progranulin in amniotic fluid of the early second trimester. Isolated human first trimester trophoblast cells also expressed and secreted progranulin. Progranulin significantly stimulated the cell proliferation of BeWo cells, but it did not influence the amount of trophoblast cell migration and invasion in vitro. Furthermore, it did not promote the cell proliferation of Jeg-3 cells. Our results suggested that progranulin, although it is mainly synthesized and secreted by villous trophoblast cells, may not primarily act on the villous trophoblast cells in a paracrine or autocrine manner. The observed effect of progranulin on cell proliferation in BeWo cells may indicate a growth stimulating effect also on the small part of proliferating extravillous trophoblast cells during placental development.

Structure, Function, and Mechanism of Progranulin; the Brain and Beyond

“…It might be expected therefore that the development in grn −/− mice would be severely disrupted. This turns out not to be the case, with grn −/− mice developing normally to term, maturing, and being fertile as adults (Stubert et al 2011;Yin et al 2010a), although reduced germline transmission was reported (Ahmed et al 2010;Wang et al 2010). As discussed above, grn −/− mice show abnormal peripheral inflammatory responses, and a correspondingly excessive activation of microglia was observed in the CNS of grn −/− mice upon inflammatory stimulation (Yin et al 2010a).…”

“…PGRN, which occurs in the trophoblasts of the preimplantation embryo (Diaz-Cueto et al 2000;Qin et al 2005), stimulates blastocyst formation and implantation (Diaz-Cueto et al 2000;Qin et al 2005) as well as the subsequent formation of the placenta (Desmarais et al 2008;Stubert et al 2011). It might be expected therefore that the development in grn −/− mice would be severely disrupted.…”

A proteomic clock of human pregnancy

“…[51][52][53][54][55][56] Their tight chronological profile in individual women over the course of pregnancy and their synthesis in placental tissue provide a strong rationale for further examining their utility as biomarkers. 57,58 GPC3 is a member of the cell surface heparan sulfate proteoglycan family and regulates cell growth by facilitating Wnt and suppressing Hedgehog signaling. [59][60][61] GPC3 is also cleaved from the cell surface and then acts as a competitive inhibitor of Wnt.…”

“…[64][65][66][67][68][69][70] GRNs are cleaved from progranulin, a secreted glycoprotein that is widely expressed in epithelia, immune cells, the central nervous system, and solid organs including the placenta. 58,71 Loss-of-function mutations have been associated with a dysregulated and proinflammatory immune responses. 72 Two recent studies reported increased placental expression of GRNs in women with preeclampsia and IUGR and increased serum GRNs in women with late-onset preeclampsia.…”

Circulating progranulin levels in women with gestational diabetes mellitus and healthy controls during and after pregnancy

“…Taking the high expression of PGRN by the human placental tissue into account, as well as its inhibitory effect on insulin signaling, it can be hypothesized that PGRN could play a role in the development of insulin resistance during pregnancy (10,11). No study so far has addressed the role of circulating PGRN in pregnancy or GDM.…”