Abstract
Genome amplification and cellular senescence are commonly associated with pathological processes. While physiological roles for polyploidization and senescence have been described in mouse development, controversy exists over their significance in humans. Here, we describe tetraploidization and senescence as phenomena of normal human placenta development. During pregnancy, placental extravillous trophoblasts (EVTs) invade the pregnant endometrium, termed decidua, to establish an adapted microenvironment required for the developing embryo. This process is critically dependent on continuous cell proliferation and differentiation, which is thought to follow the classical model of cell cycle arrest prior to terminal differentiation. Strikingly, flow cytometry and DNAseq revealed that EVT formation is accompanied with a genome-wide polyploidization, independent of mitotic cycles. DNA replication in these cells was analysed by a fluorescent cell-cycle indicator reporter system, cell cycle marker expression and EdU incorporation. Upon invasion into the decidua, EVTs widely lose their replicative potential and enter a senescent state characterized by high senescence-associated (SA) β-galactosidase activity, induction of a SA secretory phenotype as well as typical metabolic alterations. Furthermore, we show that the shift from endocycle-dependent genome amplification to growth arrest is disturbed in androgenic complete hydatidiform moles (CHM), a hyperplastic pregnancy disorder associated with increased risk of developing choriocarinoma. Senescence is decreased in CHM-EVTs, accompanied by exacerbated endoreduplication and hyperploidy. We propose induction of cellular senescence as a ploidy-limiting mechanism during normal human placentation and unravel a link between excessive polyploidization and reduced senescence in CHM.
Highlights
It is commonly assumed that trophoblasts of the human placenta exit their cell cycle as they develop into differentiated subtypes
We show that the shift from endocycle-dependent genome amplification to growth arrest is disturbed in androgenic complete hydatidiform moles (CHM), a hyperplastic pregnancy disorder associated with increased risk of developing choriocarinoma
We focused on extravillous trophoblasts (EVTs), a specific trophoblastic subtype that invades the uterus during pregnancy in order to control blood supply and nutrient transfer to the growing embryo
Summary
It is commonly assumed that trophoblasts of the human placenta exit their cell cycle as they develop into differentiated subtypes. This hypothesis follows the assumption that quiescence is a consequence of terminal differentiation in tissues. The latter undergo a multi-step differentiation process that starts at the epidermal growth factor-positive (EGFR+) proximal cell column (CC), characterized by high proliferative activity. These cells further differentiate into non-dividing human leukocyte antigen G-positive (HLA-G+) distal CC trophoblasts and invade the endometrial epithelium of the pregnant uterus, termed decidua. A single polyploid TGC nucleus contains up to 1000 copies of the
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