TY - JOUR
T1 - Genome amplification and cellular senescence are hallmarks of human placenta development
AU - Velicky, Philipp
AU - Meinhardt, Gudrun
AU - Plessl, Kerstin
AU - Vondra, Sigrid
AU - Weiss, Tamara
AU - Haslinger, Peter
AU - Lendl, Thomas
AU - Aumayr, Karin
AU - Mairhofer, Mario
AU - Zhu, Xiaowei
AU - Schütz, Birgit
AU - Hannibal, Roberta L.
AU - Lindau, Robert
AU - Weil, Beatrix
AU - Ernerudh, Jan
AU - Neesen, Jürgen
AU - Egger, Gerda
AU - Mikula, Mario
AU - Röhrl, Clemens
AU - Urban, Alexander E.
AU - Baker, Julie
AU - Knöfler, Martin
AU - Pollheimer, Jürgen
N1 - Publisher Copyright:
© 2018 Velicky et al. http://creativecommons.org/licenses/by/4.0/.
PY - 2018/10
Y1 - 2018/10
N2 - 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.
AB - 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.
KW - Cell Cycle
KW - Cell Cycle Checkpoints
KW - Cell Differentiation
KW - Cell Movement
KW - Cell Proliferation
KW - Cellular Senescence/physiology
KW - Endometrium/cytology
KW - Female
KW - Genome/physiology
KW - Humans
KW - Placenta/metabolism
KW - Placentation/genetics
KW - Polyploidy
KW - Pregnancy
KW - Pregnancy Trimester, First
KW - Primary Cell Culture
KW - Tetraploidy
KW - Trophoblasts/metabolism
UR - http://www.scopus.com/inward/record.url?scp=85055596926&partnerID=8YFLogxK
U2 - 10.1371/journal.pgen.1007698
DO - 10.1371/journal.pgen.1007698
M3 - Article
C2 - 30312291
AN - SCOPUS:85055596926
SN - 1553-7390
VL - 14
SP - e1007698
JO - PLoS Genetics
JF - PLoS Genetics
IS - 10
M1 - e1007698
ER -