Original Article Senescence and Telomere Homeostasis Might Be Involved in Placenta Percreta—Preliminary Investigation Keren Tzadikevitch Geffen, MD 1,2 , Hilah Gal, PhD 3 , Ifat Vainer, MD 4 , Ofer Markovitch, MD 2,5 , Aliza Amiel, PhD 6 , Valery Krizhanovsky, PhD 3 , and Tal Biron-Shental, MD 1,2 Abstract Objective: Placenta percreta (PP) is an abnormal condition of trophoblast maturation and terminal differentiation through the uterine wall. We opted to study telomere homeostasis and senescence expression in trophoblasts from PP, the most severe subgroup of placenta accreta. Study Design: Paraffin-embedded placental biopsies from pregnancies with percreta and normal placentation, matched by gestational age at delivery, were assessed for telomere length, aggregates, and senescence-associated heterochromatin foci using quantitative fluorescence in situ hybridization. Cyclin-dependent kinase inhibitors p21, p15, p16, and the tumor suppressor protein p53, known senescence-related markers, were assessed using immunohistochemical staining. Results: Short telomeres were found more often in trophoblasts from the samples of PP (n ¼ 9) compared to controls (n ¼ 8; 54% + 20% vs 2.3% + 1.16%, respectively; P < .05). More cells with telomere aggregates (18.3% + 6.9%) were observed in the PP than in the control group (4.8% + 5.4%; P ¼ .0005). The percentage of nucleic senescence-associated heterochromatin foci in the PP and control samples was similar (10.9% + 10.4% vs 10.7% + 15%, respectively; P ¼ .97). Immunohistochemistry of senescence markers was expressed differently in PP compared to the controls: higher p15 expression (46.42% + 15.2% vs 36.63% + 12.2%, P ¼ .004), higher p21 expression (59.8% + 22.1% vs 47.5% + 21.9%, P ¼ .011), lower p16 expression (54.8% + 26.3% vs 73.4% + 18.9%, P ¼ .000), and lower p53 expression (24.4% + 33.8% vs 34% + 14.4%, P ¼ .000). Conclusion: Placenta percreta exhibits telomere alterations and changes in expression of several senescence markers. These might be related to altered trophoblast invasion maturation and placental detachment postpartum. Keywords placenta percreta, telomere, senescence Introduction Accurate regulation of trophoblast maturation and terminal differentiation through the uterine wall is essential for normal pregnancy development. This process involves cellular pro- liferation, migration, and differentiation. Placenta accreta (PA) is an abnormal condition that occurs due to direct appo- sition of placental villi into the myometrium. It can be classi- fied into 3 subgroups. In placenta accreta vera, the villi are embedded directly onto the myometrium in the absence of decidua. In placenta increta, the villi are found deeper in the myometrium, while placenta percreta (PP) describes invasion through the uterine serosa and occasionally into adjacent organs. 1 Clinically, after the infant is delivered, PP cannot separate from the uterus. This is followed by massive hemor- rhage, which can lead to disseminated intravascular coagulo- pathy, hysterectomy, and even maternal mortality. 2 The pathophysiology and the molecular biology of PA are not fully understood. It is debated whether PA is the result of primary deficiency of decidualization or of pathologic maturation and terminal differentiation of the trophoblast cells. 1 Several studies found various changes in the extravillous trophoblast function in PA, including vascular remodeling and deep trophoblast 1 Department of Obstetrics and Gynecology, Meir Medical Center, Kfar Saba, Israel 2 Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel 3 Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot, Israel 4 Department of Pathology, Meir Medical Center, Kfar Saba, Israel 5 Ultrasound Unit, Department of Obstetrics and Gynecology, Meir Medical Center, Kfar Saba, Israel 6 Genetics Institute, Meir Medical Center, Kfar Saba, Israel Corresponding Author: Keren Tzadikevitch Geffen, Department of Obstetrics and Gynecology, Meir Medical Center, Kfar Saba 4428164, Israel. Email: kerentzad@gmail.com Reproductive Sciences 1-7 ª The Author(s) 2017 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/1933719117737852 journals.sagepub.com/home/rsx