Molecular pathways of senescence regulate placental structure and function

Abstract

The placenta is an autonomous organ that maintains fetal growth and development. Its multinucleated syncytiotrophoblast layer, providing fetal nourishment during gestation, exhibits characteristics of cellular senescence. We show that in human placentas from pregnancies with intrauterine growth restriction, these characteristics are decreased. To elucidate the functions of pathways regulating senescence in syncytiotrophoblast, we used dynamic contrast‐enhanced MRI in mice with attenuated senescence programs. This approach revealed an altered dynamics in placentas of p53−/−, Cdkn2a−/−, and Cdkn2a−/−;p53−/− mice, accompanied by histopathological changes in placental labyrinths. Human primary syncytiotrophoblast upregulated senescence markers and molecular pathways associated with cell‐cycle inhibition and senescence‐associated secretory phenotype. The pathways and components of the secretory phenotype were compromised in mouse placentas with attenuated senescence and in human placentas from pregnancies with intrauterine growth restriction. We propose that molecular mediators of senescence regulate placental structure and function, through both cell‐autonomous and non‐autonomous mechanisms.

The Senescence-Associated Secretory Phenotype (SASP) in the Challenging Future of Cancer Therapy and Age-Related Diseases

“…BCL inhibitors (such as ABT-263 and ABT-737), as well as HSP90 inhibitors (geldanamycin and 17-DAMG), have been used to overcome the anti-apoptotic and pro-survival features of senescent cells, respectively [ 104 , 105 , 106 ]. It should be taken into account that, as senescent cells participate in placental development, embryogenesis, and wound healing [ 50 , 107 , 108 , 109 ], the widespread removal of senescent cells could lead to unexpected effects.…”

On the evolution of cellular senescence

“…Furthermore, senescent cells are also found during embryogenesis in the apical ectodermal ridge and the neural roof plate (Storer et al, 2013), during development of the placenta (Chuprin et al, 2013;Gal et al, 2019;Rajagopalan & Long, 2012) as well as during the development of the inner ear (Gibaja et al, 2019;Munoz-Espin et al, 2013) (for a recent review see also Rhinn et al, (2019)). But instead of regarding these observations as a side effect, they can be seen as the starting point to provide a different explanation for the evolution of cellular senescence.…”

“…Many of the impacts of the SASP appear to be negative: it promotes chronic inflammation, which in turn is an important contributor to a wide range of age-related diseases. However, as with apoptosis, senescent cells turn out to have beneficial effects in development, wound healing, and tissue repair (Demaria et al, 2015;Gal et al, 2019;Gibaja et al, 2019;Ritschka et al, 2017).…”

Programmed Cell Senescence in the Mouse Developing Spinal Cord and Notochord

“…The fact that we detected p16 INK4A expression (but not p21 CIP1/WAF ) in some motoneurons, opens the possibility to analyze whether in the absence of p16 INK4A motoneurons senescence could be prevented. Cellular senescence mediated by p16 INK4A has also been observed during placenta development (Gal et al, 2019 ), and Cdkn2a mRNA was detected in programmed cell senescence in zebrafish (Da Silva-Alvarez et al, 2020 ); it is possible, then, that different cell types undergoing programmed cell senescence vary in the tumor suppressor gene they expressed.…”