Sensing senescence in preterm birth

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Nov 10, 2011 - in P4 levels to trigger labor, which does not occur in human ... *Correspondence to: Sudhansu K. Dey; Email: [email protected] Submitted: ...

Editorials: Cell Cycle Features

Editorials: Cell Cycle Features

Cell Cycle 11:2, 205-206; January 15, 2012; © 2012 Landes Bioscience

Sensing senescence in preterm birth Jeeyeon Cha, Yasushi Hirota and Sudhansu K. Dey* Division of Reproductive Sciences; Cincinnati Children’s Research Foundation; Cincinnati, OH USA

There are nearly 13 million premature births, with more than 3 million stillbirths worldwide each year.1 In the US alone, more than 12% of all pregnancies result in preterm birth. Prematurity is a direct cause of 30% of all neonatal deaths, averaging more than 1 million annually and often leads to developmental impediment and long-term disabilities in those who survive. Although prematurity and stillbirths present a significant global challenge, this issue remains relatively unattended. In humans, preterm delivery is defined by birth occurring earlier than 37 weeks of gestation. Many factors, including genetics, infection/inflammation, oxidative stress, uterine over-distension, cervical aberration and recently progesterone (P4) resistance2 are considered contributors to preterm birth. However, a comprehensive understanding of this aberration in pregnancy remains elusive. The incidence of preterm birth remains high even with continued clinical efforts to reduce the occurrence, such as with tocolytic drugs, antibiotics and surgical cerclage, given that the targets of these therapies are not fundamental but symptomatic. This necessitates a need for more intense basic research using different preclinical models to target this lingering global problem. Animal models that spontaneously develop preterm delivery are powerful tools to better understand the underpinning mechanism and to develop prevention and treatment strategies for preterm birth. Although rodent models of preterm birth induced by pro-inflammatory agents, such as lipopolysaccharide (LPS), are often used,3 these models are not ideal, because the onset of labor in these models is induced by ovarian luteolysis with a drop in P4 levels to trigger labor, which does not occur in human parturition. Furthermore,

LPS induces both uterine and systemic inflammation making the interpretation difficult as to the cause of preterm birth. Thus, rodent models of preterm labor without luteolysis are invaluable. We have developed a novel mouse model of preterm delivery in which a conditional uterine deletion of a tumor suppressor gene Trp53 encoding the p53 protein (p53d/d) has been introduced.4 Post-implantation decidual cells, the differentiated uterine stromal cells that support embryonic growth, in these mice show premature terminal differentiation and senescence-associated growth restriction with increased levels of p21 and phosphorylated Akt (pAKT). Strikingly, p53d/d females have increased incidence of preterm delivery without a drop in serum P4 levels, simulating human parturition. This condition is accompanied by a rise in uterine Cox2 and PGF2α levels. Interestingly, preterm birth in these mice is rescued by a Cox2 inhibitor, suggesting that a Cox2-PGFSPGF2α pathway is involved.4 Further analysis found that decidual senescence in p53d/d females is associated with heightened mammalian target of rapamycin complex 1 (mTORC1) signaling. This elevated mTORC1 signaling is a significant contributor to preterm birth, since this phenotype is rescued by a single oral gavage of a low dose of rapamycin, an mTORC1 inhibitor.5 These studies constitute an unanticipated role of mTORC1 in preterm birth upstream of p21 and Cox2, and show that the mTORC1-p21-Cox2 signaling axis is a critical component in birth timing. This is supported by the fact that targeting any of these components rescues preterm delivery.4,5 These studies corroborate mechanistic findings in cell culture systems that increased mTORC1 signaling during cell cycle arrest contributes to a senescence phenotype that is

suppressed by rapamycin, and that p53 inhibits mTORC1 signaling and thus the senescence phenotype.6-8 Our study also reveals that progressive decidual senescence approaching term birth is a normal occurrence in mice.5 These preclinical studies may help to elucidate the mechanism of human birth and develop new strategies to combat this global problem. This genetic model predisposed to preterm labor can be used to explore gene-environment interactions during pregnancy, an aspect that could not be clearly addressed by existing models. Our efforts are now being directed toward better understanding the network linking genetics and inflammation. We now have preliminary data showing that p53d/d dams subject to even low-grade immunological insults remarkably increase their predilection toward preterm birth. However, these findings have raised many more questions. How and why is the deciduum, but not the placenta, programmed to undergo senescence during pregnancy? How does decidual senescence seeded early in pregnancy trigger preterm birth? Is mTORC1 the only trigger for senescence, or are there others? With infection/inflammation known to amplify secretion of senescenceinduced cytokines IL-6/IL-8,9,10 does a senescence-associated secretory phenotype contribute to premature birth? Can diets or endocrine disruptors influence geneenvironment interactions to alter timing of birth? Answers to these questions will require intense research. If and when they are answered, it may be possible to develop efficient preventive strategies by manipulating key regulators in the labor “pathway” (Fig. 1). “Life and death are linked by a common thread.”11 Many signaling molecules that participate in tumorigenesis are also involved in pregnancy; they are

© 2012 Landes Bioscience. Do not distribute.

*Correspondence to: Sudhansu K. Dey; Email: [email protected] Submitted: 11/10/11; Accepted: 11/14/11 http://dx.doi.org/10.4161/cc.11.2.18781 Comment on: Hirota Y, et al. Proc Natl Acad Sci USA 2011; 108:18073–8. www.landesbioscience.com

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Figure 1. A scheme depicting potential contribution of decidual mTORC1 and senescence in setting the parturition clock. Term pregnancy encompasses progressive decidual senescence over the course of pregnancy (pink arrow) until a threshold is encountered, triggering PG synthesis, myometrial activation and contractility, culminating in birth. In the mouse model of preterm labor in which Trp53 is conditionally deleted in the uterus, decidual senescence begins prematurely due to activation of an pAkt-mTORC1-p21-Cox2 signaling axis and reaches the senescence threshold in a shorter gestational time frame, leading to preterm delivery. Several risk factors of preterm birth, including genetics, stress and inflammation/infection have been shown to contribute to the senescence process in other systems, and we speculate that these factors pathologically push decidual senescence toward the threshold. Furthermore, normal parturition involves cervical ripening along with myometrial activation in preparation for parturition, which does not occur in the p53d/d females: these females exhibit dystocia and stillbirth. Rapamycin, an inhibitor of mTORC1 signaling, can attenuate premature decidual senescence seen in p53d/d females and rescue preterm labor.

© 2012 Landes Bioscience.

dysregulated in cancers but highly regulated during pregnancy. Our results underscore what we believe to be a new role of decidual senescence involving the p53mTORC1-p21-Cox2 signaling axis in determining the timing of birth. It remains to be seen whether genetic alterations of any members of this signaling axis identify patients with high risk of preterm birth.

and HD068524 (to S.K.D.). J.C. is supported by a Ruth L. Kirschstein National Research Service Award fellowship from the NIH/NIA (F30AG040858). Y.H. is supported by Precursory Research for Embryonic Science and Technology, Japan.

4. Hirota Y, et al. J Clin Invest 2010; 120:803-15; PMID:20124728; http://dx.doi.org/10.1172/ JCI40051. 5. Hirota Y, et al. Proc Natl Acad Sci USA 2011; 108:18073-8; PMID:22025690; http://dx.doi. org/10.1073/pnas.1108180108. 6. Demidenko ZN, et al. Proc Natl Acad Sci USA 2010; 107:9660-4; PMID:20457898; http://dx.doi. org/10.1073/pnas.1002298107. 7. Korotchkina LG, et al. Aging (Albany NY) 2011; 2:344-52. 8. Leontieva OV, et al. Aging (Albany NY) 2010; 2:92435; PMID:21212465. 9. Liang L, et al. J Reprod Immunol 1996; 30:29-52; PMID:8920166; http://dx.doi.org/10.1016/01650378(95)00953-1. 10. Sheldon IM, et al. PLoS ONE 2010; 5:12906; PMID:20877575; http://dx.doi.org/10.1371/journal. pone.0012906. 11. Wang H, et al. Nat Rev Genet 2006; 7:185-99; PMID:16485018; http://dx.doi.org/10.1038/nrg1808.

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Acknowledgments

This study was funded in parts by a grant from the Bill and Melinda Gates Foundation through the Grand Challenges Explorations Initiative and by NIH Grants HD12304, DA06668

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References 1. Behrman R, Butler AS, Eds. Preterm birth: Causes, Consequences and Prevention. The National Academies Press, Washington DC 2007. 2. Hirota Y, et al. Nat Med 2010; 16:529-31; PMID:20448578; http://dx.doi.org/10.1038/ nm0510-529. 3. Elovitz MA, et al. Trends Endocrinol Metab 2004; 15:479-87; http://dx.doi.org/10.1016/j. tem.2004.10.009.

Cell Cycle

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