Fetal cell senescence at term is a natural physiologic response to oxidative stress (OS) that occurs as a result of increased metabolic demands by the maturing fetus. Various risk factors for preterm labor are associated with OS-induced senescence. Our pilot data suggest that fetal cell senescence causes the alarmin HMGB1 (a non-histone protein) to translocate from the nucleus to the cytosol. There it is modified by acetylation and released via exocytosis (free HMGB1) or encapsulated in exosomes, (30-100 nm particles) formed and extruded by multivesicular endosome fusion with the plasma membrane. Secreted HMGB1 functions as a proinflammatory cytokine in feto-maternal tissues. In the fetal membranes, it augments fetal cell senescence and an associated 'sterile' inflammatory reaction through TLR2-mediated p38 MAPK activation. In myocytes, HMGB1 activates p38 MAPK, resulting in upregulation of progesterone receptor (PR) isoform A and increased COX-2 expression and myocyte inflammation. A positive OS feedback loop is also established by HMGB1, accelerating amniocyte aging. Our core hypothesis posits that HMGB1 secreted from senescing fetal membranes, either by diffusion or transported via exosomes, causes myometrial activation through p38 MAPK, which in turn increases the ratio of PR-A to PR-B, leading to functional progesterone withdrawal and triggering the onset of labor. This hypothesis will be tested in 2 specific aims.
Specific Aim 1 will determine how OS stimulates fetal membrane cell-derived HMGB1 secretion, as free protein or packaged and exported in exosomes, during human pregnancy and parturition.
Specific Aim 2 will determine how free- or exosome-HMGB1 produced by fetal membrane cells in response to OS induces functional progesterone withdrawal and myometrial contractility. Primary and transformed human amnion, chorionic trophoblast, and myometrial cells, as well as fetal membrane and myometrial organ cultures, will be exposed to OS-inducing agents. Using molecular and cellular biological approaches we will quantitate OS-induced fetal cell senescence, HMGB1 release, exosome packaging, direction of exosome-HMGB1 secretion, signaling via p38 MAPK, PR isoform switching, and myometrial activation. Additionally, we will quantify the concentrations of exosome-HMGB1 in our banked feto-maternal biologic fluids (amniotic fluid, peripheral and maternal uterine venous plasma, and fetal cord plasma) from term and preterm births (PTB) to correlate their distribution with defined pregnancy outcomes. This study will evaluate a new feto-maternal signaling mechanism that triggers parturition in response to fetal OS. Identification of novel pathways and biomolecules should provide new targets to screen, diagnose, and reduce the risk of PTB.

Public Health Relevance

The proposed project is relevant to public health in that we will identify the fetal signals generated when the fetus is fully developed and uterine tissues are aged, signaling the mother to initiate labor and delivery at term. Identifying these signals will allow us to investigate them as a causal trigger for premature delivery due to the untimely aging of fetal tissues when a mother is exposed to various risk factors during her pregnancy. These findings will allow us design treatments to prevent premature aging of the fetal tissues and thus reduce the risk of premature birth.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Study Section
Pregnancy and Neonatology Study Section (PN)
Program Officer
Ilekis, John V
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University of Texas Medical Br Galveston
Obstetrics & Gynecology
Schools of Medicine
United States
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Richardson, Lauren; Menon, Ramkumar (2018) Proliferative, Migratory, and Transition Properties Reveal Metastate of Human Amnion Cells. Am J Pathol 188:2004-2015
Jin, Jin; Menon, Ramkumar (2018) Placental exosomes: A proxy to understand pregnancy complications. Am J Reprod Immunol 79:e12788
Hadley, Emily E; Sheller-Miller, Samantha; Saade, George et al. (2018) Amnion epithelial cell-derived exosomes induce inflammatory changes in uterine cells. Am J Obstet Gynecol 219:478.e1-478.e21
Sheller-Miller, Samantha; Richardson, Lauren; Martin, Laura et al. (2018) Systematic review of p38 mitogen-activated kinase and its functional role in reproductive tissues. Am J Reprod Immunol 80:e13047
Polettini, Jossimara; Richardson, Lauren S; Menon, Ramkumar (2018) Oxidative stress induces senescence and sterile inflammation in murine amniotic cavity. Placenta 63:26-31
Dixon, Christopher Luke; Richardson, Lauren; Sheller-Miller, Samantha et al. (2018) A distinct mechanism of senescence activation in amnion epithelial cells by infection, inflammation, and oxidative stress. Am J Reprod Immunol 79:
Hadley, Emily E; Richardson, Lauren S; Torloni, Maria R et al. (2018) Gestational tissue inflammatory biomarkers at term labor: A systematic review of literature. Am J Reprod Immunol 79:
Bhavnani, Suresh K; Dang, Bryant; Kilaru, Varun et al. (2018) Methylation differences reveal heterogeneity in preterm pathophysiology: results from bipartite network analyses. J Perinat Med 46:509-521
Dixon, C Luke; Sheller-Miller, Samantha; Saade, George R et al. (2018) Amniotic Fluid Exosome Proteomic Profile Exhibits Unique Pathways of Term and Preterm Labor. Endocrinology 159:2229-2240
Jin, Jin; Richardson, Lauren; Sheller-Miller, Samantha et al. (2018) Oxidative stress induces p38MAPK-dependent senescence in the feto-maternal interface cells. Placenta 67:15-23

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