Silencing P38 MAPK Reduces Cellular Senescence in Human Fetal Chorion Trophoblast Cells

Overview

Journal Am J Reprod Immunol

Specialties Allergy & Immunology
Reproductive Medicine

Date 2022 Nov 5

PMID 36334089

Authors

Brett Goldman

Enkhtuya Radnaa

Talar Kechichian

Ramkumar Menon

Affiliations

Soon will be listed here.

Abstract

Problem: Amniochorion senescence generates mechanistic signals to initiate parturition. Activation of p38 mitogen-activated kinase (MAPK) in fetal amnion cells is a key mediator of senescence as well as epithelial-mesenchymal transition (EMT) of amnion cells. However, the impact of p38 MAPK in chorion trophoblast cells (CTCs) is unclear. We tested if eliminating p38 will reduce oxidative stress (OS) induced cell fates like cellular senescence, EMT, and inflammation induced by these processes in CTCs.

Methods: p38MAPK in CTCs was silenced using CRISPR/Cas9. OS was evoked by cigarette smoke extract (CSE) exposure. EMT was evoked by transforming growth factor (TGF)-ß treatment. Cell cycle, senescence, EMT, and inflammation were analyzed.

Results: CSE-induced changes in the cell cycle were not seen in p38KO CTCs compared to WT cells. OS induced by CSE evoked senescence and senescence-associated secretory phenotype (SASP as indicated by IL-6 and IL-8 increase) in WT but not in p38MAPK KO CTCs. No changes were noted in HLA-G expression regardless of the status of p38MAPK. Neither CSE nor TGF-ß evoked EMT in either WT or p38 KO CTCs.

Conclusion: Senescence and senescence-associated inflammation in human fetal CTCs are mediated by p38MAPK. Compared to amnion epithelial cells, CTCs are resistant to EMT. This refractoriness may help them to maintain the barrier functions at the choriodecidual interface.

Citing Articles

Determining Sex-Specific Gene Expression Differences in Human Chorion Trophoblast Cells.

Goncharov D, Lintao R, Urrabaz-Garza R, Radnaa E, Kammala A, Richardson L Int J Mol Sci. 2025; 26(5).

PMID: 40076861 PMC: 11900912. DOI: 10.3390/ijms26052239.

miR-548az-5p induces amniotic epithelial cell senescence by regulating KATNAL1 expression in labor.

Jing D, Liu Q, Zhang H, Li Y, Jiang X, Cai Y Sci Rep. 2024; 14(1):30380.

PMID: 39638877 PMC: 11621115. DOI: 10.1038/s41598-024-82390-y.

PGRMC2 and HLA-G regulate immune homeostasis in a microphysiological model of human maternal-fetal membrane interface.

Lintao R, Richardson L, Kumar Kammala A, Chapa J, Yunque-Yap D, Khanipov K Commun Biol. 2024; 7(1):1041.

PMID: 39179795 PMC: 11344061. DOI: 10.1038/s42003-024-06740-2.

Enhancing adipose tissue functionality in obesity: senotherapeutics, autophagy and cellular senescence as a target.

Arias C, Alvarez-Indo J, Cifuentes M, Morselli E, Kerr B, Burgos P Biol Res. 2024; 57(1):51.

PMID: 39118171 PMC: 11312694. DOI: 10.1186/s40659-024-00531-z.

The Role of the NLRP3 Inflammasome in the Molecular and Biochemical Mechanisms of Cervical Ripening: A Comprehensive Review.

Flis W, Socha M Cells. 2024; 13(7.

PMID: 38607039 PMC: 11012148. DOI: 10.3390/cells13070600.

References

Dutta E, Behnia F, Boldogh I, Saade G, Taylor B, Kacerovsky M . Oxidative stress damage-associated molecular signaling pathways differentiate spontaneous preterm birth and preterm premature rupture of the membranes. Mol Hum Reprod. 2015; 22(2):143-57. DOI: 10.1093/molehr/gav074. View

Richardson L, Vargas G, Brown T, Ochoa L, Sheller-Miller S, Saade G . Discovery and Characterization of Human Amniochorionic Membrane Microfractures. Am J Pathol. 2017; 187(12):2821-2830. PMC: 5718093. DOI: 10.1016/j.ajpath.2017.08.019. View

Yang F, Zheng Q, Jin L . Dynamic Function and Composition Changes of Immune Cells During Normal and Pathological Pregnancy at the Maternal-Fetal Interface. Front Immunol. 2019; 10:2317. PMC: 6813251. DOI: 10.3389/fimmu.2019.02317. View

Menon R, Behnia F, Polettini J, Saade G, Campisi J, Velarde M . Placental membrane aging and HMGB1 signaling associated with human parturition. Aging (Albany NY). 2016; 8(2):216-30. PMC: 4789578. DOI: 10.18632/aging.100891. View

Menon R, Fortunato S . Fetal membrane inflammatory cytokines: a switching mechanism between the preterm premature rupture of the membranes and preterm labor pathways. J Perinat Med. 2004; 32(5):391-9. DOI: 10.1515/JPM.2004.134. View

Canzoneri B, Feng L, Grotegut C, Bentley R, Heine R, Murtha A . The chorion layer of fetal membranes is prematurely destroyed in women with preterm premature rupture of the membranes. Reprod Sci. 2013; 20(10):1246-54. DOI: 10.1177/1933719113483009. View

Jacobs S, Sheller-Miller S, Richardson L, Urrabaz-Garza R, Radnaa E, Menon R . Characterizing the immune cell population in the human fetal membrane. Am J Reprod Immunol. 2020; 85(5):e13368. DOI: 10.1111/aji.13368. View

Kumar D, Springel E, Moore R, Mercer B, Philipson E, Mansour J . Progesterone inhibits in vitro fetal membrane weakening. Am J Obstet Gynecol. 2015; 213(4):520.e1-9. DOI: 10.1016/j.ajog.2015.06.014. View

Simmons D, Natale D, Begay V, Hughes M, Leutz A, Cross J . Early patterning of the chorion leads to the trilaminar trophoblast cell structure in the placental labyrinth. Development. 2008; 135(12):2083-91. PMC: 3159581. DOI: 10.1242/dev.020099. View

10.

Menon R . Fetal inflammatory response at the fetomaternal interface: A requirement for labor at term and preterm. Immunol Rev. 2022; 308(1):149-167. PMC: 9188997. DOI: 10.1111/imr.13075. View

11.

Richardson L, Taylor R, Menon R . Reversible EMT and MET mediate amnion remodeling during pregnancy and labor. Sci Signal. 2020; 13(618). PMC: 7092701. DOI: 10.1126/scisignal.aay1486. View

12.

Erlebacher A . Immunology of the maternal-fetal interface. Annu Rev Immunol. 2013; 31:387-411. DOI: 10.1146/annurev-immunol-032712-100003. View

13.

Menon R, Boldogh I, Urrabaz-Garza R, Polettini J, Syed T, Saade G . Senescence of primary amniotic cells via oxidative DNA damage. PLoS One. 2014; 8(12):e83416. PMC: 3873937. DOI: 10.1371/journal.pone.0083416. View

14.

Mor G . Inflammation and pregnancy: the role of toll-like receptors in trophoblast-immune interaction. Ann N Y Acad Sci. 2008; 1127:121-8. DOI: 10.1196/annals.1434.006. View

15.

Menon R, Radnaa E, Behnia F, Urrabaz-Garza R . Isolation and characterization human chorion membrane trophoblast and mesenchymal cells. Placenta. 2020; 101:139-146. PMC: 7584780. DOI: 10.1016/j.placenta.2020.09.017. View

16.

Sheller-Miller S, Urrabaz-Garza R, Saade G, Menon R . Damage-Associated molecular pattern markers HMGB1 and cell-Free fetal telomere fragments in oxidative-Stressed amnion epithelial cell-Derived exosomes. J Reprod Immunol. 2017; 123:3-11. PMC: 5632595. DOI: 10.1016/j.jri.2017.08.003. View

17.

Polettini J, Dutta E, Behnia F, Saade G, Torloni M, Menon R . Aging of intrauterine tissues in spontaneous preterm birth and preterm premature rupture of the membranes: A systematic review of the literature. Placenta. 2015; 36(9):969-73. DOI: 10.1016/j.placenta.2015.05.003. View

18.

Merlino A, Welsh T, Erdonmez T, Madsen G, Zakar T, Smith R . Nuclear progesterone receptor expression in the human fetal membranes and decidua at term before and after labor. Reprod Sci. 2009; 16(4):357-63. DOI: 10.1177/1933719108328616. View

19.

Malak T, Ockleford C, Bell S, Dalgleish R, Bright N, Macvicar J . Confocal immunofluorescence localization of collagen types I, III, IV, V and VI and their ultrastructural organization in term human fetal membranes. Placenta. 1993; 14(4):385-406. DOI: 10.1016/s0143-4004(05)80460-6. View

20.

Richardson L, Dixon C, Aguilera-Aguirre L, Menon R . Oxidative stress-induced TGF-beta/TAB1-mediated p38MAPK activation in human amnion epithelial cells. Biol Reprod. 2018; 99(5):1100-1112. PMC: 7190655. DOI: 10.1093/biolre/ioy135. View