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Elevated Circulating and Placental SPINT2 Is Associated with Placental Dysfunction.

ABSTRACT: Biomarkers for placental dysfunction are currently lacking. We recently identified SPINT1 as a novel biomarker; SPINT2 is a functionally related placental protease inhibitor. This study aimed to characterise SPINT2 expression in placental insufficiency. Circulating SPINT2 was assessed in three prospective cohorts, collected at the following: (1) term delivery (n = 227), (2) 36 weeks (n = 364), and (3) 24-34 weeks' (n = 294) gestation. SPINT2 was also measured in the plasma and placentas of women with established placental disease at preterm (<34 weeks) delivery. Using first-trimester human trophoblast stem cells, SPINT2 expression was assessed in hypoxia/normoxia (1% vs. 8% O2), and following inflammatory cytokine treatment (TNFα, IL-6). Placental SPINT2 mRNA was measured in a rat model of late-gestational foetal growth restriction. At 36 weeks, circulating SPINT2 was elevated in patients who later developed preeclampsia (p = 0.028; median = 2233 pg/mL vs. controls, median = 1644 pg/mL), or delivered a small-for-gestational-age infant (p = 0.002; median = 2109 pg/mL vs. controls, median = 1614 pg/mL). SPINT2 was elevated in the placentas of patients who required delivery for preterm preeclampsia (p = 0.025). Though inflammatory cytokines had no effect, hypoxia increased SPINT2 in cytotrophoblast stem cells, and its expression was elevated in the placental labyrinth of growth-restricted rats. These findings suggest elevated SPINT2 is associated with placental insufficiency.

SUBMITTER: Murphy CN

PROVIDER: S-EPMC8305184 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

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Elevated Circulating and Placental SPINT2 Is Associated with Placental Dysfunction.

Murphy Ciara N CN Walker Susan P SP MacDonald Teresa M TM Keenan Emerson E Hannan Natalie J NJ Wlodek Mary E ME Myers Jenny J Briffa Jessica F JF Romano Tania T Roddy Mitchell Alexandra A Whigham Carole-Anne CA Cannon Ping P Nguyen Tuong-Vi TV Kandel Manju M Pritchard Natasha N Tong Stephen S Kaitu'u-Lino Tu'uhevaha J TJ

International journal of molecular sciences 20210712 14

Biomarkers for placental dysfunction are currently lacking. We recently identified SPINT1 as a novel biomarker; SPINT2 is a functionally related placental protease inhibitor. This study aimed to characterise SPINT2 expression in placental insufficiency. Circulating SPINT2 was assessed in three prospective cohorts, collected at the following: (1) term delivery (n = 227), (2) 36 weeks (n = 364), and (3) 24-34 weeks' (n = 294) gestation. SPINT2 was also measured in the plasma a ...[more]

PMID: 34299087

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Project description:Placental protein 13 (PP13) is a regulatory protein involved in remodeling the vascular system of the pregnancy and extending the immune tolerance of the mother to the growing fetus. PP13 is localized on the surface of the syncytiotrophoblast. An ex vivo placental model shows that the PP13 is released via placental-associated extracellular vesicles (PEVs) to the maternal uterine vein. This exploratory study aimed to determine PEV-associated PP13 in the maternal circulation as compared to the known soluble fraction since each has a specific communication pathway. Patients admitted to Bnai Zion Medical Center for delivery were recruited, and included 19 preeclampsia (PE) patients (7 preterm PE gestational age < 37 weeks' gestation), 16 preterm delivery (PTD, delivery at GA < 37 weeks' gestation), and 15 matched term delivery controls. Treatment by corticosteroids (Celestone), which is often given to patients with suspected preterm PE and PTD, was recorded. The PEV proteome was purified from the patients' plasma by size exclusion chromatography (SEC) to separate the soluble and PEV-associated PP13. The total level of PP13 (soluble and PEV-associated) was determined using mild detergent that depleted the PEV proteome. PP13 fractions were determined by ELISA with PP13 specific antibodies. ELISA with alkaline phosphatase (PLAP)- and cluster differentiation 63 (CD63)-specific antibodies served to verify the placental origin of the PEVs. SPSS was used for statistical analysis. The patients' medical, pregnancy, and delivery records in all groups were similar except, as expected, that a larger number of PE and PTD patients had smaller babies who were delivered earlier, and the PE patients had hypertension and proteinuria. The SEC analysis detected the presence of PP13 in the cargo of the PEVs and on their surface, in addition to the known soluble fraction. The median soluble PP13 was not significantly different across the PE, PTD, and term delivery control groups. However, after depleting the PEV of their proteome, the total PP13 (soluble and PEV-associated) was augmented in the cases of preterm PE, reaching 2153 pg/mL [IQR 1866-2838] but not in cases of PTD reaching 1576 pg/mL [1011-2014] or term delivery groups reaching 964 pg/mL [875-1636]), p < 0.01. On the surface of the circulating PEV from PTD patients, there was a decrease in PP13. Corticosteroid treatment was accompanied by a massive depletion of PP13 from the PEV, especially in preterm PE patients. This exploratory study is, thus, the first to determine PEV-associated PP13 in maternal circulation, providing a quantitative determination of the soluble and the PEV-associated fractions, and it shows that the latter is the larger. We found an increase in the amount of PP13 carried via the PEV-associated pathway in PE and PTD patients compared to term delivery cases, which was further augmented when the patients were treated with corticosteroids, especially in preterm PE. The signal conveyed by this novel communication pathway warrants further research to investigate these two differential pathways for the liberation of PP13.

Project description:BackgroundSpecific heat shock proteins are associated with pregnancy complications, including spontaneous preterm birth (SPTB). Placental proteomics and whole exome sequencing recently suggested an association between heat shock protein HSPA5 and uncomplicated SPTB. In the present study, we investigated the localization of and possible roles for HSPA5 in SPTB.MethodsWestern blot was performed to validate the result from the previously published proteomic analysis. We used qPCR to assess mRNA expression of genes and immunohistochemistry and immunoelectron microscopy to examine localization of HSPA5 in placental tissue. We silenced the HSPA5 gene in the HTR8/SVneo human trophoblast cell line to investigate possible functions of HSPA5.ResultsHSPA5 was upregulated in placentas from SPTBs compared to spontaneous term births. We did not observe upregulation of HSPA5 mRNA in placental samples. The protein was localized in placental trophoblast in both spontaneous preterm and term placentas. Gene silencing of HSPA5 in human trophoblast cell culture affected the inflammatory response and decreased the expression of several proinflammatory genes.ConclusionsWe suggest that upregulation of HSPA5 in the placenta is associated with spontaneous preterm labor. HSPA5 may promote the inflammatory response and alter the anti-inflammatory state of the placenta which could eventually lead to premature labor.ImpactWe validated upregulation of HSPA5 in placentas from spontaneous preterm birth. HSPA5 was not upregulated at transcriptional level which suggests that it may be regulated post-translationally. Silencing HSPA5 in a human trophoblast-derived cell line suggested that HSPA5 promotes expression of proinflammatory cytokines. The emerging inflammation could lead to spontaneous preterm labor. Identifying inflammatory pathways and factors associated with spontaneous preterm birth increases knowledge of the molecular mechanisms of premature labor. This could provide cues to predict imminent premature labor and lead to information about how to safely maintain pregnancies.

Dataset Information

Elevated Circulating and Placental SPINT2 Is Associated with Placental Dysfunction.

Publications

Elevated Circulating and Placental SPINT2 Is Associated with Placental Dysfunction.

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