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Increased cell‐free fetal DNA release after apoptosis and sterile inflammation in human trophoblast cells
Author(s) -
Kazemi Nazanin Yeganeh,
Fedyshyn Bohdana,
Yelsa Isabel,
Fedyshyn Yaroslav,
Ruano Rodrigo,
Markovic Svetomir N.,
Chakraborty Rana,
Enninga Elizabeth Ann L.
Publication year - 2021
Publication title -
american journal of reproductive immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.071
H-Index - 97
eISSN - 1600-0897
pISSN - 1046-7408
DOI - 10.1111/aji.13483
Subject(s) - ctbs , trophoblast , apoptosis , andrology , inflammation , immunology , medicine , cell free fetal dna , proinflammatory cytokine , fetus , placenta , biology , pregnancy , prenatal diagnosis , stimulation , genetics , primary motor cortex , transcranial magnetic stimulation
Abstract Problem Cell‐free fetal DNA (cffDNA) shed from the placenta can be detected in maternal blood and increases incrementally during gestation. Concentrations are further elevated with pregnancy complications. Specific activators of cffDNA release in such complications have not been identified. Here, we use trophoblast cells from early and term placenta to examine cffDNA release following apoptosis, infection, and sterile inflammatory stress. Method of Study HTR8/SVneo cells were used to model first‐trimester trophoblasts, and term cytotrophoblasts (CTBs) were isolated from placentae collected after uncomplicated deliveries. Trophoblasts were treated with varying concentrations of doxorubicin (DOX), lipopolysaccharide (LPS), or high‐mobility group box protein 1 (HMGB1) for 18 h. Cells or supernatants were quantified for caspase‐3/7 cleavage, pro‐inflammatory cytokine secretion, and cffDNA release. Results Both HTR8/SVneo and CTBs underwent caspase‐3/7 cleavage following DOX treatment, with HTR8/SVneo cells more sensitive to apoptosis than term CTBs. Apoptotic cells released more cffDNA in a dose‐dependent manner. Treatment with LPS resulted in an increase in pro‐inflammatory IL‐6 release, particularly in term CTBs compared to early trophoblasts; however, LPS did not affect cffDNA release. Lastly, while neither cell released more TNF‐α following stimulation with HMGB1, both HTR8/SVneo and CTBs released significantly more cffDNA in the presence of HMGB1. Conclusions These data show that apoptosis and sterile inflammation induced by DOX and HMGB1, respectively, cause an increase in cffDNA concentrations in both first‐trimester and term trophoblasts. Understanding physiologic release of cffDNA during healthy and complicated pregnancy can identify new targets for the diagnosis and treatment of gestational complications.