bims-reprim 2022-01-30 papers

Issue of 2022–01–30
five papers selected by
Iva Filipovic, Karolinska Institutet

Placenta. 2022 Jan 11. pii: S0143-4004(22)00009-1. [Epub ahead of print]119 8-16

Uterine damage induces placenta accreta and immune imbalance at the maternal-fetal interface in the mouse.

Jiayi Zhou, Huanpeng Chen, Xiuting Xu, Yunyun Liu, Shengzhu Chen, Si Yang, Fang He, Bolan Yu.

INTRODUCTION: Placenta accreta spectrum (PAS) disorder is one of the major complications resulting in maternal death and serious adverse pregnancy outcomes. Uterine damage - principally that associated with cesarean section - is the leading risk factor for the development of PAS. However, the underlying pathogenesis of PAS related to uterine damage remains unclear.
METHODS: For this study, we constructed a mouse PAS model using hysterotomy to simulate a cesarean section in humans. Pregnant mice were sacrificed on embryonic days 12.5 (E12.5) and E17.5. Trophoblast invasion and placental vascularization were analyzed using Hematoxylin-Eosin (H&E) staining and immunohistochemistry (IHC), and the proportions of immune cells at the maternal-fetal interface were analyzed using flow cytometry. We analyzed the expressions of genes in the decidua and placenta using RNA sequencing and subsequent validation by QPCR, and measured serum angiogenic factors by ELISA.
RESULTS: Uterine damage led to increased trophoblast invasion and placental vascularization, with extensive changes to the immune-cell profiles at the maternal-fetal interface. The proportions of T and NK cells in the deciduas diminished significantly, with the decidual NK cells and M - 2 macrophages showing the greatest decline. The expression of TNF-α and IL4 was upregulated in the deciduas, while that of IFN-γ and IL10 was downregulated significantly. The expression of Mmp2, Mmp9, Mmp3, and Dock4 was significantly elevated in the placenta, and the serum levels of anti-angiogenic factors were significantly attenuated.
DISCUSSION: Uterine damage can cause immune imbalance at the maternal-fetal interface, which may contribute to abnormal trophoblast invasion and enhanced vascularization of the mouse placenta.

Keywords: Immune cells; Maternal-fetal interface; PAS; Trophoblast invasion; Uterine damage

DOI: https://doi.org/10.1016/j.placenta.2022.01.002

J Reprod Immunol. 2022 Jan 11. pii: S0165-0378(22)00003-1. [Epub ahead of print]150 103475

Isolation and culture of decidual natural killer cells from term placenta and complete hydatidiform mole.

Kornél F Lakatos, Kathleen Hasselblatt, Vilmos Fülöp, György Lajos Végh, Thomas McElrath, Ross S Berkowitz, Kevin M Elias.

Decidual natural killer cells (dNK) have been the focus of many studies because of their unique roles in both the anti-tumor immune response and healthy placental formation. Revealing the immunological mechanisms by which they interact with their target cells may lead to a better understanding of immune evasion of certain tumor cells, including abnormal cells of the different forms of gestational trophoblast disease and miscarriages of immunologic origin. Efforts to perform functional immunological studies on dNK cells have been limited by difficulty obtaining sufficent quantities of cells and sustaining the dNK phenotype. A novel protocol was developed to isolate and culture dNK cells from fresh, term placentas and complete hydatidiform moles.The placental samples were collected from healthy women undergoing scheduled elective cesarean delivery. The molar samples were collected after evacuation and curettage. Tissue samples were made into single cell suspensions using mechanical and enzymatic degradation, followed by fluorescence-activated cell sorting (FACS) using surface markers. The dNK cells were then expanded in cell culture. Their surface markers and cytotoxicity were reassessed by flow cytometry and functional assays. The protocol produces high quantities of enriched dNK cells which can be sustained in cell culture for at least a month, preserving their phenotype and funcionality for a week.

Keywords: Complete hydatidiform mole; Decidual NK cells; Fetal- maternal interface; NK cell isolation

DOI: https://doi.org/10.1016/j.jri.2022.103475

J Reprod Immunol. 2022 Jan 19. pii: S0165-0378(22)00015-8. [Epub ahead of print]150 103487

Post-hoc evaluation of peripheral blood natural killer cell cytotoxicity in predicting the risk of recurrent pregnancy losses and repeated implantation failures.

Maria Dinorah Salazar, Wen Juan Wang, Annie Skariah, Qiaohua He, Kathryn Field, Margaret Nixon, Rachel Reed, Svetlana Dambaeva, Kenneth Beaman, Alice Gilman-Sachs, Joanne Kwak-Kim.

Peripheral blood NK cytotoxicity assay (NKC) is one of the commonly utilized diagnostic tools for recurrent pregnancy losses (RPL) and repeated implantation failures (RIF). In this retrospective cohort study, we aimed to assess the cutoff values of NKC for RPL and RIF. A total of 883 women were included in this study; 24 nonpregnant fertile women, 604 nonpregnant women with three or more RPL, 163 nonpregnant women with two or more of RIF, 48 normal pregnant women, and 44 pregnant women with a history of RPL. Peripheral blood NKC assay was performed by flow cytometry. The differences between groups were analyzed using Student's t-test, a logistic regression analysis, and the area under the receiver operating characteristic curve analysis. Both nonpregnant fertile and normal pregnant women had significantly lower NKC at an effector to target cell ratio (E:T) of 50:1 (13.5 ± 1.1% and 12.9 ± 1.0%, respectively) when compared to women with RPL and RIF, and pregnant women with a history of RPL (23.6 ± 0.3%, 23.9 ± 0.5%, and 23.7 ± 1.0%, P < 0.0001 respectively). In addition, the area under the receiver operating characteristics curve for RPL and RIF using pre-conception NKC was 0.863 (P < 0.0001) and 0.879 (P < 0.0001), respectively, and for RPL using post-conception NKC was 0.736 (P = 0.001). These findings suggest that NKC significantly distinguishes nonpregnant women with RPL and RIF from fertile controls and pregnant RPLwomen from normal pregnant controls.

Keywords: NK cells; NK cytotoxicity; Recurrent pregnancy loss; Repeated implantation failure

DOI: https://doi.org/10.1016/j.jri.2022.103487

Exp Neurol. 2022 Jan 23. pii: S0014-4886(22)00013-9. [Epub ahead of print] 113988

Perinatal infection, inflammation, preterm birth, and brain injury: A review with proposals for future investigations.

Jonathan D Reiss, Laura S Peterson, Sophia N Nesamoney, Alan L Chang, Anca M Pasca, Ivana Marić, Gary M Shaw, Brice Gaudilliere, Ronald J Wong, Karl G Sylvester, Sonia L Bonifacio, Nima Aghaeepour, Ronald S Gibbs, David K Stevenson.

Preterm newborns are exposed to several risk factors for developing brain injury. Clinical studies have suggested that the presence of intrauterine infection is a consistent risk factor for preterm birth and white matter injury. Animal models have confirmed these associations by identifying inflammatory cascades originating at the maternofetal interface that penetrate the fetal blood-brain barrier and result in brain injury. Acquired diseases of prematurity further potentiate the risk for cerebral injury. Systems biology approaches incorporating ante- and post-natal risk factors and analyzing omic and multiomic data using machine learning are promising methodologies for further elucidating biologic mechanisms of fetal and neonatal brain injury.

Keywords: Brain Injury; Intrauterine Infection; Machine Learning; Metabolomics; Multiomics; Perinatal Infection; Perinatal Inflammation; Preterm Birth; Systems Biology; White Matter Injury

DOI: https://doi.org/10.1016/j.expneurol.2022.113988