Comparative analysis of high field MRI and histology for ex vivo whole organ imaging: assessment of placental functional morphology in a murine model.

OBJECTIVES: The purpose of our study was to evaluate MRI as a tool to examine placental morphology in a murine model in comparison to classical histology techniques. METHODS: Assessment of placental samples (n = 24) from C57Bl/6 J mice was performed using MR imaging and histomorphological analyses. To optimize image contrast for MRI, a protocol for gadolinium-mediated enhancement of placental tissue was established. To test method sensitivity, placental zone assessment with MRI and histology was applied to a model of prenatal stress exposure known to affect placental morphology (n = 10). Mean data acquisition time for both methods was estimated. Difference between groups was calculated using the Mann-Whitney U test. RESULTS: Tissue fixation with formaldehyde and staining with gadolinium resulted in the best image quality. Placental functional zones were identified and measured with both MRI and histology. MRI and histology were able to detect changes in the L/Jz ratio upon a prenatal stress challenge (p = 0.001; p = 0.003). Data acquisition time was shorter using MRI assessment. CONCLUSIONS: Ex vivo MRI analyses of murine placental functional morphology with MRI are feasible and results are comparable to time-consuming histology. Both MRI and histology allow the detection of experimentally induced morphological tissue alterations.

DCE MRI reveals early decreased and later increased placenta perfusion after a stress challenge during pregnancy in a mouse model.

OBJECTIVES: Stress during pregnancy is known to have negative effects on fetal outcome. The purpose of this exploratory study was to examine placental perfusion alterations after stress challenge during pregnancy in a mouse model. MATERIAL AND METHODS: Seven Tesla MRI was performed on pregnant mice at embrionic day (ED) 14.5 and 16.5. Twenty dams were exposed to an established acoustic stress challenge model while twenty non-exposed dams served as controls. Placental perfusion was analyzed in dynamic contrast-enhanced (DCE) MRI using the steepest slope model. The two functional placental compartments, the highly vascularized labyrinth and the endocrine junctional zone, were assessed separately. RESULTS: Statistical analysis revealed decreased perfusion levels in the stress group at ED 14.5 compared to controls in both placenta compartments. On ED 16.5, the perfusion level increased significantly in the stress group while placenta perfusion in controls remained similar or even slightly decreased leading to an overall increased perfusion in the stress group on ED 16.5 compared to controls. CONCLUSION: MR imaging allows noninvasive placenta perfusion assessment in this fetal stress mimicking animal model. In this exploratory study, we demonstrated that stress challenge during pregnancy leads to an initial reduction followed by an increase of placenta perfusion.

Progesterone and HMOX-1 promote fetal growth by CD8+ T cell modulation.

Intrauterine growth restriction (IUGR) affects up to 10% of pregnancies in Western societies. IUGR is a strong predictor of reduced short-term neonatal survival and impairs long-term health in children. Placental insufficiency is often associated with IUGR; however, the molecular mechanisms involved in the pathogenesis of placental insufficiency and IUGR are largely unknown. Here, we developed a mouse model of fetal-growth restriction and placental insufficiency that is induced by a midgestational stress challenge. Compared with control animals, pregnant dams subjected to gestational stress exhibited reduced progesterone levels and placental heme oxygenase 1 (Hmox1) expression and increased methylation at distinct regions of the placental Hmox1 promoter. These stress-triggered changes were accompanied by an altered CD8+ T cell response, as evidenced by a reduction of tolerogenic CD8+CD122+ T cells and an increase of cytotoxic CD8+ T cells. Using progesterone receptor- or Hmox1-deficient mice, we identified progesterone as an upstream modulator of placental Hmox1 expression. Supplementation of progesterone or depletion of CD8+ T cells revealed that progesterone suppresses CD8+ T cell cytotoxicity, whereas the generation of CD8+CD122+ T cells is supported by Hmox1 and ameliorates fetal-growth restriction in Hmox1 deficiency. These observations in mice could promote the identification of pregnancies at risk for IUGR and the generation of clinical interventional strategies.