Effect of Placenta-Derived Mesenchymal Stromal Cells Conditioned Media on an LPS-Induced Mouse Model of Preeclampsia.

Carola Eva,Laura Moretti,Anna Maria Nuzzo,Paolo Mele,Alessandro Rolfo,Tullia Todros

doi:10.3390/ijms23031674

Abstract

We tested the pro-angiogenic and anti-inflammatory effects of human placenta-derived mesenchymal stromal cells (hPDMSCs)-derived conditioned media (CM) on a mouse model of preeclampsia (PE), a severe human pregnancy-related syndrome characterized by maternal hypertension, proteinuria, endothelial damage, inflammation, often associated with fetal growth restriction (FGR). At d11 of pregnancy, PE was induced in pregnant C57BL/6N mice by bacterial lipopolysaccharide (LPS) intravenous injection. At d12, 300 μL of unconditioned media (control group) or 300 μL PDMSCs-CM (CM group) were injected. Maternal systolic blood pressure was measured from 9 to 18 days of pregnancy. Urine protein content were analyzed at days 12, 13, and 17 of pregnancy. At d19, mice were sacrificed. Number of fetuses, FGR, fetal reabsorption, and placental weight were evaluated. Placentae were analyzed for sFlt-1, IL-6, and TNF-α gene and protein expressions. No FGR and/or reabsorbed fetuses were delivered by PDMSCs-CM-treated PE mice, while five FGR fetuses were found in the control group accompanied by a lower placental weight. PDMSCs-CM injection significantly decreased maternal systolic blood pressure, proteinuria, sFlt-1, IL-6, and TNF-α levels in PE mice. Our data indicate that hPDMSCs-CM can reverse PE-like features during pregnancy, suggesting a therapeutic role for hPDMSCs for the treatment of preeclampsia.

Highlights

The preeclamptic syndrome (PE), exclusive to human pregnancy, represents the main cause of fetal–maternal mortality and morbidity worldwide [1,2]
PDMSCs used for conditioned media (CM) preparation presented proper mesenchymal stromal phenotype as assessed by flow cytometry
In order to determine if PDMSCs-CM treatment was effective at the placental level, we evaluated placental expression of sFlt-1, TNF-α, and IL-6, key hallmarks of preeclampsia, in CM and control mice

Summary

Introduction

The preeclamptic syndrome (PE), exclusive to human pregnancy, represents the main cause of fetal–maternal mortality and morbidity worldwide [1,2]. PE generally resolves at delivery with placenta removal, but it causes severe long-term complications for both the mother and the fetus, such as cardiovascular and neurological disorders, diabetes, and metabolic syndrome [3]. The main problem with preeclampsia is that, as a syndrome, it is multifactorial, a destructive mix of inflammation, endothelial damage, and immunological impairment [2,4]. Key features of PE are a maternal immune maladaptation towards the fetoplacental district with a shift towards Th1 immunity [5,6,7], increased placental release of proinflammatory cytokines (e.g., Tumor Necrosis Factor-α—TNF-α; Interleukin-6–IL-6), and anti-angiogenic factors (e.g., soluble FMS-like tyrosine kinase-1—sFlt-1) that promote aberrant placental angiogenesis and generalized endothelial cell activation and damage [8,9,10,11]. An ideal PE therapeutic approach must be able to contemporarily target all preeclamptic culprits and not to just mitigate a single clinical symptom as hypertension or inflammation

Methods

Results

Conclusion