Abstract
Pre-eclampsia (PE) is one of the most severe syndromes in human pregnancy, and the underlying mechanisms of PE have yet to be determined. Pre-eclampsia is characterized by the alteration of the immune system's activation status, an increase in inflammatory Th1/Th17/APC cells, and a decrease in Th2/Treg subsets/cytokines. Moreover, inflammatory infiltrates have been detected in the amniotic membranes of pre-eclamptic placentae, and to this date limited data are available regarding the role of amniotic membrane cells in PE. Interestingly, we and others have previously shown that human amniotic mesenchymal stromal cells (hAMSC) possess anti-inflammatory properties towards almost all immune cells described to be altered in PE. In this study we investigated whether the immunomodulatory properties of hAMSC were altered in PE. We performed a comprehensive study of cell phenotype and investigated the in vitro immunomodulatory properties of hAMSC isolated from pre-eclamptic pregnancies (PE-hAMSC), comparing them to hAMSC from normal pregnancies (N-hAMSC). We demonstrate that PE-hAMSC inhibit CD4/CD8 T-cell proliferation, suppress Th1/Th2/Th17 polarization, induce Treg and block dendritic cells and M1 differentiation switching them to M2 cells. Notably, PE-hAMSC generated a more prominent induction of Treg and higher suppression of interferon-γ when compared to N-hAMSC, and this was associated with higher transforming growth factor-β1 secretion and PD-L2/PD-L1 expression in PE-hAMSC. In conclusion, for the first time we demonstrate that there is no intrinsic impairment of the immunomodulatory features of PE-hAMSC. Our results suggest that amniotic mesenchymal stromal cells do not contribute to the disease, but conversely, could participate in offsetting the inflammatory environment which characterizes PE.
Highlights
Pre-eclampsia is one of the main causes of maternal and foetal morbidity and mortality, causing nearly 40% of premature births delivered before 35 weeks of gestation, and complicating around 2–8% of all pregnancies worldwide [1, 2]
These include those described to be expressed by mesenchymal stem/stromal cells (MSC) (Fig. 1A), co-stimulatory molecules (Fig. 1B), haematopoietic markers (Fig. 1C), human leucocyte antigens (HLA) class I and class II (Fig. 1D), cytokine receptors (Fig. 1E), integrins and adhesion molecules (Fig. 1F), and others (Fig. 1G)
Flow cytometry analysis revealed that the surface marker profile of PE-human amniotic mesenchymal stromal cells (hAMSC) was similar to that of N-hAMSC
Summary
Pre-eclampsia is one of the main causes of maternal and foetal morbidity and mortality, causing nearly 40% of premature births delivered before 35 weeks of gestation, and complicating around 2–8% of all pregnancies worldwide [1, 2]. It is widely accepted that the pathophysiological process of PE begins with an abnormal trophoblast invasion early in pregnancy, which produces increased placental oxidative stress contributing to the development of systemic endothelial dysfunction in the later phases of the disease [2]. In addition to the imbalance of Th1 and Th2 cells, increases of Th17 and reduction in Treg cells have been found in maternal blood [6,7,8] and placenta [9].
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