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Human placenta-derived stromal cells decrease inflammation, placental injury, and blood pressure in hypertensive pregnant mice.
Preeclampsia, the development of hypertension and proteinuria or end-organ damage during pregnancy, is a leading cause of both maternal and fetal morbidity and mortality and there are no effective clinical treatments for preeclampsia aside from delivery. The development of preeclampsia is characterized by maladaptation of the maternal immune system, excessive inflammation, and endothelial dysfunction. We have reported that detection of extracellular RNA by Toll-like receptors (TLRs) 3 and 7 is a key initiating signal that contributes to the development of preeclampsia. PLacental eXpanded (PLX-PAD; Pluristem Therapeutics, Inc., Haifa, Israel) cells are human placenta-derived, mesenchymal-like adherent stromal cells that have anti-inflammatory, pro-angiogenic, cytoprotective, and regenerative properties secondary to paracrine secretion of various molecules in response to environmental stimulation. We hypothesized that PLX-PAD cells would reduce the associated inflammation and tissue damage and lower blood pressure in mice with preeclampsia induced by TLR3 or TLR7 activation. Injection of PLX-PAD cells on gestational day 14 significantly decreased systolic blood pressure by day 17 in TLR3-induced and TLR7-induced hypertensive mice (TLR3: 144 to 111 mmHg and TLR7: 145 to 106 mmHg; both p<0.05), and also normalized their elevated urinary protein/creatinine ratios (TLR3: 5.68 to 3.72 and TLR7: 5.57 to 3.84; both p<0.05). Gestational day 17 aortic endothelium-dependent relaxation responses improved significantly in TLR3-induced and TLR7-induced hypertensive mice who received PLX-PAD cells on gestational day 14 (TLR3: 35 to 65% and TLR7: 37 to 63%; both p<0.05). Additionally, markers of systemic inflammation and placental injury, increased markedly in both groups of TLR-induced hypertensive mice, were reduced by PLX-PAD cells. Importantly, PLX-PAD cell therapy had no effects on these measures in pregnant control mice or on the fetuses. These data demonstrate that PLX-PAD cell therapy can safely reverse preeclampsia-like features during pregnancy and have a potential therapeutic role in preeclampsia treatment.
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