Abstract
PLacental eXpanded (PLX) cells (Pluristem Therapeutics Inc.) are human placenta-derived, mesenchymal-like adherent stromal cells that release proteins in response to the environment of the host. PLX cells are non-immunogenic and have been shown to decrease inflammation and increase angiogenesis in inflammatory and ischemic conditions. Therefore, we tested whether PLX cell treatment could attenuate symptoms of preeclampsia (PE) in mice. We hypothesized that one-time PLX cell treatment would decrease the pregnancy-dependent hypertension, proteinuria, endothelial dysfunction, splenomegaly, inflammation, and placental injury induced by Toll-like receptor (TLR) activation during pregnancy. Pregnant C57BL/6 mice were given ip injections of saline vehicle (P), the TLR3 agonist poly I:C (PPIC), or the TLR7 agonist R837 (PR) on days 13, 15, and 17 of gestation. P, PPIC, and PR mice were also given either plasmalyte A (PLA, vehicle) or PLX cells (1 million) by im injection in the right leg on gestational day 14 (n=8 in each group). PLX cell treatment progressively decreased SBP over 3 days in PPIC and PR mice and had no effect in P control mice (day 17 SBP in mmHg: P+PLA = 100±4, P+PLX = 96±4, PPIC+PLA = 144±3, PPIC+PLX = 111±1, PR+PLA = 145±2, PR+PLX = 106±3; PPIC+PLA and PR+PLA p<0.05 vs. P+PLA). PLX cell treatment also normalized the urinary protein/creatinine ratio and aortic endothelium-dependent relaxation responses in PPIC and PR mice to that of P mice while having no significant effects on the number of fetuses or incidence of fetal demise per litter. Inflammation plays a central role in the development of TLR-induced PE and PLX cell treatment reduced spleen weight/body weight ratios, normalized splenic levels of gamma-delta T cells, decreased plasma IL-6 levels, and restored plasma IL-4 levels in PPIC and PR mice. Additionally, PLX cell treatment reduced fibrin deposition in the placental vasculature and significantly reduced placental HIF-1alpha protein levels. These data demonstrate that one-time PLX cell treatment after PE is induced was able to decrease inflammation, proteinuric hypertension, endothelial dysfunction, and placental injury in mice and may be beneficial in women with PE.
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