Plx-Pad Cell Treatment Mitigate Toll-Like Receptor Induced Preeclampsia Symptomology In Mice

Preeclampsia is a human pregnancy-specific disease, defined as the occurrence of hypertension and significant proteinuria after the 20th week of gestation, and affects 2-6% of previously healthy women. Preeclampsia is characterized by a generalized systemic maternal inflammatory response, placental dysfunction and has no effective treatment except abortion or delivery. PLacenta eXpanded (PLX)-PAD are placenta derived mesenchymal-like adherent stromal cells expanded in Pluristem's proprietary bioreactor system using a three-dimensional culture method. PLX-PAD possess immunomodulatory properties as well as pro-angiogenic and anti-fibrotic properties and have demonstrated a therapeutic potential in various animal models. PLX-PAD are suitable for allogeneic administration without HLA-matching due to their low immunogenicity. . The therapeutic effect of PLX-PAD was tested in a mouse model of preeclampsia. Preeclampsia was generated by intra-peritoneal introduction of either TLR3 agonist (poly I:C) or TLR7 agonist (R837) on days 13, 15, and 17 of gestation in C57BL/6 mice followed by PLX-PAD administration on day 14 of gestation. PLX-PAD treatment resulted in progressive reduction of SBP over a 3 day period and normalization of urinary protein/creatinine ratio and aortic endothelium-dependent relaxation responses within 4 days after treatment. PLX-PAD had no significant effects on the number of fetuses or incidence of fetal demise. PLX-PAD also 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 TLR agonist treated mice. Additionally, PLX-PAD treatment decreased fibrin deposition in the placental vasculature and significantly reduced placental HIF-1alpha protein levels. These data suggest that PLX-PAD treatment is a potential therapy for preeclampsia.