Human placenta-derived stromal cells decrease inflammation, placental injury and blood pressure in hypertensive pregnant mice

Abstract

Pre-eclampsia, 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 pre-eclampsia aside from delivery. The development of pre-eclampsia is characterized by maladaptation of the maternal immune system, excessive inflammation and endothelial dysfunction. We have reported that detection of extracellular RNA by the Toll-like receptors (TLRs) 3 and 7 is a key initiating signal that contributes to the development of pre-eclampsia. PLacental eXpanded (PLX-PAD) cells are human placenta-derived, mesenchymal-like, adherent stromal cells that have anti-inflammatory, proangiogenic, 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 pre-eclampsia 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 144-111 mmHg; TLR7 145-106 mmHg; both P<0.05), and also normalized their elevated urinary protein:creatinine ratios (TLR3 5.68-3.72; TLR7 5.57-3.84; both P<0.05). On gestational day 17, aortic endothelium-dependent relaxation responses improved significantly in TLR3-induced and TLR7-induced hypertensive mice that received PLX-PAD cells on gestational day 14 (TLR3 35-65%; TLR7 37-63%; both P<0.05). In addition, 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 pre-eclampsia-like features during pregnancy and have a potential therapeutic role in pre-eclampsia treatment.

Human Placenta Hydrolysate Promotes Liver Regeneration <i>via</i> Activation of the Cytokine/Growth Factor-Mediated Pathway and Anti-oxidative Effect

“…10,11) Over the last few decades, hPH has been prescribed clinically to treat chronic hepatitis, 12,13) liver cirrhosis 14) and other hepatic diseases. 15) hPH reportedly ameliorated hepatic injury through liver regeneration 9) and inhibited inflammatory reactions and apoptosis. 16) Kong and Park recently reported that injection of hPH improved the health status of elderly Koreans.…”

Immune activation by nucleic acids: A role in pregnancy complications

“…TLR3 and TLR7 bind to extracellular RNA and are also thought to initiate a cascade of reactions that leads to inflammation during PE. 34 Hypomethylated DNA, which is found in bacteria as well as DNA from placental cells, activates TLR9. Hypomethylated DNA is especially important during PE when the cffDNA concentration is increased in maternal plasma.…”

“…Caspases mediate nuclear DNA degradation and therefore contribute to increased levels of cffDNA in circulation. TLR3 and TLR7 bind to extracellular RNA and are also thought to initiate a cascade of reactions that leads to inflammation during PE …”

Rescue from lethal acute radiation syndrome (ARS) with severe weight loss by secretome of intramuscularly injected human placental stromal cells

“…The cell product PLX, consisting of placental stromal cells (PSC) from pure maternal tissues, was initially developed and tested pre‐clinically and clinically as an allogeneic cell therapy for treating different chronic conditions for peripheral artery disease (e.g. critical limb ischemia), neurological disorders, pulmonary hypertension, muscle injury and preeclampsia . While conducting a preliminary study on mitigation of radiation effects, cells consisting predominantly of expanded mesenchymal stromal cells of the newborn tissues of the placenta (which we termed PLX‐RAD) were found to be most effective in mitigating ARS.…”

“…critical limb ischemia), neurological disorders, pulmonary hypertension, muscle injury and preeclampsia. 26,40,[58][59][60][61][62] While conducting a preliminary study on mitigation of radiation effects, cells consisting predominantly of expanded mesenchymal stromal cells of the newborn tissues of the placenta (which we termed PLX-RAD) were found to be most effective in mitigating ARS. Following IM injections with PLX-RAD cells to 7.7 Gy pre-irradiated mice, close to 100% survival was recorded, relative to~30% survival of the irradiated untreated controls.…”