HUMAN UMBILICAL MESENCHYMAL STEM CELL-DERIVED MITOCHONDRIA AMELIORATE MATERNAL PHENOTYPE BY IMPROVING PLACENTAL MITOCHONDRIAL FUNCTION IN ANGIOTENSIN II-INDUCED RAT PREECLAMPSIA MO

Objective: Preeclampsia (PE) is one of the primary contributors of neonatal and maternal morbidity and mortality. Clinical manifestations of PE include elevated blood pressure and renal dysfunction (albuminuria), 20 weeks into the gestation. Presently, preterm labor, intravenous MgSO4 for vasospasm relief or termination of pregnancy remain the treatments for PE. There is an urgent need to develop effective strategies to prevent PE-associated abnormalities to secure maternal and neonatal health. Here, we investigated the efficacy of mitochondrial transplantation (derived from human umbilical cord mesenchymal stem cells, hUC-MSC) on a rat model of PE. Design and method: A rat model of PE was established by infusing angiotensin-II (Ang II, 1 microg/kg/min) to pregnancy rats (from gestation day 8 for 2 weeks). Mitochondria from hUC-MSC was administered (100microg / <micro>l) via jugular vein on gestation day 14. Results: Blood pressure was increased in Ang II-rats, accompanied by reduced glomerular capillaries, impaired fetal weight and placental vascular development. Soluble fms-like tyrosine kinase 1 (sFlt-1) content was increased in the plasma of Ang II rats, confirming the establishment of PE. Mitochondria from hUC-MSC reversed both fetal and maternal manifestations of PE (fetal weight was increased and blood pressure, glomerular abnormalities and placental vasculature were restored to normal). Mitochondrial biogenesis markers (PGC-1α, NRF1, Tfam) were improved, mitophagy markers (PINK1, BNIP3, BNIP3L, FUNDC 1) and mitochondrial fission markers (DRP1, FIS1) were reduced and mitochondrial fusion markers (OPA1, MFN1, MFN2) were increased in the mitochondria from placental tissue. Reactive oxygen species (ROS) was reduced, activities of ATP synthase and citrate synthase were increased. Further investigations into trophoblast cells and placental tissue revealed elevated sFLT-1 mRNA and protein levels in PE. Additionally, calcineurin protein content and nuclear factor of activated T cells (NFAT) in the nucleus were increased in placental trophoblasts of PE, hUC-MSC reversed the effects. Conclusions: In summary, mitochondria from hUC MSC can be an effective therapeutic modality for the treatment of PE in our rat model. This study sheds light on novel therapeutic options for PE targeting angiogenesis.