Huc-MSC-derived exosomal miR-144 alleviates inflammation in LPS-induced preeclampsia-like pregnant rats via the FosB/Flt-1 pathway

Abstract

BackgroundPreeclampsia (PE) is a common and severe hypertensive disorder in pregnancy. Mesenchymal stem cell-derived exosomes (Exos-MSC) have been reported to mitigate the progression of inflammatory diseases. The study aimed to explore the effects of human umbilical cord-derived Exos-MSC (huc-Exos-MSC) on PE-like models. MethodsLipopolysaccharide (LPS) was used to construct in vitro and in vivo PE-like models. Exosomes were treated with LPS-induced PE-like cells and rats. ResultsPE-like inflammatory models of pregnant rats and cells were successfully constructed in vivo and in vitro. miR-144 was screened by bioinformatics analysis. Exosomes were successfully extracted. Silencing FosB, overexpressing miR-144 or treating with exosomes extracted from huc-MSC overexpressing miR-144 in (Exos-MSCmiR−144) reversed the LPS-induced decline in HTR-8/SVneo cell viability and migration. In addition, the above groups decreased LPS-induced increases in interleukin 6 (IL-6), tumor necrosis factor-α (TNF-α), phosphorylated nuclear factor-kappaB (p–NF–κB)/NF-κB, soluble FMS-like tyrosine kinase 1 (sFlt-1), and Flt-1 levels. Simultaneously, transfection of miR-144 mimics and overexpressing FosB reversed those changes in the miR-144 mimics group. miR-144 might alleviate LPS-induced HTR-8/SVneo cell inflammation by targeting FosB. Injection of Exos-MSCmiR−144 in PE-like pregnant rats reversed LPS-induced increases in FosB expression, systolic and diastolic blood pressure (SBP and DBP), as well as mean arterial pressure (MAP), heart rate, urine albumin/creatine ratio, inflammatory factors, p–NF–κB/NF-κB, and sFlt-1 levels. Furthermore, compared with the model group, the proportion of live births was significantly higher in the model + Exos-MSCmiR−144 group, while the apoptosis rate of fetal rat brain tissue was significantly lower. ConclusionsWe found that huc-Exos-MSC-derived miR-144 alleviated gestational hypertension and inflammation in PE-like pregnant rats by regulating the FosB/Flt-1 pathway. In addition, huc-Exos-MSC-derived miR-144 could partially reverse the LPS-induced adverse pregnancy outcome and brain injury in fetal rats, laying the foundation for developing new treatments for PE.