Mesenchymal stromal cell-derived extracellular vesicle therapy prevents preeclamptic physiology through intrauterine immunomodulation

Biol Reprod. 2020 Oct 28;ioaa198. doi: 10.1093/biolre/ioaa198. Online ahead of print.

Abstract

Human umbilical cord-derived mesenchymal stromal cells (MSCs) are a widely recognized treatment modality for a variety of pre-clinical disease models and have been transitioned to human clinical trials. We have previously shown in neonatal lung disease that the therapeutic capacity of MSCs is conferred by their secreted extracellular vesicles (MEx), which function primarily through immunomodulation. We hypothesize MEx have significant therapeutic potential pertinent to immune-mediated gestational diseases. Of particular interest is early-onset preeclampsia, which can be caused by alterations of the maternal intrauterine immune environment. Using a heme-oxygenase-1 null mouse model of pregnancy loss with preeclamptic features, we examined the preventative effects of maternal MEx treatment early in pregnancy. Heme oxygenase-1 null females (Hmox1-/-) or wild type (WT) control females were bred in homozygous matings followed by evaluation of maternal and fetal parameters. A single dose of MEx was administered intravenously on gestational day 1 to Hmox1-/- females (Hmox1-/- MEx). Compared to untreated Hmox1-/- females, Hmox1-/- MEx treated pregnancies showed significant improvement in fetal loss, intrauterine growth restriction, placental spiral artery modification and maternal preeclamptic stigmata. Biodistribution studies demonstrated that MEx localize to a subset of cells in the preimplantation uterus. Further, mass cytometric (CyTOF) evaluation of utero-placental leukocytes in Hmox1-/- MEx vs untreated pregnancies showed alteration in the abundance, surface marker repertoire and cytokine profiles of multiple immune populations. Our data demonstrate the therapeutic potential of MEx to optimize the intrauterine immune environment and prevent maternal and fetal sequelae of preeclamptic disease.

Keywords: biologic therapeutics; dendritic cells; extracellular vesicles; fetal growth restriction; immunomodulation; macrophages; mesenchymal stromal cells; preeclampsia; uterine natural killer cells.