Antenatal Mesenchymal Stromal Cell Extracellular Vesicle Therapy Prevents Preeclamptic Lung Injury in Mice

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Abstract
In preeclamptic pregnancies, a variety of intrauterine alterations lead to abnormal placentation, release of inflammatory and/or antiangiogenic factors, and subsequent fetal growth restriction with significant potential to cause a primary insult to the developing fetal lung. Thus, modulation of the maternal intrauterine environment may be a key therapeutic avenue to prevent preeclampsia-associated developmental lung injury. A biologic therapy of interest is mesenchymal stromal cell–derived extracellular vesicles (MEx), which we have previously shown to ameliorate preeclamptic physiology through intrauterine immunomodulation. To evaluate the therapeutic potential of MEx to improve developmental lung injury in experimental preeclampsia, using the heme oxygenase-1–null mouse (Hmox1− /−) model, preeclamptic pregnant dams were administered intravenous antenatal MEx treatment during each week of pregnancy followed by analysis of fetal and postnatal lung tissues, amniotic fluid protein profiles, and lung explant and amniotic fluid cocultures in comparison with control and untreated preeclamptic pregnancies. We first identified that a preeclamptic intrauterine environment had a significant adverse impact on fetal lung development, including alterations in fetal lung developmental gene profiles in addition to postnatal alveolar and bronchial changes. Amniotic fluid proteomic analysis and fetal lung explant and amniotic fluid cocultures further demonstrated that maternally administered MEx altered the expression of multiple inflammatory mediators in the preeclamptic intrauterine compartment, resulting in the normalization of fetal lung branching morphogenesis and developmental gene expression. Our evaluation of fetal and postnatal parameters overall suggests that antenatal MEx treatment may provide a highly valuable preventative therapeutic modality for amelioration of lung development in preeclamptic disease.
Funding Information
  • National Heart, Lung, and Blood Institute (R01 HL146128)
  • National Heart, Lung, and Blood Institute (T32HL007633)
  • Charles H. Hood Foundation (Major Grants Initiative to Advance Child Health)
  • National Institute of Child Health and Human Development (T32HD098061)
  • National Institute of Allergy and Infectious Diseases (R21 AI134025)
  • National Heart, Lung, and Blood Institute (R01 HL146128)
  • National Heart, Lung, and Blood Institute (T32HL007633)
  • Charles H. Hood Foundation (Major Grants Initiative to Advance Child Health)
  • National Institute of Child Health and Human Development (T32HD098061)
  • National Institute of Allergy and Infectious Diseases (R21 AI134025)

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