Mesenchymal stromal cell-derived extracellular vesicle therapy prevents preeclamptic physiology through intrauterine immunomodulation†.
biologic therapeutics
dendritic cells
extracellular vesicles
fetal growth restriction
immunomodulation
macrophages
mesenchymal stromal cells
preeclampsia
uterine natural killer cells
Journal
Biology of reproduction
ISSN: 1529-7268
Titre abrégé: Biol Reprod
Pays: United States
ID NLM: 0207224
Informations de publication
Date de publication:
11 02 2021
11 02 2021
Historique:
received:
12
06
2020
revised:
29
09
2020
accepted:
23
10
2020
pubmed:
29
10
2020
medline:
27
11
2021
entrez:
28
10
2020
Statut:
ppublish
Résumé
Human umbilical cord-derived mesenchymal stromal cells (MSCs) are a widely recognized treatment modality for a variety of preclinical 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 that 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 preeclampsia-like features, we examined the preventative effects of maternal MEx treatment early in pregnancy. Heme oxygenase-1 null females (Hmox1-/-) or wild-type 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 (GD)1 to Hmox1-/- females (Hmox1-/- MEx). Compared with 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 versus 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.
Identifiants
pubmed: 33112369
pii: 5941974
doi: 10.1093/biolre/ioaa198
pmc: PMC7876668
doi:
Substances chimiques
Membrane Proteins
0
Heme Oxygenase-1
EC 1.14.14.18
Hmox1 protein, mouse
EC 1.14.14.18
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
457-467Subventions
Organisme : NHLBI NIH HHS
ID : R01 HL146128
Pays : United States
Organisme : NIAID NIH HHS
ID : R21 AI134025
Pays : United States
Organisme : NICHD NIH HHS
ID : T32 HD098061
Pays : United States
Informations de copyright
© The Author(s) 2020. Published by Oxford University Press on behalf of Society for the Study of Reproduction. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
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