PMID- 33112369
OWN - NLM
STAT- MEDLINE
DCOM- 20211126
LR  - 20211126
IS  - 1529-7268 (Electronic)
IS  - 0006-3363 (Print)
IS  - 0006-3363 (Linking)
VI  - 104
IP  - 2
DP  - 2021 Feb 11
TI  - Mesenchymal stromal cell-derived extracellular vesicle therapy prevents 
      preeclamptic physiology through intrauterine immunomodulationdagger.
PG  - 457-467
LID - 10.1093/biolre/ioaa198 [doi]
AB  - 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.
CI  - (c) 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.
FAU - Taglauer, Elizabeth S
AU  - Taglauer ES
AD  - Division of Newborn Medicine and Department of Pediatrics, Boston Children's 
      Hospital, Boston, MA, USA.
AD  - Department of Pediatrics, Harvard Medical School, Boston, MA, USA.
FAU - Fernandez-Gonzalez, Angeles
AU  - Fernandez-Gonzalez A
AD  - Division of Newborn Medicine and Department of Pediatrics, Boston Children's 
      Hospital, Boston, MA, USA.
AD  - Department of Pediatrics, Harvard Medical School, Boston, MA, USA.
FAU - Willis, Gareth R
AU  - Willis GR
AD  - Division of Newborn Medicine and Department of Pediatrics, Boston Children's 
      Hospital, Boston, MA, USA.
AD  - Department of Pediatrics, Harvard Medical School, Boston, MA, USA.
FAU - Reis, Monica
AU  - Reis M
AD  - Division of Newborn Medicine and Department of Pediatrics, Boston Children's 
      Hospital, Boston, MA, USA.
AD  - Department of Pediatrics, Harvard Medical School, Boston, MA, USA.
FAU - Yeung, Vincent
AU  - Yeung V
AD  - Division of Newborn Medicine and Department of Pediatrics, Boston Children's 
      Hospital, Boston, MA, USA.
AD  - Department of Pediatrics, Harvard Medical School, Boston, MA, USA.
FAU - Liu, Xianlan
AU  - Liu X
AD  - Division of Newborn Medicine and Department of Pediatrics, Boston Children's 
      Hospital, Boston, MA, USA.
AD  - Department of Pediatrics, Harvard Medical School, Boston, MA, USA.
FAU - Mitsialis, S Alex
AU  - Mitsialis SA
AD  - Division of Newborn Medicine and Department of Pediatrics, Boston Children's 
      Hospital, Boston, MA, USA.
AD  - Department of Pediatrics, Harvard Medical School, Boston, MA, USA.
FAU - Kourembanas, Stella
AU  - Kourembanas S
AD  - Division of Newborn Medicine and Department of Pediatrics, Boston Children's 
      Hospital, Boston, MA, USA.
AD  - Department of Pediatrics, Harvard Medical School, Boston, MA, USA.
LA  - eng
GR  - R01 HL146128/HL/NHLBI NIH HHS/United States
GR  - R21 AI134025/AI/NIAID NIH HHS/United States
GR  - T32 HD098061/HD/NICHD NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Biol Reprod
JT  - Biology of reproduction
JID - 0207224
RN  - 0 (Membrane Proteins)
RN  - EC 1.14.14.18 (Heme Oxygenase-1)
RN  - EC 1.14.14.18 (Hmox1 protein, mouse)
SB  - IM
MH  - Animals
MH  - Extracellular Vesicles
MH  - Female
MH  - Fetal Growth Retardation
MH  - Gene Expression Regulation
MH  - Heme Oxygenase-1/genetics/*metabolism
MH  - Humans
MH  - Immunomodulation
MH  - Membrane Proteins/genetics/*metabolism
MH  - Mesenchymal Stem Cells
MH  - Mice
MH  - Mice, Knockout
MH  - Pre-Eclampsia/*prevention & control
MH  - Pregnancy
MH  - Umbilical Cord
MH  - Uterus
PMC - PMC7876668
OTO - NOTNLM
OT  - biologic therapeutics
OT  - dendritic cells
OT  - extracellular vesicles
OT  - fetal growth restriction
OT  - immunomodulation
OT  - macrophages
OT  - mesenchymal stromal cells
OT  - preeclampsia
OT  - uterine natural killer cells
EDAT- 2020/10/29 06:00
MHDA- 2021/11/27 06:00
PMCR- 2021/10/28
CRDT- 2020/10/28 12:11
PHST- 2020/06/12 00:00 [received]
PHST- 2020/09/29 00:00 [revised]
PHST- 2020/10/23 00:00 [accepted]
PHST- 2020/10/29 06:00 [pubmed]
PHST- 2021/11/27 06:00 [medline]
PHST- 2020/10/28 12:11 [entrez]
PHST- 2021/10/28 00:00 [pmc-release]
AID - 5941974 [pii]
AID - ioaa198 [pii]
AID - 10.1093/biolre/ioaa198 [doi]
PST - ppublish
SO  - Biol Reprod. 2021 Feb 11;104(2):457-467. doi: 10.1093/biolre/ioaa198.