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Investigating the source of free fetal hemoglobin in preeclampsia. The role of the placenta and the fetus.

Masoumi, Zahra LU orcid (2018) In Lund University, Faculty of Medicine Doctoral Dissertation Series 2018(18).
Abstract
Preeclampsia (PE) is an important pregnancy complication that affects 3-8% of women worldwide and is a leading cause of maternal and fetal morbidity and mortality. It is known that PE is associated with placental dysfunction, resulting in hypoxia, oxidative stress, altered metabolism and production of inflammatory cytokines. Hypoxia could enhance erythropoiesis and induce non-erythroid hemoglobin production. Elevated fetal hemoglobin (HbF) levels in term placentas and maternal circulation, as well as higher erythroblast count in the umbilical cord blood (UCB) have been previously described in PE pregnancies. It has been suggested that free HbF damages and leaks through the placental barrier into the maternal circulation and that could... (More)
Preeclampsia (PE) is an important pregnancy complication that affects 3-8% of women worldwide and is a leading cause of maternal and fetal morbidity and mortality. It is known that PE is associated with placental dysfunction, resulting in hypoxia, oxidative stress, altered metabolism and production of inflammatory cytokines. Hypoxia could enhance erythropoiesis and induce non-erythroid hemoglobin production. Elevated fetal hemoglobin (HbF) levels in term placentas and maternal circulation, as well as higher erythroblast count in the umbilical cord blood (UCB) have been previously described in PE pregnancies. It has been suggested that free HbF damages and leaks through the placental barrier into the maternal circulation and that could trigger inflammation, general endothelial dysfunction and organ damage in the mother. But to date, the source of the increased HbF is unknown.
The aim of this thesis is to elucidate whether altered fetal and placental erythropoiesis and hemolysis could contribute to the excess placental HbF. In addition, the effect of hypoxia-induced oxidative stress on non-erythroid hemoglobin production was analyzed.
Our results indicated an absence of erythropoiesis in term placentas in both PE and normotensive pregnancies. However, hypoxia-triggered oxidative stress induced production of alpha globin protein in non-erythroid cells. Analysis of placental and fetal hematopoietic stem/ progenitor cells (HSPCs) and erythropoiesis (in vitro and in vivo) did not indicate a significant difference in HSPC migration/ homing capacity or erythroid differentiation. However, proteomics and transcriptome analyses of fetal erythroid precursors indicated an imbalance in mammalian target of rapamycin (mTOR)/ AMP-activated protein kinase (AMPK) pathways. Considering that AMPK pathway activation is required for erythroid maturation, this imbalance is therefore suggested to underlie the higher erythroblast count in the UCB.
In summary, our results suggest that hypoxia-induced oxidative stress may lead to non-erythroid globin production in PE placentas. In addition, we propose that PE could lead to an imbalance in mTOR/AMPK pathways in fetal erythroid cells that could hinder their maturation and lead to higher UCB erythroblast count observed in PE. Further analysis is required to indicate the effect of non-erythroid or hemolysisinduced hemoglobin in PE. (Less)
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author
supervisor
opponent
  • Professor Burton, Graham J, University of Cambridge
organization
publishing date
type
Thesis
publication status
published
subject
keywords
Preeclampsia/pregnancy, Placenta, Umbilical cord blood, Fetal erythropoiesis, Non-erythroid globin
in
Lund University, Faculty of Medicine Doctoral Dissertation Series
volume
2018
issue
18
pages
73 pages
publisher
Lund University: Faculty of Medicine
defense location
Segerfalksalen, BMC A10, Sölvegatan 17 i Lund
defense date
2018-05-12 09:00:00
ISSN
1652-8220
ISBN
978-91-7619-581-9
language
English
LU publication?
yes
additional info
ISSN: 1652-8220 Lund University, Faculty of Medicine Doctoral Dissertation Series 2018:14
id
c6a5c82a-90cc-4974-9783-f54ecd9c258f
date added to LUP
2018-05-02 22:20:41
date last changed
2019-11-19 13:49:36
@phdthesis{c6a5c82a-90cc-4974-9783-f54ecd9c258f,
  abstract     = {{Preeclampsia (PE) is an important pregnancy complication that affects 3-8% of women worldwide and is a leading cause of maternal and fetal morbidity and mortality. It is known that PE is associated with placental dysfunction, resulting in hypoxia, oxidative stress, altered metabolism and production of inflammatory cytokines. Hypoxia could enhance erythropoiesis and induce non-erythroid hemoglobin production. Elevated fetal hemoglobin (HbF) levels in term placentas and maternal circulation, as well as higher erythroblast count in the umbilical cord blood (UCB) have been previously described in PE pregnancies. It has been suggested that free HbF damages and leaks through the placental barrier into the maternal circulation and that could trigger inflammation, general endothelial dysfunction and organ damage in the mother. But to date, the source of the increased HbF is unknown.<br/>The aim of this thesis is to elucidate whether altered fetal and placental erythropoiesis and hemolysis could contribute to the excess placental HbF. In addition, the effect of hypoxia-induced oxidative stress on non-erythroid hemoglobin production was analyzed.<br/>Our results indicated an absence of erythropoiesis in term placentas in both PE and normotensive pregnancies. However, hypoxia-triggered oxidative stress induced production of alpha globin protein in non-erythroid cells. Analysis of placental and fetal hematopoietic stem/ progenitor cells (HSPCs) and erythropoiesis (in vitro and in vivo) did not indicate a significant difference in HSPC migration/ homing capacity or erythroid differentiation. However, proteomics and transcriptome analyses of fetal erythroid precursors indicated an imbalance in mammalian target of rapamycin (mTOR)/ AMP-activated protein kinase (AMPK) pathways. Considering that AMPK pathway activation is required for erythroid maturation, this imbalance is therefore suggested to underlie the higher erythroblast count in the UCB.<br/>In summary, our results suggest that hypoxia-induced oxidative stress may lead to non-erythroid globin production in PE placentas. In addition, we propose that PE could lead to an imbalance in mTOR/AMPK pathways in fetal erythroid cells that could hinder their maturation and lead to higher UCB erythroblast count observed in PE. Further analysis is required to indicate the effect of non-erythroid or hemolysisinduced hemoglobin in PE.}},
  author       = {{Masoumi, Zahra}},
  isbn         = {{978-91-7619-581-9}},
  issn         = {{1652-8220}},
  keywords     = {{Preeclampsia/pregnancy; Placenta; Umbilical cord blood; Fetal erythropoiesis; Non-erythroid globin}},
  language     = {{eng}},
  month        = {{05}},
  number       = {{18}},
  publisher    = {{Lund University: Faculty of Medicine}},
  school       = {{Lund University}},
  series       = {{Lund University, Faculty of Medicine Doctoral Dissertation Series}},
  title        = {{Investigating the source of free fetal hemoglobin in preeclampsia. The role of the placenta and the fetus.}},
  url          = {{https://lup.lub.lu.se/search/files/42497840/Masoumi_Z_Kappa.pdf}},
  volume       = {{2018}},
  year         = {{2018}},
}