Abstract
Preeclampsia (PE) has been associated with placental dysfunction, resulting in fetal hypoxia, accelerated erythropoiesis, and increased erythroblast count in the umbilical cord blood (UCB). Although the detailed effects remain unknown, placental dysfunction can also cause inflammation, nutritional, and oxidative stress in the fetus that can affect erythropoiesis. Here, we compared the expression of surface adhesion molecules and the erythroid differentiation capacity of UCB hematopoietic stem/progenitor cells (HSPCs), UCB erythroid profiles along with the transcriptome and proteome of these cells between male and female fetuses from PE and normotensive pregnancies. While no significant differences were observed in UCB HSPC migration/homing and in vitro erythroid colony differentiation, the UCB HSPC transcriptome and the proteomic profile of the in vitro differentiated erythroid cells differed between PE vs. normotensive samples. Accordingly, despite the absence of significant differences in the UCB erythroid populations in male or female fetuses from PE or normotensive pregnancies, transcriptional changes were observed during erythropoiesis, particularly affecting male fetuses. Pathway analysis suggested deregulation in the mammalian target of rapamycin complex 1/AMP-activated protein kinase (mTORC1/AMPK) signaling pathways controlling cell cycle, differentiation, and protein synthesis. These results associate PE with transcriptional and proteomic changes in fetal HSPCs and erythroid cells that may underlie the higher erythroblast count in the UCB in PE.
Highlights
Preeclampsia (PE) is a pregnancy related disorder that remains a major cause of maternal and fetal mortality by affecting 3% to 8% of pregnancies worldwide [1]
While no significant differences were observed in umbilical cord blood (UCB) hematopoietic stem/progenitor cells (HSPCs) migration/homing and in vitro erythroid colony differentiation, the UCB HSPC transcriptome and the proteomic profile of the in vitro differentiated erythroid cells differed between PE vs. normotensive samples
This suggests that a mechanism other than hypoxia-induced EPO-dependent enhanced fetal erythropoiesis may affect erythroid maturation, underlying the higher erythroblast count documented in the UCB of PE pregnancies
Summary
Preeclampsia (PE) is a pregnancy related disorder that remains a major cause of maternal and fetal mortality by affecting 3% to 8% of pregnancies worldwide [1]. Previous studies investigating in vitro colony formation of UCB HSPCs have not demonstrated any significant differences in the erythroid differentiation capacity of the cells obtained from PE vs normotensive pregnancies [26,27] This suggests that a mechanism other than hypoxia-induced EPO-dependent enhanced fetal erythropoiesis may affect erythroid maturation, underlying the higher erythroblast count documented in the UCB of PE pregnancies. The effects of these changes on the molecular pathways that control HSPC differentiation and late erythroid maturation in the fetus have not been investigated in detail Another important factor in regulating fetal hemoglobin levels is fetal sex [37,38], which determines the onset of the disease and severity of maternal symptoms in PE [39,40] as well as maternal adaptation to pregnancy [41]. Transcriptome analysis on isolated erythroid cells was performed, with particular attention to sex-specific differences, using SE50bp RNA sequencing
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