Placental Transcriptome Adaptations to Maternal Nutrient Restriction in Sheep

Steinhauser, Chelsie B.; Lambo, C. A.; Askelson, Katharine; Burns, Gregory W.; Behura, Susanta K.; Spencer, Thomas E.; Bazer, Fuller W.; Satterfield, M. Carey

doi:10.3390/ijms22147654

“…To illuminate gestational age-dependent transcriptional changes in across a healthy pregnancy, we collected whole mouse placentas at 48 hr intervals spanning embryonic day 13.5–17.5 (e13.5–e17.5) and quantified mRNA and protein targets that emerged from network analysis of an independently published microarray dataset from healthy mouse pregnancies. Upon searching Gene Expression Omnibus (GEO) ( Edgar et al, 2002 ) datasets for ‘placenta AND transcriptome’, we were surprised that among 326 results, only 9 included data from normal placenta across a series of gestational timepoints extending to late pregnancy ( Knox and Baker, 2008 ; Zhou et al, 2009 ; Loux et al, 2019 ; Soncin et al, 2018 ; Maeda et al, 2019 ; Morey et al, 2021 ; Steinhauser et al, 2021 ; Figure 1 ). We applied weighted gene correlation network analysis (WGCNA) to a microarray study of mouse placenta ( Knox and Baker, 2008 ) (GEO accession GSE11224) spanning e8.5 to postnatal day 0 (p0) to assess the mRNA signature of the aging mouse placenta, using the dataset with the best temporal resolution across gestation.…”

Section: Resultsmentioning

confidence: 99%

Hypoxia-inducible factor 1 signaling drives placental aging and can provoke preterm labor

Ciampa

¹

,

Flahardy

²

,

Srinivasan³

et al. 2023

eLife

View full text Add to dashboard Cite

Most cases of pre-term labor have unknown cause, and the burden of preterm birth is immense. Placental aging has been proposed to promote labor onset, but specific mechanisms remain elusive. We report findings stemming from unbiased transcriptomic analysis of mouse placenta, which revealed that hypoxia-inducible factor 1 (HIF-1) stabilization is a hallmark of advanced gestational timepoints, accompanied by mitochondrial dysregulation and cellular senescence; we detected similar effects in aging human placenta. In parallel in primary mouse trophoblasts and human choriocarcinoma cells, we modeled HIF-1 induction and demonstrated resultant mitochondrial dysfunction and cellular senescence. Transcriptomic analysis revealed that HIF-1 stabilization recapitulated gene signatures observed in aged placenta. Further, conditioned media from trophoblasts following HIF-1 induction promoted contractility in immortalized uterine myocytes, suggesting a mechanism by which the aging placenta may drive the transition from uterine quiescence to contractility at the onset of labor. Finally, pharmacological induction of HIF-1 via intraperitoneal administration of dimethyloxalyl glycine (DMOG) to pregnant mice caused preterm labor. These results provide clear evidence for placental aging in normal pregnancy, and demonstrate how HIF-1 signaling in late gestation may be a causal determinant of the mitochondrial dysfunction and senescence observed within the trophoblast as well as a trigger for uterine contraction.

show abstract

“…To illuminate gestational age-dependent transcriptional changes in across a healthy pregnancy, we collected whole mouse placentas at 48h intervals spanning embryonic day network analysis of an independently published microarray dataset from healthy mouse pregnancies. Upon searching Gene Expression Omnibus (GEO) (21) datasets for "placenta AND transcriptome", we were surprised that among 326 results, only nine included data from normal placenta across a series of gestational timepoints extending to late pregnancy (22)- (28) (Figure 1). We applied weighted gene correlation network analysis (WGCNA) to a microarray study of mouse placenta (22) (GEO accession GSE11224) spanning e8.5 to postnatal day 0 (p0) to assess the mRNA signature of the aging mouse placenta, using the dataset with the best temporal resolution across gestation.…”

Section: Resultsmentioning

confidence: 99%

Hypoxia-inducible factor 1 signaling drives placental aging and can provoke preterm labor

Ciampa

¹

,

Flahardy

²

,

Srinivasan³

et al. 2023

Preprint

0

View full text Add to dashboard Cite

Most cases of pre-term labor have unknown cause, and the burden of preterm birth is immense. Placental aging has been proposed to promote labor onset, but specific mechanisms remain elusive. We report findings stemming from unbiased transcriptomic analysis of mouse placenta, which revealed that hypoxia-inducible factor 1 (HIF-1) stabilization is a hallmark of advanced gestational timepoints, accompanied by mitochondrial dysregulation and cellular senescence; we detected similar effects in aging human placenta. In parallel in primary mouse trophoblasts and human choriocarcinoma cells, we modeled HIF-1 induction and demonstrated resultant mitochondrial dysfunction and cellular senescence. Transcriptomic analysis revealed that HIF-1 stabilization recapitulated gene signatures observed in aged placenta. Further, conditioned media from trophoblasts following HIF-1 induction promoted contractility in immortalized uterine myocytes, suggesting a mechanism by which the aging placenta may drive the transition from uterine quiescence to contractility at the onset of labor. Finally, pharmacological induction of HIF-1 via intraperitoneal administration of dimethyloxalyl glycine (DMOG) to pregnant mice caused preterm labor. These results provide clear evidence for placental aging in normal pregnancy, and demonstrate how HIF-1 signaling in late gestation may be a causal determinant of the mitochondrial dysfunction and senescence observed within the trophoblast as well as a trigger for uterine contraction.

show abstract

“…To illuminate gestational age-dependent transcriptional changes in across a healthy pregnancy, we collected whole mouse placentas at 48h intervals spanning embryonic day 13.5 to 17.5 (e13.5-e17.5) and quantified mRNA and protein targets that emerged from network analysis of an independently published microarray dataset from healthy mouse pregnancies. Upon searching Gene Expression Omnibus (GEO) 21 datasets for "placenta AND transcriptome", we were surprised that among 326 results, only nine included data from normal placenta across a series of gestational timepoints extending to late pregnancy [22][23][24][25][26][27][28] (Figure 1). We applied weighted gene correlation network analysis (WGCNA) to a microarray study of mouse placenta 22 (GEO accession GSE11224) spanning e8.5 to postnatal day 0 (p0) to assess the mRNA signature of the aging mouse placenta, using the dataset with the best temporal resolution across gestation.…”

Section: Resultsmentioning

confidence: 99%

Hypoxia-inducible factor 1 signaling drives placental aging and can provoke preterm labor

Ciampa

¹

,

Flahardy

²

,

Srinivasan

³

et al. 2022

Preprint

View full text Add to dashboard Cite

Most cases of pre-term labor have unknown cause, and the burden of preterm birth on neonatal and child health is immense. Placental aging has been proposed to promote labor onset, but specific mechanisms remain elusive. We report here findings stemming from an unbiased transcriptomic analysis of healthy mouse placenta, which revealed that hypoxia-inducible factor 1 (HIF-1) stabilization is a hallmark of advanced gestational timepoints, accompanied by mitochondrial dysfunction and cellular senescence. We validated these gestational age-associated changes through similar findings in human placenta. In parallel in primary mouse trophoblasts and human choriocarcinoma JAR cells, we modeled HIF-1 induction using prolyl hydroxylase inhibitors cobalt chloride (CoCl2) and dimethyloxalylglycine (DMOG), and demonstrated that mitochondrial dysfunction and cellular senescence occur secondary to HIF-1 stabilization. Whole transcriptome analysis revealed that HIF-1 stabilization in JAR cells recapitulated the dysregulation of several pathways observed in aged placenta. Further, conditioned media from cultured trophoblasts following HIF-1 induction is sufficient to induce a contractile phenotype in immortalized uterine myocytes, suggesting a mechanism by which the aging placenta may help drive the transition from uterine quiescence to contractility at the onset of labor. These results provide clear evidence for placental aging in normal pregnancy. Mechanistic dissection of this phenomenon further demonstrates how hypoxia in late gestation may be both a causal determinant of the mitochondrial dysfunction and senescence observed within the trophoblast as well as a trigger to induce uterine contraction.

show abstract

Placental Transcriptome Adaptations to Maternal Nutrient Restriction in Sheep

Cited by 8 publications

References 56 publications

Hypoxia-inducible factor 1 signaling drives placental aging and can provoke preterm labor

Hypoxia-inducible factor 1 signaling drives placental aging and can provoke preterm labor

Hypoxia-inducible factor 1 signaling drives placental aging and can provoke preterm labor

Hypoxia-inducible factor 1 signaling drives placental aging and can provoke preterm labor

Contact Info

Product

Resources

About