Biology subjects

Jones, H. N.

Publications and source records attributed to Jones, H. N..

7 recordsLinked to original sources

bioRxiv2026

Plasma Extracellular Vesicle and miRNA Profiles in Pregnancies Complicated by Fetal Congenital Heart Defects

Congenital heart defects (CHDs) are the most common form of fetal malformation however, our understanding of trophoblast health and communication throughout gestation in CHD pregnancies remains limited. The purpose of this study was to assess extracellular vesicles (EVs) and microRNA (miRNA) present in maternal and umbilical cord plasma from a spectrum of CHD subtypes during gestation and at time of delivery. We hypothesized that circulating placenta-derived EVs and miRNA will differ in CHD when compared to controls. Maternal plasma samples were collected between 16-24 weeks of gestation and at the time of delivery. Umbilical cord plasma was obtained following delivery. EVs were isolated from plasma samples using nanoscale flow cytometry, and total EV counts as well as counts by cellular origin were determined. MicroRNA was extracted from maternal plasma and levels quantified using qPCR. Maternal plasma from pregnancies complicated by fetal CHD exhibited higher total EV counts at delivery compared to control. Platelets derived extracellular vesicles (pdEVs) were significantly higher both in maternal and cord blood plasma at the time of delivery in CHD pregnancies compared to gestationally age-matched control pregnancies. Circulating miR22 and miR421 levels were reduced, while miR29c levels were increased in maternal plasma from CHD pregnancies between 16-24 weeks but no differences seen at time of delivery. Pregnancies complicated by CHD are associated with an altered in utero environment by changes in extracellular vesicles and miRNA profile in maternal serum. Circulating EVs and miRNA profiles may therefore serve as minimally invasive indicators of placental and maternal vascular dysfunction in CHD.

cell biology↗

bioRxiv2020

Impaired labyrinth formation prevents the establishment of the maternal-fetal interface in conditional Hand1-deficient mice

IntroductionCongenital heart defects (CHD) affect approximately 1% of all live births, and often require complex surgeries at birth. Placental development and function is vital to ensure normal fetal development. We have previously demonstrated abnormal placental development and vascularization in human CHD placentas, and placental expression changes in genes important for heart development. Hand1 has roles in both heart and placental development and is implicated in CHDs including double right outlet, hypoplastic left heart syndrome, and septal defects; however, Hand1 involvement in placental vascularization and development is under-investigated. We utilized the Hand1A126fs/+ murine model to investigate Hand1 in placentation and vascularization. MethodsHand1A126fs/+ female mice were time-mated with Nkx2.5cre (placenta- and heart-specific) males to produce either Nkx2.5cre;Hand1+/+ or Nkx2.5cre;Hand1A126fs/+ fetuses. Feto-placental units were harvested at timepoints from E8.5 to E14.5 for histological analysis; vascular assessment by immunohistochemistry for Hand1, CD-31, and CK-7; and angiogenesis by qPCR. ResultsEmbryonic lethality occurs in Nkx2.5cre/Hand1A126fs/+ by E14.5 due to a failure of placental labyrinth formation and vascularization. Chorionic trophoblasts did not form, although trophoblast giant cell subtypes were present. Fetal vessels failed to develop properly and were significantly lower in the labyrinth by day E12.5. Placental growth factor levels were significantly increased, and Angiopoietin2 expression trended higher in Nkx2.5cre/Hand1 A126fs/+ placental labyrinths compared to control littermates. ConclusionWe demonstrate that Hand1 expression in placental chorion and trophoblast is necessary for proper patterning of the labyrinth and vascularization within the labyrinth. Multiple angiogenic factors known to be expressed in trophoblast were disrupted in Nkx2.5cre/Hand1 A126fs/+ placental labyrinths compared to control littermates. Alterations in Hand1 expression represent a potential mechanism for abnormal placentation and early miscarriage in cases of CHD.

developmental biology↗

bioRxiv2020

Insulin-like growth factor 1 signaling in the placenta requires endothelial nitric oxide synthase to support trophoblast function and normal fetal growth

Currently, there is no effective treatment for placenta dysfunction in utero. In a ligated mouse model of fetal growth restriction (FGR), nanoparticle-mediated human insulin-like 1 growth factor (hIGF1) gene delivery (NP-Plac1-hIGF1) increased hIGF1 expression and maintained fetal growth. However, whether it can restore fetal growth remains to be determined. Using the endothelial nitric oxide synthase knockout (eNOS-/-) mouse model, a genetic model of FGR, we found that despite inducing expression of hIGF1 in the placentas treated with NP-Plac1-hIGF1 (P=0.0425), FGR did not resolve. This was associated with no change to the number of fetal capillaries in the placenta labyrinth; an outcome increased with NP-Plac1-hIGF1 treatment in the ligated mouse model, despite increased expression of angiopoietin 1 (P=0.05) and suggested IGF1 signaling in the placenta requires eNOS to modulate placenta angiogenesis. To further assess this hypothesis, we used the BeWo Choriocarcinoma cell line and human placenta explant cultures that were treated with NP-Plac1-hIGF1, oxidative stress was induced with hydrogen peroxide (H2O2) and NOS activity inhibited using the inhibitor L-NMMA. In both BeWo and explants, the protective effect of NP-Plac1-hIGF1 treatment against H2O2 induced cell death/lactate dehydrogenase release was prevented by eNOS inhibition (P=0.003 and P<0.0001, respectively). This was associated with an increase in mRNA expression of oxidative stress markers HIF1 (P<0.0001) and ADAM10 (P=0.0002) in the NP-Plac1-hIGF1+H2O2+L-NMMA treated BeWo cells. These findings show for the first time the requirement of eNOS/NOS in IGF1 signaling in placenta cells that may have implications for placental angiogenesis and fetal growth.

physiology↗

bioRxiv2020

Time mating guinea pigs by monitoring changes to the vaginal membrane throughout the estrus cycle and with ultrasound confirmation

Guinea pig development in utero is more similar to humans than any other rodent species. As such, their importance to reproductive studies is evident, particularly those studies focused on therapeutic interventions to improve human pregnancy outcome. Tracking the guinea pig estrus cycle is imperative to ensuring appropriately timed mating and can be performed by monitoring the guinea pig vaginal membrane. Here, we describe, and provide picture representation, of changes to the guinea pig vaginal membrane throughout the estrus cycle. Utilization of this monitoring enabled a 100% pregnancy success rate on the first mating attempt in a cohort of five guinea pigs. This approach, along with early pregnancy ultrasounds as a secondary method to confirm pregnancy, offers a cost effective and reliable approach to timed-mating in the guinea pig.

physiology↗

bioRxiv2020

Placental and fetal characteristics of the Ohia mouse line recapitulate outcomes in human hypoplastic left heart syndrome

Congenital heart defects (CHDs) are the most common birth defect worldwide. The morbidity and mortality associated with these defects is compounded by increased frequency of fetal growth abnormalities. In the Ohia mouse model of hypoplastic left heart syndrome (HLHS), the double homozygous genotype is embryonically lethal at mid-pregnancy; a time in which optimal establishment of the placenta is crucial to fetal survival. We aimed to characterize placental and fetal growth and development in the double heterozygous genotype (Sap130m/+Pcdha9m/+) to determine whether the genetic mutations associated with HLHS in the Ohia mouse also affect the placenta. The frequency of fetuses with reduced weight near term was shifted in the Sap130m/+Pcdha9m/+ fetuses compared to wildtype. This shift in fetal weight distribution in the Sap130m/+Pcdha9m/+ fetuses was associated with reduced labyrinth region area (P<0.001) and reduced fetal capillary density (P<0.001) in the placentas. Positive correlations were observed between fetal weight and placenta mRNA expression of several nutrient transporters in the Sap130m/+Pcdha9m/+ fetuses but not observed in the wildtype. Increased protein expression of Slc7a5 (P<0.05) and Slc7a8 (P<0.05) was also found in the placenta of Sap130m/+Pcdha9m/+ fetuses. This data shows, despite a potential compensatory mechanism to increase nutrient transport, abhorrent placental vascularization leads to inadequate fetal growth in the Ohia mouse model. Such differences are similar to findings in studies of human placentas and highlights the importance of this mouse model in continuing to understand the developmental links and disruptions to the heart-placenta axis.

physiology↗

bioRxiv2018

Abnormalities of placental development and function are associated with the different fetal growth patterns of hypoplastic left heart syndrome and transposition of the great arteries.

BackgroundBirthweight is a critical predictor of congenital heart disease (CHD) surgical outcomes. Hypoplastic left heart syndrome (HLHS) is cyanotic CHD with known fetal growth restriction and placental abnormalities. Transposition of the great arteries (TGA) is cyanotic CHD with normal fetal growth. Comparison of the placenta in these diagnoses may provide insights on the fetal growth abnormality of CHD.\n\nMethodsClinical data and placental histology from placentas associated with Transposition of the Great Arteries (TGA) were analyzed for gross pathology, morphology, maturity and vascularity and compared to both control and previously analyzed HLHS placentas [1]. RNA was isolated from HLHS, TGA and control placentas and sequenced by Illumina HiSeq.Gene, analysis was performed using TopHat, R and MSigDB. Cluster analysis was performed using GoElite and Pathway analysis performed using PANTHERdb Overrepresentation Test. Immunohistochemistry was utilized to assess placental nutrient transporter expression in all three groups.\n\nResultsPlacental weight was reduced in TGA cases, and demonstrated reduced villous vasculature, immature terminal villi, and increased fibrin deposition in the parenchyma compared to controls and reflected our previous data from HLHS placentas. However, birth weight was not reduced in TGA cases compared to controls in contrast to the HLHS cohort and birthweight:placental weight ratio was significantly increased in TGA cases but not HLHS compared to control. Need to include RNA and IHC.\n\nConclusionsDespite common vascular disturbances in placentas from HLHAs and TGA, these do not account for the

physiology↗

bioRxiv2018

Assessing placental maturity through histological and transcriptomic analyses in idiopathic spontaneous preterm birth

Preterm birth (PTB) is leading contributor to infant death in the United States and globally, yet the underlying mechanistic causes are not well understood. Histopathological studies of preterm birth suggest advanced villous maturity may have a role in idiopathic spontaneous preterm birth (isPTB). To better understand pathological and molecular basis of isPTB, we compared placental villous transcriptomes from carefully phenotyped cohorts of PTB due to infection or isPTB between 28-36 weeks gestation and healthy term placentasu. Transcriptomic analyses revealed a unique expression signature for isPTB distinct from the age-matched controls that were delivered prematurely due to infection. This signature included the upregulation of three IGF binding proteins (IGFBP1, IGFBP2, and IGFBP6), supporting a role for aberrant IGF signaling in isPTB. However, within the isPTB expression signature, we detected secondary signature of inflammatory markers including TNC, C3, CFH, and C1R, which have been associated with placental maturity. In contrast, the expression signature of the gestational age-matched infected samples included upregulation of proliferative genes along with cell cycling and mitosis pathways. Together, these data suggest an isPTB molecular signature of placental hypermaturity, likely contributing to the premature activation of inflammatory pathways associated with birth and providing a molecular basis for idiopathic spontaneous birth.

developmental biology↗