Joanne C. Mockler

Preterm human amnion epithelial cells have limited reparative potential

The collection and use of stem cells from the fetal membranes as cell therapy for a variety of lung diseases, including preterm lung disease, have been previously proposed. To date, only cells from term amnion have been assessed. In the setting of a future therapy for the preterm neonate, it would be ideal if autologous cells could be given. However, the reparative and anti-inflammatory actions of stem cells isolated from preterm amnions have not been evaluated. In this study, with a view to developing an autologous cell therapy for preterm lung injury, we compared the differentiation potential and efficacy of term versus preterm human amnion epithelial cells (hAECs) to protect against inflammation and fibrosis in a bleomycin mouse model of lung injury. We found that, unlike term hAECs, preterm hAECs did not differentiate into a lung lineage following culture in small airway growth media. Preterm hAECs also exerted significantly less protective effects than term hAEC following acute lung injury. Specifically, preterm hAEC did not improve Ashcroft scoring or collagen deposition in the lung despite a reduction in activated myofibroblasts. Term hAECs expressed double the levels of HLA-G compared to preterm hAECs. These findings indicate that while hAECs can be isolated from term and preterm amnions in similar numbers, they bear distinctive characteristics, which may impact upon their clinical use.

An Australian and New Zealand survey of practice of the use of oxytocin at elective caesarean section

Background:  The use of oxytocin to prevent postpartum haemorrhage at elective caesarean section is largely based on evidence derived from vaginal births. Overseas studies indicate wide variation in practice with regard to specific doses of oxytocin administered at caesarean section. No such surveys have been undertaken in Australia or New Zealand.

Evaluating the Impact of Human Amnion Epithelial Cells on Angiogenesis

The effects of human amnion epithelial cells (hAECs) on angiogenesis remain controversial. It is yet unknown if the presence of inflammation and/or gestational age of hAEC donors have an impact on angiogenesis. In this study, we examined the differences between term and preterm hAECs on angiogenesis in vitro and in vivo. Conditioned media from term hAECs induced the formation of longer huVEC tubules on Matrigel. Both term and preterm hAECs expressed VEGFA, PDGFB, ANGPT1, and FOXC1, which significantly increased after TNFα and IFNγ stimulation. In the presence of TNFα and IFNγ, coculture with term hAECs reduced gene transcription of Tie-2 and Foxc1 in huVECs, while coculture with preterm hAECs increased gene transcription of PDGFRα and PDGFRβ and reduced gene transcription of FOXC1 in huVECs. In vivo assessment of angiogenesis using vWF immunostaining revealed that hAEC treatment decreased angiogenesis in a bleomycin model of lung fibrosis but increased angiogenesis in a neonatal model of hyperoxia-induced lung injury. In summary, our findings suggested that the impact of hAECs on angiogenesis may be influenced by the presence of inflammation and underlying pathology.

The effects of hydroxychloroquine on endothelial dysfunction

Hydroxychloroquine is an anti-malarial drug which, due to its anti-inflammatory and immunomodulatory effects, is widely used for the treatment of autoimmune diseases. In a model of systemic lupus erythematosus hydroxychloroquine has been shown to exert protective endothelial effects. In this study, we aimed to investigate whether hydroxychloroquine was endothelial protective in an in vitro model of TNF-α and preeclamptic serum induced dysfunction. We showed that hydroxychloroquine significantly reduced the production of TNF-α and preeclamptic serum induced endothelin-1 (ET-1). Hydroxychloroquine also significantly mitigated TNF-α induced impairment of angiogenesis. These findings support the further assessment of hydroxychloroquine as an adjuvant therapy in preeclampsia.

Amnion Epithelial Cells Promote Lung Repair via Lipoxin A4

Human amnion epithelial cells (hAECs) have been shown to possess potent immunomodulatory properties across a number of disease models. Recently, we reported that hAECs influence macrophage polarization and activity, and that this step was dependent on regulatory T cells. In this study, we aimed to assess the effects of hAEC‐derived proresolution lipoxin‐A4 (LXA4) on T‐cell, macrophage, and neutrophil phenotype and function during the acute phase of bleomycin‐induced lung injury. Using C57Bl6 mice, we administered 4 million hAECs intraperitoneally 24 hours after bleomycin challenge. Outcomes were measured at days 3, 5, and 7. hAEC administration resulted in significant changes to T‐cell, macrophage, dendritic cell, and monocyte/macrophage infiltration and phenotypes. Endogenous levels of lipoxygenases, LXA4, and the lipoxin receptor FPR2 were elevated in hAEC‐treated animals. Furthermore, we showed that the effects of hAECs on macrophage phagocytic activity and T‐cell suppression are LXA4 dependent, whereas the inhibition of neutrophil‐derived myleoperoxidase by hAECs is independent of LXA4. This study provides the first evidence that lipid‐based mediators contribute to the immunomodulatory effects of hAECs and further supports the growing body of evidence that LXA4 is proresolutionary in lung injury. This discovery of LXA4‐dependent communication between hAECs, macrophages, T cells, and neutrophils is important to the understanding of hAEC biodynamics and would be expected to inform future clinical applications. Stem Cells Translational Medicine 2017;6:1085–1095

Fetal-growth-restricted preterm infants display compromised autonomic cardiovascular control on the first postnatal day but not during infancy

BackgroundFetal growth restriction (FGR) is associated with increased perinatal mortality and long-term cardiovascular and neurodevelopmental sequelae. We hypothesized that FGR impacts on the development of autonomic heart rate and blood pressure control, contributing to unfavorable short- and long-term outcomes following FGR.MethodsWe studied 25 preterm FGR and 22 preterm and 19 term appropriate for gestational age (AGA) infants. Preterm neonates were studied on postnatal day 1, and all infants were studied at 1 and 6 months post-term age. To investigate autonomic cardiovascular control, we examined heart rate variability (HRV) and baroreflex sensitivity using spectral power and transfer-function analyses.ResultsPreterm FGR neonates exhibited higher heart rates and reduced HRV compared with preterm AGA controls on postnatal day 1. No significant differences were found between the three groups at 1 or 6 months post-term age.ConclusionPreterm FGR neonates display compromised HRV on postnatal day 1, which may suggest increased vulnerability to circulatory instability. This may predispose these neonates to systemic and cerebral hypoperfusion and increase the risk of long-term neurodevelopmental sequelae. Differences were no longer found at 1 and 6 months post-term age, suggesting that the maturation of autonomic cardiovascular control may be preserved following FGR.

Maternal 25-hydroxyvitamin D is inversely correlated with foetal serotonin.

Maternal vitamin D deficiency during pregnancy has been linked to impaired neurocognitive development in childhood. The mechanism by which vitamin D affects childhood neurocognition is unclear but may be via interactions with serotonin, a neurotransmitter involved in foetal brain development. In this study, we aimed to explore associations between maternal and foetal vitamin D concentrations, and foetal serotonin concentrations at term.

Obesity and pregnancy outcomes: Do the relationships differ by maternal region of birth? A retrospective cohort study

BackgroundWe aimed to determine whether the association between obesity and a range of adverse maternal and perinatal outcomes differed in South Asian and Australian and New Zealand born women.MethodsA retrospective cohort study of singleton births in South Asian (SA) and Australian/New Zealand (AUS/NZ) born women at an Australian hospital between 2009 and 2013. The interaction between maternal region of birth and obesity on a range of maternal and perinatal outcomes was assessed using multivariate logistic regression.ResultsObesity was more strongly associated with gestational hypertension/Preeclampsia/HELLP and Gestational Diabetes Mellitus in AUS/NZ born women (p = 0.001 and p < 0.001, respectively for interaction) and was only associated with shoulder dystocia in SA born women (p = 0.006 for interaction). There was some evidence that obesity was more strongly related with admission to NICU/Special care nursery (SCN) (p = 0.06 for interaction) and any perinatal morbidity (p = 0.05 for interaction) in SA born women.ConclusionsInterventions targeted at reducing maternal obesity will have different impacts in SA compared to AUS/NZ born women.

Maternal Asian ethnicity and the risk of anal sphincter injury

To examine associations between maternal Asian ethnicity (South Asian and South East/East Asian) and anal sphincter injury.

Non-pharmacological and non-surgical interventions for managing retained placenta

The objective of this study is to evaluate the benefits and harms of non-pharmacological/non-surgical interventions in the management of retained placenta.