Publications by authors named "Bill Kalionis"

86 Publications

The Emerging Role of the Prokineticins and Homeobox Genes in the Vascularization of the Placenta: Physiological and Pathological Aspects.

Front Physiol 2020 12;11:591850. Epub 2020 Nov 12.

Department of Maternal-Fetal Medicine, Obstetrics and Gynaecology, Pregnancy Research Centre, Royal Women's Hospital, The University of Melbourne, Parkville, VIC, Australia.

Vasculogenesis and angiogenesis are key processes of placental development, which occur throughout pregnancy. Placental vasculogenesis occurs during the first trimester of pregnancy culminating in the formation of hemangioblasts from intra-villous stem cells. Placental angiogenesis occurs subsequently, forming new blood vessels from existing ones. Angiogenesis also takes place at the fetomaternal interface, allowing essential spiral arteriole remodeling to establish the fetomaternal circulation. Vasculogenesis and angiogenesis in animal models and in humans have been studied in a wide variety of , physiological and pathological conditions, with a focus on the pro- and anti-angiogenic factors that control these processes. Recent studies revealed roles for new families of proteins, including direct participants such as the prokineticin family, and regulators of these processes such as the homeobox genes. This review summarizes recent advances in understanding the molecular mechanisms of actions of these families of proteins. Over the past decade, evidence suggests increased production of placental anti-angiogenic factors, as well as angiogenic factors are associated with fetal growth restriction (FGR) and preeclampsia (PE): the most threatening pathologies of human pregnancy with systemic vascular dysfunction. This review also reports novel clinical strategies targeting members of these family of proteins to treat PE and its consequent effects on the maternal vascular system.
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http://dx.doi.org/10.3389/fphys.2020.591850DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7689260PMC
November 2020

Innate immune responses to malaria-infected erythrocytes in pregnant women: Effects of gravidity, malaria infection, and geographic location.

PLoS One 2020 29;15(7):e0236375. Epub 2020 Jul 29.

Department of Medicine at the Doherty Institute, University of Melbourne, Melbourne, Australia.

Background: Malaria in pregnancy causes maternal, fetal and neonatal morbidity and mortality, and maternal innate immune responses are implicated in pathogenesis of these complications. The effects of malaria exposure and obstetric and demographic factors on the early maternal immune response are poorly understood.

Methods: Peripheral blood mononuclear cell responses to Plasmodium falciparum-infected erythrocytes and phytohemagglutinin were compared between pregnant women from Papua New Guinea (malaria-exposed) with and without current malaria infection and from Australia (unexposed). Elicited levels of inflammatory cytokines at 48 h and 24 h (interferon γ, IFN-γ only) and the cellular sources of IFN-γ were analysed.

Results: Among Papua New Guinean women, microscopic malaria at enrolment did not alter peripheral blood mononuclear cell responses. Compared to samples from Australia, cells from Papua New Guinean women secreted more inflammatory cytokines tumor necrosis factor-α, interleukin 1β, interleukin 6 and IFN-γ; p<0.001 for all assays, and more natural killer cells produced IFN-γ in response to infected erythrocytes and phytohemagglutinin. In both populations, cytokine responses were not affected by gravidity, except that in the Papua New Guinean cohort multigravid women had higher IFN-γ secretion at 24 h (p = 0.029) and an increased proportion of IFN-γ+ Vδ2 γδ T cells (p = 0.003). Cytokine levels elicited by a pregnancy malaria-specific CSA binding parasite line, CS2, were broadly similar to those elicited by CD36-binding line P6A1.

Conclusions: Geographic location and, to some extent, gravidity influence maternal innate immunity to malaria.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0236375PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7390391PMC
September 2020

Decidual mesenchymal stem/stromal cell-derived extracellular vesicles ameliorate endothelial cell proliferation, inflammation, and oxidative stress in a cell culture model of preeclampsia.

Pregnancy Hypertens 2020 Oct 15;22:37-46. Epub 2020 Jul 15.

Department of Maternal-Fetal Medicine Pregnancy Research Centre and University of Melbourne Department of Obstetrics and Gynaecology, Royal Women's Hospital, Parkville, Victoria, Australia.

Oxidative stress and endothelial dysfunction contribute substantially to the pathogenesis of preeclampsia (PE). Decidual mesenchymal stem/stromal cells (DMSC), reportedly reduce endothelial cell dysfunction and alleviate PE-like symptoms in a murine model. However, as a therapeutic strategy, the use of whole DMSC presents significant technical limitations, which may be overcome by employing DMSC-secreted extracellular vesicles (DMSC_EV). DMSC_EV restoration of endothelial dysfunction through a paracrine effect may alleviate the clinical features of PE.

Objective: To determine whether DMSC-secreted, extracellular vesicles (DMSC_EV) restore endothelial cell function and reduce oxidative stress.

Methods: DMSC were isolated from the placentae of uncomplicated term pregnancies and DMSC_EV prepared by ultracentrifugation. Human umbilical vein endothelial cells (HUVEC) were treated with bacterial lipopolysaccharide (LPS), or with serum from PE patients, to model the effects of PE. DMSC_EV were then added to treated HUVEC and their growth profiles, inflammatory state, and oxidative stress levels measured.

Results: DMSC_EV displayed characteristic features of extracellular vesicles. In both LPS- and PE serum-treatment models, addition of DMSC_EV significantly increased HUVEC cell attachment and proliferation, and significantly reduced production of pro-inflammatory cytokine IL-6. The addition of DMSC_EV to LPS-treated HUVEC had no significant effect on total antioxidant capacity, superoxide dismutase levels or on lipid peroxidation levels. In contrast, the addition of DMSC_EV to PE serum-treated HUVEC resulted in a significant reduction in levels of lipid peroxidation.

Conclusion: Addition of DMSC_EV had beneficial effects in both LPS- and PE serum- treated HUVEC but the two treatment models to induce endothelial cell dysfunction showed differences. The LPS treatment of HUVEC model may not accurately model the endothelial cell dysfunction characteristic of PE. Human cell culture models of PE show that DMSC_EV improve endothelial cell dysfunction in PE, but testing in in vivo models of PE is required.
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http://dx.doi.org/10.1016/j.preghy.2020.07.003DOI Listing
October 2020

Functional changes in decidual mesenchymal stem/stromal cells are associated with spontaneous onset of labour.

Mol Hum Reprod 2020 08;26(8):636-651

Department of Maternal-Fetal Medicine Pregnancy Research Centre, Royal Women's Hospital, Parkville, VIC 3052, Australia.

Ageing and parturition share common pathways, but their relationship remains poorly understood. Decidual cells undergo ageing as parturition approaches term, and these age-related changes may trigger labour. Mesenchymal stem/stromal cells (MSCs) are the predominant stem cell type in the decidua. Stem cell exhaustion is a hallmark of ageing, and thus ageing of decidual MSCs (DMSCs) may contribute to the functional changes in decidual tissue required for term spontaneous labour. Here, we determine whether DMSCs from patients undergoing spontaneous onset of labour (SOL-DMSCs) show evidence of ageing-related functional changes compared with those from patients not in labour (NIL-DMSCs), undergoing Caesarean section. Placentae were collected from term (37-40 weeks of gestation), SOL (n = 18) and NIL (n = 17) healthy patients. DMSCs were isolated from the decidua basalis that remained attached to the placenta after delivery. DMSCs displayed stem cell-like properties and were of maternal origin. Important cell properties and lipid profiles were assessed and compared between SOL- and NIL-DMSCs. SOL-DMSCs showed reduced proliferation and increased lipid peroxidation, migration, necrosis, mitochondrial apoptosis, IL-6 production and p38 MAPK levels compared with NIL-DMSCs (P < 0.05). SOL- and NIL-DMSCs also showed significant differences in lipid profiles in various phospholipids (phosphatidylethanolamine, phosphatidylglycerol, phosphatidylinositol, phosphatidylserine), sphingolipids (ceramide, sphingomyelin), triglycerides and acyl carnitine (P < 0.05). Overall, SOL-DMSCs had altered lipid profiles compared with NIL-DMSCs. In conclusion, SOL-DMSCs showed evidence of ageing-related reduced functionality, accumulation of cellular damage and changes in lipid profiles compared with NIL-DMSCs. These changes may be associated with term spontaneous labour.
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http://dx.doi.org/10.1093/molehr/gaaa045DOI Listing
August 2020

Ageing in human parturition: impetus of the gestation clock in the decidua†.

Biol Reprod 2020 10;103(4):695-710

Pregnancy Research Centre, Department of Maternal-Fetal Medicine, Royal Women's Hospital, Parkville, Victoria, Australia.

Despite sharing many common features, the relationship between ageing and parturition remains poorly understood. The decidua is a specialized lining of endometrial tissue, which develops in preparation for pregnancy. The structure and location of the decidua support its role as the physical scaffold for the growing embryo and placenta, and thus, it is vital to sustain pregnancy. Approaching term, the physical support properties of the decidua are naturally weakened to permit parturition. In this review, we hypothesize that the natural weakening of decidual tissue at parturition is promoted by the ageing process. Studies of the ageing-related functional and molecular changes in the decidua at parturition are reviewed and classified using hallmarks of ageing as the framework. The potential roles of decidual mesenchymal stem/stromal cell (DMSC) ageing in labor are also discussed because, although stem cell exhaustion is also a hallmark of ageing, its role in labor is not completely understood. In addition, the potential roles of extracellular vesicles secreted by DMSCs in labor, and their parturition-related miRNAs, are reviewed to gain further insight into this research area. In summary, the literature supports the notion that the decidua ages as the pregnancy progresses, and this may facilitate parturition, suggesting that ageing is the probable impetus of the gestational clocks in the decidua. This conceptual framework was developed to provide a better understanding of the natural ageing process of the decidua during parturition as well as to encourage future studies of the importance of healthy ageing for optimal pregnancy outcomes.
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http://dx.doi.org/10.1093/biolre/ioaa113DOI Listing
October 2020

Correction to: Preconditioning of Human Decidua Basalis Mesenchymal Stem/Stromal Cells with Glucose Increased Their Engraftment and Anti-diabetic Properties.

Tissue Eng Regen Med 2020 06;17(3):401

Stem Cells and Regenerative Medicine Department, King Abdullah International Medical Research Center, King Abdulaziz Medical City, Ministry of National Guard Health Affairs, Mail Code 1515, P.O. Box 22490, Riyadh, 11426, Kingdom of Saudi Arabia.

The author would like to correct the names for the below co-authors in the online published article.
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http://dx.doi.org/10.1007/s13770-020-00251-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7260300PMC
June 2020

Preconditioning of Human Decidua Basalis Mesenchymal Stem/Stromal Cells with Glucose Increased Their Engraftment and Anti-diabetic Properties.

Tissue Eng Regen Med 2020 04 19;17(2):209-222. Epub 2020 Feb 19.

Stem Cells and Regenerative Medicine Department, King Abdullah International Medical Research Center, King Abdulaziz Medical City, Ministry of National Guard Health Affairs, Mail Code 1515, P.O. Box 22490, Riyadh, 11426, Kingdom of Saudi Arabia.

Background: Mesenchymal stem/stromal cells (MSCs) from the decidua basalis (DBMSCs) of the human placenta have important functions that make them potential candidates for cellular therapy. Previously, we showed that DBMSC functions do not change significantly in a high oxidative stress environment, which was induced by hydrogen peroxide (HO) and immune cells. Here, we studied the consequences of glucose, another oxidative stress inducer, on the phenotypic and functional changes in DBMSCs.

Methods: DBMSCs were exposed to a high level of glucose, and its effect on DBMSC phenotypic and functional properties was determined. DBMSC expression of oxidative stress and immune molecules after exposure to glucose were also identified.

Results: Conditioning of DBMSCs with glucose improved their adhesion and invasion. Glucose also increased DBMSC expression of genes with survival, proliferation, migration, invasion, anti-inflammatory, anti-chemoattractant and antimicrobial properties. In addition, DBMSC expression of B7H4, an inhibitor of T cell proliferation was also enhanced by glucose. Interestingly, glucose modulated DBMSC expression of genes involved in insulin secretion and prevention of diabetes.

Conclusion: These data show the potentially beneficial effects of glucose on DBMSC functions. Preconditioning of DBMSCs with glucose may therefore be a rational strategy for increasing their therapeutic potential by enhancing their engraftment efficiency. In addition, glucose may program DBMSCs into insulin producing cells with ability to counteract inflammation and infection associated with diabetes. However, future in vitro and in vivo studies are essential to investigate the findings of this study further.
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http://dx.doi.org/10.1007/s13770-020-00239-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7105536PMC
April 2020

Combined Antioxidant, Anti-inflammaging and Mesenchymal Stem Cell Treatment: A Possible Therapeutic Direction in Elderly Patients with Chronic Obstructive Pulmonary Disease.

Aging Dis 2020 Feb 1;11(1):129-140. Epub 2020 Feb 1.

6Department of Thoracic Surgery, Huadong Hospital, Fudan University, Shanghai, China.

Chronic Obstructive Pulmonary Disease (COPD) is a worldwide health problem associated with high morbidity and mortality, especially in elderly patients. Aging functions include mitochondrial dysfunction, cell-to-cell information exchange, protein homeostasis and extracellular matrix dysregulation, which are closely related to chronic inflammatory response and oxidation-antioxidant imbalance in the pathogenesis of COPD. COPD displays distinct inflammaging features, including increased cellular senescence and oxidative stress, stem cell exhaustion, alterations in the extracellular matrix, reduced levels of endogenous anti-inflammaging molecules, and reduced autophagy. Given that COPD and inflammaging share similar general features, it is very important to identify the specific mechanisms of inflammaging, which involve oxidative stress, inflammation and lung mesenchymal stem cell function in the development of COPD, especially in elderly COPD patients. In this review, we highlight the studies relevant to COPD progression, and focus on mechanisms associated with inflammaging.
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http://dx.doi.org/10.14336/AD.2019.0508DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6961773PMC
February 2020

The role of insulin-like growth factor 2 receptor-mediated homeobox gene expression in human placental apoptosis, and its implications in idiopathic fetal growth restriction.

Mol Hum Reprod 2019 09;25(9):572-585

University of Melbourne Department of Obstetrics and Gynaecology, Royal Women's Hospital, Parkville, Victoria, Australia.

Fetal growth restriction (FGR) is caused by poor placental development and function early in gestation. It is well known that placentas from women with FGR exhibit reduced cell growth, elevated levels of apoptosis and perturbed expression of the growth factors, cytokines and the homeobox gene family of transcription factors. Previous studies have reported that insulin-like growth factor-2 (IGF2) interacts with its receptor-2 (IGF2R) to regulate villous trophoblast survival and apoptosis. In this study, we hypothesized that human placental IGF2R-mediated homeobox gene expression is altered in FGR and contributes to abnormal trophoblast function. This study was designed to determine the association between IGF2R, homeobox gene expression and cell survival in pregnancies affected by FGR. Third trimester placentas were collected from FGR-affected pregnancies (n = 29) and gestation matched with control pregnancies (n = 30). Functional analyses were then performed in vitro using term placental explants (n = 4) and BeWo trophoblast cells. mRNA expression was determined by real-time PCR, while protein expression was examined by immunoblotting and immunohistochemistry. siRNA transfection was used to silence IGF2R expression in placental explants and the BeWo cell-line. cDNA arrays were used to screen for downstream targets of IGF2R, specifically homeobox gene transcription factors and apoptosis-related genes. Functional effects of silencing IGF2R were then verified by β-hCG ELISA, caspase activity assays and a real-time electrical cell-impedance assay for differentiation, apoptosis and cell growth potential, respectively. IGF2R expression was significantly decreased in placentas from pregnancies complicated by idiopathic FGR (P < 0.05 versus control). siRNA-mediated IGF2R knockdown in term placental explants and the trophoblast cell line BeWo resulted in altered expression of homeobox gene transcription factors, including increased expression of distal-less homeobox gene 5 (DLX5), and decreased expression of H2.0-Like Homeobox 1 (HLX) (P < 0.05 versus control). Knockdown of IGF2R transcription increased the expression and activity of caspase-6 and caspase-8 in placental explants, decreased BeWo proliferation and increased BeWo differentiation (all P < 0.05 compared to respective controls). This is the first study linking IGF2R placental expression with changes in the expression of homeobox genes that control cellular signalling pathways responsible for increased trophoblast cell apoptosis, which is a characteristic feature of FGR.
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http://dx.doi.org/10.1093/molehr/gaz047DOI Listing
September 2019

Placenta Stem/Stromal Cell-Derived Extracellular Vesicles for Potential Use in Lung Repair.

Proteomics 2019 09;19(17):e1800166

Sydney Pharmacy School, Faculty of Medicine and Health, The University of Sydney, New South Wales, 2006, Australia.

Many acute and chronic lung injuries are incurable and rank as the fourth leading cause of death globally. While stem cell treatment for lung injuries is a promising approach, there is growing evidence that the therapeutic efficacy of stem cells originates from secreted extracellular vesicles (EVs). Consequently, EVs are emerging as next-generation therapeutics. While EVs are extensively researched for diagnostic applications, their therapeutic potential to promote tissue repair is not fully elucidated. By housing and delivering tissue-repairing cargo, EVs refine the cellular microenvironment, modulate inflammation, and ultimately repair injury. Here, the potential use of EVs derived from two placental mesenchymal stem/stromal cell (MSC) lines is presented; a chorionic MSC line (CMSC29) and a decidual MSC cell line (DMSC23) for applications in lung diseases. Functional analyses using in vitro models of injury demonstrate that these EVs have a role in ameliorating injuries caused to lung cells. It is also shown that EVs promote repair of lung epithelial cells. This study is fundamental to advancing the field of EVs and to unlock the full potential of EVs in regenerative medicine.
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http://dx.doi.org/10.1002/pmic.201800166DOI Listing
September 2019

Iron Deposition Leads to Hyperphosphorylation of Tau and Disruption of Insulin Signaling.

Front Neurol 2019 19;10:607. Epub 2019 Jun 19.

Department of Neurology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Iron deposition in the brain is an early issue in Alzheimer's disease (AD). However, the pathogenesis of iron-induced pathological changes in AD remains elusive. Insulin resistance in brains is an essential feature of AD. Previous studies determined that insulin resistance is involved in the development of pathologies in AD. Tau pathology is one of most important hallmarks in AD and is associated with the impairment of cognition and clinical grades of the disease. In the present study, we observed that ferrous (Fe) chloride led to aberrant phosphorylation of tau, and decreased tyrosine phosphorylation levels of insulin receptor β (IRβ), insulin signal substrate 1 (IRS-1) and phosphoinositide 3-kinase p85α (PI3K p85α), in primary cultured neurons. In the studies using mice with supplemented dietary iron, learning and memory was impaired. As well, hyperphosphorylation of tau and disrupted insulin signaling in the brain was induced in iron-overloaded mice. Furthermore, in our work we identified the activation of insulin signaling following exogenous supplementation of insulin. This was further attenuated by iron-induced hyperphosphorylation of tau in primary neurons. Together, these data suggest that dysfunctional insulin signaling participates in iron-induced abnormal phosphorylation of tau in AD. Our study highlights the promising role of insulin signaling in pathological lesions induced by iron overloading.
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http://dx.doi.org/10.3389/fneur.2019.00607DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6593079PMC
June 2019

Isolation and Characterization of Extracellular Vesicles from Mesenchymal Stromal Cells.

Methods Mol Biol 2019 ;2029:15-23

Faculty of Medicine and Health, The University of Sydney School of Pharmacy, Sydney, NSW, Australia.

Extracellular vesicles (EVs) have received immense attention in the past decade for their diverse use in diagnosis and therapeutics. Enhancing our understanding of EVs and increasing the reliability and reproducibility of EV research demands the use of standard isolation procedures and multiple characterization methods. Here we describe the most commonly used EV isolation method involving ultracentrifugation, and various characterization methods that include nanoparticle tracking analysis, atomic force microscopy and electron microscopy, which measure the size, concentration, and morphology of EVs.
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http://dx.doi.org/10.1007/978-1-4939-9631-5_2DOI Listing
April 2020

Valproic acid stimulates migration of the placenta-derived mesenchymal stem/stromal cell line CMSC29.

Stem Cell Investig 2019 13;6. Epub 2019 Feb 13.

Department of Maternal-Fetal Medicine, Pregnancy Research Centre, Royal Women's Hospital, Parkville, Victoria 3052, Australia.

Background: The placenta is an abundant source of mesenchymal stem/stromal cells (MSC), but our understanding of their functional properties remains limited. We previously created a placental-derived chorionic MSC (CMSC) cell line to overcome the difficulties associated with conducting extensive optimization and experimental work on primary cells. The aim of this study was to characterize the migratory behavior of the CMSC29 cell line .

Methods: Stimulators of MSC migration, including two cytokines, stromal cell-derived factor-1α (SDF-1α) and hepatocyte growth factor (HGF), and a pharmacological agent, valproic acid (VPA), were tested for their ability to stimulate CMSC29 cell migration. Assessment of cell migration was performed using the xCELLigence Real-Time Cell Analyzer (RTCA).

Results: There was no significant increase in CMSC29 cell migration towards serum free medium with increasing concentration gradients of SDF-1α or HGF. In contrast, treating CMSC29 cells with VPA alone significantly increased their migration towards serum free medium.

Conclusions: Immortalized CMSC29 cells retain important properties of primary CMSC, but their migratory properties are altered. CMSC29 cells do not migrate in response to factors that reportedly stimulate primary MSC/CMSC migration. However, CMSC29 increase their migration in response to VPA treatment alone. Further studies are needed to determine the mechanism by which VPA acts alone to stimulate CMSC29 migration. Still, this study provides evidence that VPA pre-treatment may improve the benefits of cell-based therapies that employ certain MSC sub-types.
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http://dx.doi.org/10.21037/sci.2019.01.01DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6414337PMC
February 2019

An human placental vessel perfusion method to study mesenchymal stem/stromal cell migration.

Stem Cell Investig 2019 2;6. Epub 2019 Jan 2.

Pregnancy Research Centre, Department of Maternal-Fetal Medicine, Royal Women's Hospital, Parkville, Victoria 3052, Australia.

Background: To initiate tissue repair, mesenchymal stem/stromal cells (MSCs) must enter the blood stream, migrate to the targeted area, cross the endothelial barrier and home to the damaged tissue. This process is not yet fully understood in humans and thus, the aim of this study was to develop an placental vessel perfusion method to examine human MSC movement from a blood vessel into human tissue. This will provide a better understanding of MSC migration, movement through the endothelial barrier and engraftment into target tissue, in a setting that more closely represents the state, compared with conventional human cell culture models. Moreover, important similarities and differences to animal experimental model systems may be revealed by this method.

Methods: Human placental hTERT transformed MSC lines were labelled with live-cell fluorescence dyes, and then perfused into term human placental blood vessel. After labelled MSCs were perfused into the vessel, the vessel was dissected from the placenta and incubated at cell growth conditions. Following incubation, the vessel was washed thoroughly to remove unattached, labelled MSCs and then snap frozen for sectioning. After sectioning, immunofluorescence staining of the endothelium was carried out to detect if labelled MSCs crossed the endothelial barrier.

Results: Twelve placental vessel perfusions were successfully completed. In eight of the twelve perfused vessels, qualitative assessment of immunofluorescence in sections (n=20, 5 µm sections/vessel) revealed labelled MSCs had crossed the endothelial barrier.

Conclusions: The human placental vessel perfusion method could be used to assess human MSC migration into human tissue. Cells of the MSC lines were able to adhere and transmigrate through the endothelial barrier in a manner similar to that of leukocytes. Notably, cells that transmigrated remained in close proximity to the endothelium, which is consistent with the reported MSC vascular niche in placental blood vessels.
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http://dx.doi.org/10.21037/sci.2018.12.03DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6378240PMC
January 2019

Decidua Basalis Mesenchymal Stem Cells Favor Inflammatory M1 Macrophage Differentiation In Vitro.

Cells 2019 02 18;8(2). Epub 2019 Feb 18.

Stem Cells and Regenerative Medicine Department, King Abdullah International Medical Research Center, King Abdulaziz Medical City, Ministry of National Guard Health Affairs, P.O. Box 22490, Riyadh 11426, Mail Code 1515, Saudi Arabia.

Placental mesenchymal stem cells from maternal decidua basalis tissue (DBMSCs) are promising cells for tissue repair because of their multilineage differentiation and ability to protect endothelial cells from injury. Here, we examined DBMSC interaction with macrophages and whether this interaction could modulate the characteristics and functions of these macrophages. We induced monocytes to differentiate into M1-like macrophages in the presence of DBMSCs. DBMSC effects on differentiation were evaluated using microscopy, flow cytometry, and ELISA. DBMSC effects on M1-like macrophage induction of T cell function were also examined. The culture of DBMSCs with monocytes did not inhibit monocyte differentiation into M1-like inflammatory macrophages. This was confirmed by the morphological appearance of M1-like macrophages, increased expression of inflammatory molecules, and reduced expression of anti-inflammatory molecules. In addition, DBMSCs did not interfere with M1-like macrophage phagocytic activity; rather, they induced stimulatory effects of M1-like macrophages on CD4⁺ T cell proliferation and subsequent secretion of inflammatory molecules by T cells. We showed that DBMSCs enhanced the differentiation of M1-like inflammatory macrophages, which function as antitumor cells. Therefore, our findings suggest that DBMSCs are inflammatory cells that could be useful in cancer treatment via the enhancement of M1- like macrophages.
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http://dx.doi.org/10.3390/cells8020173DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6406276PMC
February 2019

High-fidelity probing of the structure and heterogeneity of extracellular vesicles by resonance-enhanced atomic force microscopy infrared spectroscopy.

Nat Protoc 2019 02;14(2):576-593

Faculty of Medicine and Health, Sydney Pharmacy School, The University of Sydney, Sydney, NSW, Australia.

Extracellular vesicles (EVs) are highly specialized nanoscale assemblies that deliver complex biological cargos to mediate intercellular communication. EVs are heterogeneous, and characterization of this heterogeneity is paramount to understanding EV biogenesis and activity, as well as to associating them with biological responses and pathologies. Traditional approaches to studying EV composition generally lack the resolution and/or sensitivity to characterize individual EVs, and therefore the assessment of EV heterogeneity has remained challenging. We have recently developed an atomic force microscope IR spectroscopy (AFM-IR) approach to probe the structural composition of single EVs with nanoscale resolution. Here, we provide a step-by-step procedure for our approach and show its power to reveal heterogeneity across individual EVs, within the same population of EVs and between different EV populations. Our approach is label free and able to detect lipids, proteins and nucleic acids within individual EVs. After isolation of EVs from cell culture medium, the protocol involves incubation of the EV sample on a suitable substrate, setup of the AFM-IR instrument and collection of nano-IR spectra and nano-IR images. Data acquisition and analyses can be completed within 24 h, and require only a basic knowledge of spectroscopy and chemistry. We anticipate that new understanding of EV composition and structure through AFM-IR will contribute to our biological understanding of EV biology and could find application in disease diagnosis and the development of EV therapies.
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http://dx.doi.org/10.1038/s41596-018-0109-3DOI Listing
February 2019

Genistein protects against acute pancreatitis via activation of an apoptotic pathway mediated through endoplasmic reticulum stress in rats.

Biochem Biophys Res Commun 2019 02 26;509(2):421-428. Epub 2018 Dec 26.

Department of Emergency Medicine, Huadong Hospital, Fudan University, Shanghai, 200040, PR China. Electronic address:

Acute pancreatitis (AP) is a severe and frequently lethal disorder, but the precise mechanisms are not well understood and there is lack of effective drugs. Therefore, our study examined the in vivo intervention effects of genistein and elucidated its mechanism in acute experimental pancreatitis models. We used cerulein or taurocholate to induce acute pancreatitis (AP) in Sprague-Dawley rats with prior genistein treatment. Histological examination of the pancreas was performed and the expression of unfolded protein response (UPR) components and apoptotic mediators like caspase 12 and c-Jun N-terminal protein kinase (JNK) were measured. The amount of apoptosis in pancreatic acinar cells was also determined. Our studies found that the severity of cerulein- or taurocholate-induced AP was rescued by prior genistein treatment. Genistein stimulated the activation of multiple endoplasmic reticulum (ER) stress-related regulators like GRP78, PERK, eIF2α, and upregulated the expression of the apoptotic genes, caspase 12 and CHOP. Moreover, TUNEL assays showed that genistein treatment promoted acinar cell apoptosis. Taken together, we speculated that ER stress-associated apoptotic pathways in AP are induced by genistein, which showed cytoprotective capacity in the exocrine pancreas. These data suggest novel therapeutic strategies that employ genistein in the prevention of AP.
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http://dx.doi.org/10.1016/j.bbrc.2018.12.108DOI Listing
February 2019

Pancreatic carcinoma underlying a complex presentation in late pregnancy: a case report.

J Med Case Rep 2018 Dec 15;12(1):369. Epub 2018 Dec 15.

Department of Maternal-Fetal Medicine Pregnancy Research Centre, Royal Women's Hospital, Parkville, Australia.

Background: Gestational diabetes mellitus is strongly related to the risk of pancreatic cancer in pregnant women, but gestational diabetes can precede a diagnosis of pancreatic cancer by many years. Women with a history of gestational diabetes showed a relative risk of pancreatic cancer of 7.1. Pancreatic adenocarcinoma is one of the most common malignancies associated with thromboembolic events. A clinical study showed that thromboembolic events were detected in 36% of patients diagnosed as having pancreatic cancer. Studies showed that gestational diabetes mellitus could be one of the important risk factors for pancreatic cancer.

Case Presentation: Gestational diabetes mellitus is associated with increased risk of breast and pancreatic cancer. This case report describes a 29-year-old Chinese woman who presented with: gestational diabetes mellitus; International Society on Thrombosis and Haemostasis criteria suggested disseminated intravascular coagulation with a score of 5; hemolysis, elevated liver enzymes, low platelet count syndrome; and pulmonary hypertension. After an intravenous injection of fibrinogen, she gave birth to a normal baby and following delivery, her blood pressure reached 180/110 mmHg. Laboratory analysis results showed elevated lactic dehydrogenase, decreased platelets and fibrinogen, and urine protein was positive. She was transfused with fresh frozen plasma, blood coagulation factor, and fibrinogen. Subsequently, she was transferred to a maternity intensive care unit, where magnesium sulfate seizure prophylaxis was continued for 24 hours to keep her magnesium level at a low therapeutic range. However, continuous oxygen therapy was needed to maintain her oxygenation. Further laboratory investigations revealed elevated carcinoembryonic antigen, carbohydrate antigen 19-9, and carbohydrate antigen 72-4. Positron emission tomography-computed tomography showed malignant carcinoma in the head of her pancreas with lymph node involvement along with bone, peritoneal, and left adrenal metastasis, as well as double lung lymphangitic carcinomatosis.

Conclusion: A differential diagnosis of digestive system neoplasm should be considered when a pregnant patient presents with gestational diabetes mellitus and disseminated intravascular coagulation, where the disseminated intravascular coagulation has no specific cause and cannot be readily resolved.
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http://dx.doi.org/10.1186/s13256-018-1911-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6295019PMC
December 2018

Improved ex vivo expansion of mesenchymal stem cells on solubilized acellular fetal membranes.

J Biomed Mater Res A 2019 01 31;107(1):232-242. Epub 2018 Oct 31.

Department of Biomedical Engineering, Particulate Fluids Processing Centre, The University of Melbourne, Parkville, Victoria, Australia.

Coatings produced from extracellular matrixes (ECMs) have emerged as promising surfaces for the improved ex vivo expansion of mesenchymal stem cells (MSCs). However, identifying a readily available source of ECM to generate these coatings is currently the bottleneck of this technology. In this study, we assessed if ECM coatings derived from decellularized fetal membranes were a suitable substrate for MSC expansion. We separated and decellularized the two main components of the fetal membranes, the amnion and the chorion. Characterization of the decellularized membranes revealed that each membrane component has a distinct composition, implying that coatings produced from these materials would have unique biological properties. The membranes were processed further to produce solubilized forms of the decellularized amniotic membrane (s-dAM) and decellularized chorionic membrane (s-dCM). On s-dAM coatings decidual MSCs (DMSC) were more proliferative than those cultured on tissue culture plastic alone or on Matrigel coatings; were smaller in size (a measure of MSC potency); exhibited greater adipogenic differentiation capacity; and improved osteogenic capacity. Additionally, long term culture studies showed late passage DMSCs (passage 8) cultured on s-dAM showed a decrease in cell diameter over three passages. These data support the use of s-dAM as a substrate for improved MSC expansion. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 107A: 232-242, 2019.
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http://dx.doi.org/10.1002/jbm.a.36557DOI Listing
January 2019

Low-dose aspirin treatment enhances the adhesion of preeclamptic decidual mesenchymal stem/stromal cells and reduces their production of pro-inflammatory cytokines.

J Mol Med (Berl) 2018 11 1;96(11):1215-1225. Epub 2018 Oct 1.

Department of Maternal-Fetal Medicine Pregnancy Research Centre, The Royal Women's Hospital, Parkville, Victoria, Australia.

Preeclampsia (PE) is a hypertensive disorder of human pregnancy. Low-dose aspirin (acetylsalicylic acid) (60-150 mg/day) is used to prevent PE when taken early in pregnancy. The effect of aspirin on term PE remains uncertain. Abnormal placentation is a hallmark of PE and leads to increased placental oxidative stress, which triggers the release of anti-angiogenic factors that cause local damage to the decidual vasculature. The damage subsequently spreads systemically and culminates in maternal clinical symptoms. Decidua basalis mesenchymal stem/stromal cells (DMSCs) reside in a vascular microenvironment. In PE, DMSCs are exposed to abnormally high levels of oxidative stress and circulating inflammatory factors from the maternal blood. We previously showed that colony-forming unit ability and resistance to oxidative stress in DMSCs are reduced in MSCs derived from term PE pregnancies (PE-DMSCs). The action, if any, of aspirin on term PE-DMSCs has not been reported. In this study, aspirin (5 μg/mL) was found to significantly increase PE-DMSC adhesion compared to untreated PE-DMSCs and gestation-matched control DMSCs (p value < 0.001) but had no effect on PE-DMSC proliferation. ELISA analysis showed that aspirin significantly decreased the production of inflammatory cytokines IFN-γ (p value < 0.05) and IL-8 (p value < 0.001) in PE-DMSCs. In addition, aspirin treatment increased the antioxidant capacity of PE-DMSCs compared with the untreated group (p value < 0.05). This study is the first to reveal a novel, beneficial action of aspirin on PE-DMSCs from term PE pregnancies by improving their adhesion, suppressing their production of pro-inflammatory cytokines production, and increasing their antioxidant capacity. KEY MESSAGES: Preeclampsia (PE) is a serious hypertensive disorder of pregnancy. The risk of PE is reduced by aspirin but the mechanism is poorly understood. Decidua basalis mesenchymal stem/stromal cells (DMSCs) are abnormal in PE. Aspirin treatment improves multiple functions of PE-DMSCs. Improved DMSC function may contribute to the beneficial effect of aspirin.
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http://dx.doi.org/10.1007/s00109-018-1695-9DOI Listing
November 2018

None of us is the same as all of us: resolving the heterogeneity of extracellular vesicles using single-vesicle, nanoscale characterization with resonance enhanced atomic force microscope infrared spectroscopy (AFM-IR).

Nanoscale Horiz 2018 Jul 13;3(4):430-438. Epub 2018 Apr 13.

Faculty of Pharmacy, The University of Sydney, NSW, Australia.

Extracellular vesicles (EVs) are highly specialized, nanoscale messengers that deliver biological signals and in doing so mediate intercellular communication. Increasing evidence shows that within populations of EVs, important properties including morphology, membrane composition, and content vary substantially. This heterogeneity arises in response to the nature, state, and environmental conditions of the cell source. However, currently there are no effective approaches, which unequivocally discriminate differences between individual EVs, which critically hampers progress in this emerging scientific area. Measuring EV heterogeneity is paramount to our understanding of how EVs influence the physiological and pathological functions of their target cells. Moreover, understanding EV heterogeneity is essential for their application as diagnostics and therapeutics. We propose an innovative approach using resonance enhanced atomic force microscope infrared spectroscopy (AFM-IR) to identify the nanoscale structural composition of EVs, as demonstrated and validated using EVs derived from two types of placenta stem cells. The particular strength of this approach is that it is a label-free and ultra-high sensitivity technique that has the power to measure individual EV heterogeneity. New insights gained by this method into EV heterogeneity will have a profound impact not only on our basic understanding of EV biology but also on disease diagnostics and the emerging area of EV-therapies.
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http://dx.doi.org/10.1039/c8nh00048dDOI Listing
July 2018

Characteristics of circular RNA expression in lung tissues from mice with hypoxia‑induced pulmonary hypertension.

Int J Mol Med 2018 Sep 21;42(3):1353-1366. Epub 2018 Jun 21.

Department of Geriatrics, Shanghai Institute of Geriatrics, Huadong Hospital, Fudan University, Shanghai 200040, P.R. China.

Pulmonary hypertension (PH) is a life‑threatening lung disease, characterized by an increase in pulmonary arterial pressure caused by vasoconstriction and vascular remodeling. The pathogenesis of PH is not fully understood, and there is a lack of potential biomarkers for the diagnosis and treatment of patients with PH. Non‑coding RNAs with a characteristic covalently closed loop structure, termed circular RNAs (circRNAs), are present in a number of pulmonary diseases. To the best of our knowledge, the present study is the first to use microarray analysis to determine the expression profile of circRNAs in lung tissues from mice with hypoxia‑induced PH. In total, 23 significantly upregulated and 41 significantly downregulated circRNAs were identified. Of these, 12 differentially expressed circRNAs were selected for further validation using reverse transcription‑quantitative polymerase chain reaction. Putative microRNAs (miRNAs) that bind to the dysregulated circRNAs were predicted. Subsequently, bioinformatics tools were used to construct circRNA‑miRNA‑mRNA networks for the two most promising circRNAs, namely mmu_circRNA_004592 and mmu_circRNA_018351. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses of target genes of the dysregulated circRNAs revealed that these dysregulated circRNAs may serve an important role in the pathogenesis of hypoxia‑induced PH. Therefore, these dysregulated circRNAs are candidate diagnostic biomarkers and potential therapeutic targets for PH.
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http://dx.doi.org/10.3892/ijmm.2018.3740DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6089758PMC
September 2018

Transferable Matrixes Produced from Decellularized Extracellular Matrix Promote Proliferation and Osteogenic Differentiation of Mesenchymal Stem Cells and Facilitate Scale-Up.

ACS Biomater Sci Eng 2018 May 16;4(5):1760-1769. Epub 2018 Apr 16.

School of Chemical and Biomedical Engineering, Particulate Fluids Processing Centre, The University of Melbourne, Parkville, Victoria 3052, Australia.

Decellularized extracellular matrixes (dECM) derived from mesenchymal stem cell (MSC) cultures have recently emerged as cell culture substrates that improve the proliferation, differentiation, and maintenance of MSC phenotype during ex vivo expansion. These biomaterials have considerable potential in the fields of stem cell biology, tissue engineering, and regenerative medicine. Processing the dECMs into concentrated solutions of biomolecules that enable the useful properties of the native dECM to be transferred to a new surface via a simple adsorption step would greatly increase the usefulness and impact of this technology. The development of such solutions, hereafter referred to as transferable matrixes, is the focus of this article. In this work, we produced transferable matrixes from dECM derived from two human placental MSC cell lines (DMSC23 and CMSC29) using pepsin digestion (P-ECM), urea extraction (U-ECM), and mechanical homogenization in acetic acid (AA-ECM). Native dECMs improved primary DMSC proliferation as well as osteogenic and adipogenic differentiation, compared with traditional expansion procedures. Interestingly, tissue culture plastic coated with P-ECM was able to replicate the proliferative effects of native dECM, while U-ECM was able to replicate osteogenic differentiation. These data illustrate the feasibility of producing dECM-derived transferable matrixes that replicate key features of the native matrixes and show that different processing techniques produce transferable matrixes with varying bioactivities. Additionally, these transferable matrixes are able to coat 1.3-5.2 times the surface area covered by the native dECM, facilitating scale-up of this technology.
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http://dx.doi.org/10.1021/acsbiomaterials.7b00747DOI Listing
May 2018

Tailoring the properties of a hypoxia-responsive 1,8-naphthalimide for imaging applications.

Org Biomol Chem 2018 01;16(4):619-624

School of Chemistry, The University of Sydney, NSW, 2006 Australia.

Sensing hypoxia in tissues and cell models can provide insights into its role in disease states and cell development. Fluorescence imaging is a minimally-invasive method of visualising hypoxia in many biological systems. Here we present a series of improved bioreductive fluorescent sensors based on a nitro-naphthalimide structure, in which selectivity, photophysical properties, toxicity and cellular uptake are tuned through structural modifications. This new range of compounds provides improved probes for imaging and monitoring hypoxia, customised for a range of different applications. Studies in monolayers show the different reducing capabilities of hypoxia-resistant and non-resistant cell lines, and studies in tumour models show successful staining of the hypoxic region.
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http://dx.doi.org/10.1039/c7ob03164eDOI Listing
January 2018

Expression of Homeobox Gene HLX and its Downstream Target Genes are Altered in Placentae From Discordant Twin Pregnancies.

Twin Res Hum Genet 2018 02 7;21(1):42-50. Epub 2017 Dec 7.

Department of Maternal-Fetal Medicine Pregnancy Research Centre,The Royal Women's Hospital,Melbourne,Victoria,Australia.

A discordant twin gestation, in which one fetus is significantly growth restricted, compared to the other normal twin, is a unique model that can be used to elucidate the mechanism(s) by which the intrauterine environment affects fetal growth. In many model systems, placental transcription factor genes regulate fetal growth. Transcription factors regulate growth through their activation or repression of downstream target genes that mediate important cell functions. The objective of this study was to determine the expression of the placental HLX homeobox gene transcription factor and its downstream target genes in dizygotic twins with growth discordance. In this cross-sectional study, HLX and its downstream target genes' retinoblastoma 1 (RB1) and cyclin kinase D (CDKN1C) expression levels were determined in placentae obtained from dichorionic diamniotic twin pregnancies (n = 23) where one of the twins was growth restricted. Fetal growth restriction (FGR) was defined as small for gestational age with abnormal umbilical artery Doppler indices when compared with the normal control co-twin. Homeobox gene HLX expression was significantly decreased at both the mRNA and protein levels in FGR twin placentae compared with the normal control co-twin placentae (p < .05). Downstream target genes CDKN1C and RB1 were also significantly decreased and increased, respectively, at both the mRNA and protein levels in FGR twin placentae compared with normal control co-twin placentae (p < .05). Together, these observations suggest an important association between HLX transcription factor expression and abnormal human placental development in discordant twin pregnancies.
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http://dx.doi.org/10.1017/thg.2017.66DOI Listing
February 2018

Decidual ACVR2A regulates extravillous trophoblast functions of adhesion, proliferation, migration and invasion in vitro.

Pregnancy Hypertens 2018 Apr 14;12:189-193. Epub 2017 Nov 14.

The University of Melbourne, Department of Obstetrics and Gynaecology and Department of Maternal-Fetal Medicine, Pregnancy Research Centre, The Royal Women's Hospital, Locked Bag 300, Corner Grattan Street and Flemington Road, Parkville 3052, Victoria, Australia.

Decidual stromal cells form the largest proportion of maternal cells at the maternal-fetal interface. Our aim was to investigate the role of the pre-eclampsia associated decidual activin receptor, ACVR2A, in regulating trophoblast functions at this interface. St-T1b and HTR-8/SVneo cell lines were used to model decidual stromal and trophoblast cells respectively. St-T1b conditioned medium inhibited HTR-8/SVneo adhesion, proliferation, migration and invasion; all effects that were attenuated by decidual ACVR2A siRNA transfection. These findings suggest that altered decidual ACVR2A expression perturbs the maternal-fetal crosstalk involved in regulating trophoblast function at the interface, which may affect placentation and lead to pre-eclampsia.
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http://dx.doi.org/10.1016/j.preghy.2017.11.002DOI Listing
April 2018

Isolation and Characterization of Mesenchymal Stem/Stromal Cells Derived from Human Third Trimester Placental Chorionic Villi and Decidua Basalis.

Methods Mol Biol 2018 ;1710:247-266

Department of Obstetrics and Gynaecology, Royal Women's Hospital, University of Melbourne, Parkville, VIC, Australia.

The decidua basalis and placental chorionic villi are critical components of maternal-fetal interface, which plays a critical role in normal placental development. Failure to form a proper maternal-fetal interface is associated with clinically important placental pathologies including preeclampsia and fetal growth restriction. Placental trophoblast cells are well known for their critical roles in establishing the maternal-fetal interface; however accumulating evidence also implicates mesenchymal stem/stromal cells that envelop the maternal and fetal blood vessels as playing an important role in the formation and efficient functioning of the interface. Moreover, recent studies associate abnormal mesenchymal stem/stromal cell function in the development of preeclampsia. Further research is needed to fully understand the role that these cells play in this clinically important placental pathology.The intimate relationship between maternal and fetal tissues at the interface poses significant problems in the enrichment of decidua basalis and chorionic villous mesenchymal stem/stromal cells without significant cross-contamination. The protocols described below for the enrichment and characterization of mesenchymal stem/stromal cells from the maternal-fetal interface produce highly enriched cells that conform to international standards and show minimal cross-contamination.
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http://dx.doi.org/10.1007/978-1-4939-7498-6_19DOI Listing
July 2018

Circular RNAs: Isolation, characterization and their potential role in diseases.

RNA Biol 2017 12 21;14(12):1715-1721. Epub 2017 Sep 21.

a Department of Geriatrics , Shanghai Institute of Geriatrics, Huadong Hospital, Fudan University , Shanghai , China.

Circular RNA (circRNA) generated by alternative splicing represents a special class of non-coding RNA molecule. CircRNAs are abundant in the eukaryotic cell cytoplasm and have a characteristic organization, timing of action and disease specificity. In contrast to linear RNA, circRNAs are resistant to RNA exonuclease. Consequently, circRNA escapes normal RNA turnover and this improves circRNA stability. CircRNAs can be degraded by microRNA (miRNA) and this results in linearization of the circRNA, which can then act as competitor to endogenous RNA. Through interactions with disease-related miRNA, circRNA can play an important regulatory role in specific diseases. Furthermore, circRNAs have significant potential to become new clinical diagnostic markers.
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http://dx.doi.org/10.1080/15476286.2017.1367886DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5731806PMC
December 2017

The effect of endothelial cell activation and hypoxia on placental chorionic mesenchymal stem/stromal cell migration.

Placenta 2017 Nov 27;59:131-138. Epub 2017 Jun 27.

University of Melbourne, Department of Obstetrics and Gynaecology, Royal Women's Hospital, Parkville, Victoria, 3052, Australia; Pregnancy Research Centre, Department of Maternal-Fetal Medicine, Royal Women's Hospital, Parkville, Victoria, 3052, Australia. Electronic address:

Introduction: Chorionic mesenchymal stem/stromal cells (CMSC) can be isolated from the placenta in large numbers. Although their functions are yet to be fully elucidated, they have a role in tissue development and repair. To fulfil such a role, CMSC must be able to migrate to the microenvironment of the injury site. This process is not fully understood and the aim of this study therefore, was to examine in vitro CMSC migration in response to tissue inflammation and hypoxic conditioning.

Methods: CMSC were derived from the chorionic villi. A trans-endothelium migration (TEM) assay was used to study CMSC migration through an activated endothelial cell monolayer using the HMEC-1 cell line. A cytokine array was used to identify and compare the cytokine production profile of activated versus non-activated HMEC-1.

Results: There were significant changes in cytokine production by HMEC-1 cells following lipopolysaccharide (LPS) treatment and hypoxic conditioning. Despite this, results from the TEM assay showed no significant change in the average number of CMSC that migrated through the LPS activated HMEC-1 layer compared to the untreated control. Furthermore, there was no significant change in the average number of CMSC that migrated through the HMEC-1 monolayer when exposed to hypoxic (1% O), normoxic (8% O) or hyperoxic (21% O) conditions.

Conclusion: These data suggest that cell functions such as transendothelial migration can vary between MSC derived from different tissues in response to the same biological cues.
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http://dx.doi.org/10.1016/j.placenta.2017.06.341DOI Listing
November 2017

The application of decellularized human term fetal membranes in tissue engineering and regenerative medicine (TERM).

Placenta 2017 Nov 4;59:124-130. Epub 2017 Jul 4.

Department of Maternal-Fetal Medicine, Pregnancy Research Centre, Royal Women's Hospital, Parkville, Victoria, Australia; Department of Obstetrics and Gynaecology, University of Melbourne, Parkville, Victoria, Australia. Electronic address:

Tissue engineering and regenerative medicine (TERM) is a field that applies biology and engineering principles to "restore, maintain or repair a tissue after injury". Besides the potential to treat various diseases, these endeavours increase our understanding of fundamental cell biology. Although TERM has progressed rapidly, engineering a whole organ is still beyond our skills, primarily due to the complexity of tissues. Material science and current manufacturing methods are not capable of mimicking this complexity. Therefore, many researchers explore the use of naturally derived materials that maintain important biochemical, structural and mechanical properties of tissues. Consequently, employing non-cellular components of tissues, particularly the extracellular matrix, has emerged as an alternative to synthetic materials. Because of their complexity, decellularized tissues are not as well defined as synthetic materials but they provide cells with a microenvironment that resembles their natural niche. Decellularized tissues are produced from a variety of sources, among which the fetal membranes are excellent candidates since their supply is virtually unlimited, they are readily accessible with minimum ethical concerns and are often discarded as a biological waste. In this review, we will discuss various applications of decellularized fetal membranes as substrates for the expansion of stem cells, their use as two and three-dimensional scaffolds for tissue regeneration, and their use as cell delivery systems. We conclude that fetal membranes have great potential for use in TERM.
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http://dx.doi.org/10.1016/j.placenta.2017.07.002DOI Listing
November 2017