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Identification of candidate genes in human placenta involved in the development of childhood allergy
Abstracts / Placenta 34 (2013) A1–A99
Conclusion: In conclusion, the YS in Necromys is able to generate MSCs with satisfactory characteristics of growth, expansion, freezing and in vitro differentiation. These cells resulted as potential stem cells with promising therapeutic values for cell therapy. Supported by FAPESP (Proc.09/53392-8). Keywords: fetal membranes, fibroblast-like cells, immunophenotyping, flow citometry, immunofluorescence, cell differentiation, tumorigenicity assay, cell therapy. http://dx.doi.org/10.1016/j.placenta.2013.06.025
NI.2. INTRA PLACENTAL GENE TRANSFER OF AD-HIGF-1 IN A MOUSE MODEL OF PLACENTAL INSUFFICIENCY (PI) CORRECTS LIVER GROWTH FACTOR EXPRESSION (IGFBP-1) Khaled Omar, Helen Jones, Charles Klanke, Mounira Habli Cincinnati Childrens Hospital Medical Centre, Cincinnati, Ohio, USA Objectives: Previous work in our laboratory demonstrated that selective uterine artery branch ligation in a mouse model of placental insufficiency significantly reduces fetal weight and is associated with an increase risk of adult disease and interestingly, is rescued by Ad-hIGF-1 intraplacental gene therapy. Furthermore, we have shown changes in different liver growth factors expression in growth-restricted pups suggesting that these alterations may contribute to the increased risk of adult disease. Our aim was to investigate if Ad-hIGF-1 intraplacental gene transfer reprograms the fetus and maintains normal levels of gene expression. Methods: At gestational day 18, animals were divided into three groups; sham-operated controls or selective uterine artery branch ligation (ligated) or Ad-hIGF-1 treated group after ligation. At gestational day 20, Csection delivered pups were cross fostered to surrogate CD-1 mice. At week 12 and 24, offspring were sacrificed and livers dissected and snap frozen for qPCR analysis (IGF-1, IGFBP-1, PlGF, PDGF-B and PDGF-Rb), data are presented as mean SEM, and analyzed using Anova and Post hoc test. Results: At 12 weeks there was a significant (p < 0.05, n > 4 per group) increase in the expression of IGFBP-1 in the livers of the ligated group compared to sham (5.15 2.6 vs. 1.4 0.64). Interestingly, Ad-hIGF-1 treatment maintains normal IGFBP-1 levels (1.4 0.28). These findings persisted up to 24weeks (2.79 2.9 vs 0.85 0.44 vs 0.36 0.17), however there was no significant difference in other growth factors tested. Conclusion: Increased IGFBP-1 levels may reduce the bioavailability of the IGFs leading to alterations in liver development or function; Intraplacental gene therapy of Ad-hIGF-1 maintains normal IGFBP-1 liver growth factor gene expression and reprograms the fetus carrying an innovative therapy to placental insufficiency. The changes may represent a mechanism linking intrauterine growth restriction with adult diseases.
A7
NI.3. IDENTIFICATION OF CANDIDATE GENES IN HUMAN PLACENTA INVOLVED IN THE DEVELOPMENT OF CHILDHOOD ALLERGY Astrud Tuck 1, 2, Annette Osei-Kumah 1, 2, Zarqa Saif 1, 2, Vicki Clifton 1, 2 1
University of Adelaide, Adelaide, South Australia, Australia; Institute, Adelaide, South Australia, Australia
2
Robinson
Objectives: The prevalence of childhood allergic disease has increased dramatically in developed countries. The increasing prevalence of allergic disease with modern urbanisation and the early onset of disease in childhood indicates that allergy originates during prenatal life. Modern environmental changes are hypothesised to be causing deviations in fetal programming, in which the placenta plays a central role, increasing the susceptibility and prevalence of disease throughout life. We hypothesised that susceptibility to childhood allergy is determined by changes in placental function that programs immune function in the fetus in a sexspecific manner. In this study we aimed to identify candidate genes and pathways in human placental tissue that may contribute to the development of childhood allergy. Methods: Human placental tissue was obtained after delivery from women giving informed consent at the Lyell McEwin Hospital, Adelaide, and global gene expression was examined via microarray analysis. Placentae from pregnancies that gave rise to children with allergy by 4 years of age (n ¼ 45) were compared to placentae from children with no allergy (n ¼ 17), and sex-specific differences were also examined. Differentially expressed genes and pathways were identified using Ingenuity Pathway Analysis software. Results: Microarray analysis identified increased expression of cytokine growth factor kit ligand (KITL), its receptor kit, and matrix metalloproteinase 2 and 9 (MMP2, MMP9) in placenta associated with allergy compared to control. qPCR validation showed increased expression of these genes in female placentae compared to male placentae in control and allergy groups. Conclusion: This study has identified genes known to be involved in inflammation that appear to be differentially regulated in male and female placentae, suggesting sex-specific roles in fetal development. The roles of each gene in placental function and fetal development are unknown, and may have sex-specific roles in the programming of fetal immune function and contribution of allergy susceptibility. http://dx.doi.org/10.1016/j.placenta.2013.06.027
NI.4. GENE EXPRESSION DIFFERENCES REVEAL ANCESTRY-SPECIFIC ENVIRONMENTAL INTERACTIONS IN PLACENTAL ADAPTION TO HIGH-ALTITUDE HYPOXIA William E. Gundling 1, Stacy Zamudio 2, Nicholas P. Illsley 2, Lourdes Echalar 3, Derek E. Wildman 1, 4 1 Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, Michigan, USA; 2 Department of Obstetrics and Gynecology Division of Maternal Fetal Medicine and Surgery, Hackensack University Medical Center, Hackensack, New Jersey, USA; 3 Instituto Boliviano de Biología de Altura, Universidad de San Andreas Mayor, La Paz, Bolivia; 4 Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, Michigan, USA
Ă
http://dx.doi.org/10.1016/j.placenta.2013.06.026
Objective: Placental hypoxia is associated with obstetrical syndromes including preeclampsia and IUGR. The incidence of these conditions is increased two-four fold at high altitude. We and others have shown that fetal growth is enhanced in populations with thousands of years of exposure to hypoxia due to altitude. Species-specific differences in placental gene expression are more pronounced in late pregnancy when fetal growth is maximal. We examined gene expression in term placentas from high and low altitude in Native Americans versus recent European
Conclusion: In conclusion, the YS in Necromys is able to generate MSCs with satisfactory characteristics of growth, expansion, freezing and in vitro differentiation. These cells resulted as potential stem cells with promising therapeutic values for cell therapy. Supported by FAPESP (Proc.09/53392-8). Keywords: fetal membranes, fibroblast-like cells, immunophenotyping, flow citometry, immunofluorescence, cell differentiation, tumorigenicity assay, cell therapy. http://dx.doi.org/10.1016/j.placenta.2013.06.025
NI.2. INTRA PLACENTAL GENE TRANSFER OF AD-HIGF-1 IN A MOUSE MODEL OF PLACENTAL INSUFFICIENCY (PI) CORRECTS LIVER GROWTH FACTOR EXPRESSION (IGFBP-1) Khaled Omar, Helen Jones, Charles Klanke, Mounira Habli Cincinnati Childrens Hospital Medical Centre, Cincinnati, Ohio, USA Objectives: Previous work in our laboratory demonstrated that selective uterine artery branch ligation in a mouse model of placental insufficiency significantly reduces fetal weight and is associated with an increase risk of adult disease and interestingly, is rescued by Ad-hIGF-1 intraplacental gene therapy. Furthermore, we have shown changes in different liver growth factors expression in growth-restricted pups suggesting that these alterations may contribute to the increased risk of adult disease. Our aim was to investigate if Ad-hIGF-1 intraplacental gene transfer reprograms the fetus and maintains normal levels of gene expression. Methods: At gestational day 18, animals were divided into three groups; sham-operated controls or selective uterine artery branch ligation (ligated) or Ad-hIGF-1 treated group after ligation. At gestational day 20, Csection delivered pups were cross fostered to surrogate CD-1 mice. At week 12 and 24, offspring were sacrificed and livers dissected and snap frozen for qPCR analysis (IGF-1, IGFBP-1, PlGF, PDGF-B and PDGF-Rb), data are presented as mean SEM, and analyzed using Anova and Post hoc test. Results: At 12 weeks there was a significant (p < 0.05, n > 4 per group) increase in the expression of IGFBP-1 in the livers of the ligated group compared to sham (5.15 2.6 vs. 1.4 0.64). Interestingly, Ad-hIGF-1 treatment maintains normal IGFBP-1 levels (1.4 0.28). These findings persisted up to 24weeks (2.79 2.9 vs 0.85 0.44 vs 0.36 0.17), however there was no significant difference in other growth factors tested. Conclusion: Increased IGFBP-1 levels may reduce the bioavailability of the IGFs leading to alterations in liver development or function; Intraplacental gene therapy of Ad-hIGF-1 maintains normal IGFBP-1 liver growth factor gene expression and reprograms the fetus carrying an innovative therapy to placental insufficiency. The changes may represent a mechanism linking intrauterine growth restriction with adult diseases.
A7
NI.3. IDENTIFICATION OF CANDIDATE GENES IN HUMAN PLACENTA INVOLVED IN THE DEVELOPMENT OF CHILDHOOD ALLERGY Astrud Tuck 1, 2, Annette Osei-Kumah 1, 2, Zarqa Saif 1, 2, Vicki Clifton 1, 2 1
University of Adelaide, Adelaide, South Australia, Australia; Institute, Adelaide, South Australia, Australia
2
Robinson
Objectives: The prevalence of childhood allergic disease has increased dramatically in developed countries. The increasing prevalence of allergic disease with modern urbanisation and the early onset of disease in childhood indicates that allergy originates during prenatal life. Modern environmental changes are hypothesised to be causing deviations in fetal programming, in which the placenta plays a central role, increasing the susceptibility and prevalence of disease throughout life. We hypothesised that susceptibility to childhood allergy is determined by changes in placental function that programs immune function in the fetus in a sexspecific manner. In this study we aimed to identify candidate genes and pathways in human placental tissue that may contribute to the development of childhood allergy. Methods: Human placental tissue was obtained after delivery from women giving informed consent at the Lyell McEwin Hospital, Adelaide, and global gene expression was examined via microarray analysis. Placentae from pregnancies that gave rise to children with allergy by 4 years of age (n ¼ 45) were compared to placentae from children with no allergy (n ¼ 17), and sex-specific differences were also examined. Differentially expressed genes and pathways were identified using Ingenuity Pathway Analysis software. Results: Microarray analysis identified increased expression of cytokine growth factor kit ligand (KITL), its receptor kit, and matrix metalloproteinase 2 and 9 (MMP2, MMP9) in placenta associated with allergy compared to control. qPCR validation showed increased expression of these genes in female placentae compared to male placentae in control and allergy groups. Conclusion: This study has identified genes known to be involved in inflammation that appear to be differentially regulated in male and female placentae, suggesting sex-specific roles in fetal development. The roles of each gene in placental function and fetal development are unknown, and may have sex-specific roles in the programming of fetal immune function and contribution of allergy susceptibility. http://dx.doi.org/10.1016/j.placenta.2013.06.027
NI.4. GENE EXPRESSION DIFFERENCES REVEAL ANCESTRY-SPECIFIC ENVIRONMENTAL INTERACTIONS IN PLACENTAL ADAPTION TO HIGH-ALTITUDE HYPOXIA William E. Gundling 1, Stacy Zamudio 2, Nicholas P. Illsley 2, Lourdes Echalar 3, Derek E. Wildman 1, 4 1 Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, Michigan, USA; 2 Department of Obstetrics and Gynecology Division of Maternal Fetal Medicine and Surgery, Hackensack University Medical Center, Hackensack, New Jersey, USA; 3 Instituto Boliviano de Biología de Altura, Universidad de San Andreas Mayor, La Paz, Bolivia; 4 Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, Michigan, USA
Ă
http://dx.doi.org/10.1016/j.placenta.2013.06.026
Objective: Placental hypoxia is associated with obstetrical syndromes including preeclampsia and IUGR. The incidence of these conditions is increased two-four fold at high altitude. We and others have shown that fetal growth is enhanced in populations with thousands of years of exposure to hypoxia due to altitude. Species-specific differences in placental gene expression are more pronounced in late pregnancy when fetal growth is maximal. We examined gene expression in term placentas from high and low altitude in Native Americans versus recent European