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Investigation of T-box gene function in patterning second heart field progenitor cells
Topic 27 — Miscellaneous — B cells sorted out by FACS and used for single cell RNA sequencing using the 10X genomics technology. Results and conclusions Preliminary results point to a cell heterogeneity in each cell population so far investigated. A full panel of both clonal analysis and single cell RNA analysis will be presented. Disclosure of interest The authors declare that they have no competing interest. https://doi.org/10.1016/j.acvdsp.2018.02.176 371
Investigation of T-box gene function in patterning second heart field progenitor cells C. Thellier 1 , C. De Bono 1 , S. Zaffran 2 , M. Theveniau-Ruissy 1,∗ , R. Kelly 1 1 IBDM, CNRS UMR7288 2 INSERM, GMGF UMR S910, Aix-Marseille université, Marseille, France ∗ Corresponding author. E-mail address: [email protected] (M. Theveniau-Ruissy) The heart is derived from two sources of progenitor cells: the first heart field giving rise to the left ventricle and atria, and the Second Heart Field (SHF) that progressively contributes to the right ventricle, outflow tract and parts of the atria. Perturbation of SHF cell addition leads to a spectrum of congenital heart defects, exemplified by conotruncal and atrioventricular septal defects observed in mouse embryos lacking the T-box transcription factor Tbx1, encoded by the major 22q11.2 deletion (DiGeorge) syndrome candidate gene. Tbx1 is expressed in the SHF where it regulates proliferation, differentiation and epithelial properties. Tbx1 is also required for the segregation of distinct anterior and posterior subpopulations of the SHF giving rise to arterial and venous pole myocardium, respectively. Here we show using genetic lineage tracing and immunofluorescence labeling that a second T-box gene Tbx5, implicated in Holt-Oram syndrome, is activated in Tbx1positive pharyngeal mesoderm in response to retinoic acid signaling at the onset of progenitor cell segregation. Loss of retinoic acid signaling results in failure to establish the posterior SHF domain and atrioventricular septal defects. SHF cells coexpressing Tbx1 and Tbx5 subsequently downregulate Tbx1 expression, in a Tbx1dependent manner, leading to the emergence of a transcriptional boundary between anterior and posterior SHF domains. Analysis of Tbx5 lineage and conditional loss of function implicate de novo activation of Tbx5 in boundary formation. Our results provide new insights into progenitor cell patterning during SHF deployment and the origins of common forms of congenital heart defects. Disclosure of interest The authors declare that they have no competing interest. https://doi.org/10.1016/j.acvdsp.2018.02.177
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Cardiopulmonary fitness in children with congenital heart diseases versus healthy children: A multicenter cross-sectional study M. Rola 1,∗ , A. Gavotto 1,2 , S. Guillaumont 1,2 , M. Vincenti 1,3 , C. Bredy 1 , G. De La Villeon 1,2 , M.C. Picot 4 , H. Bertet 4 , D. Vandenberghe 1 , O. Werner 1 , C. Ovaert 5 , P. Acar 6 , S. Matecki 3 , P. Amedro 1,3 1 Pediatric and Congenital Cardiology Department, M3C Regional Reference CHD Centre, Montpellier University Hospital, Montpellier 2 Pediatric Cardiology and Rehabilitation Unit, Saint-Pierre Institute, Palavas-Les-Flots 3 Physiology and Experimental Biology of Heart and Muscles Laboratory — PHYMEDEXP, UMR CNRS 9214 — INSERM U1046, Montpellier University 4 Epidemiology and Clinical Research Department, Montpellier University Hospital, Montpellier 5 Pediatric and Congenital Cardiology Department, M3C Regional Reference CHD Centre, La Timone University Hospital, Marseille 6 Pediatric and Congenital Cardiology Department, M3C Regional Reference CHD Centre, Toulouse University Hospital, Toulouse, France ∗ Corresponding author. Objective We aimed to compare the cardiopulmonary fitness of children with congenital heart diseases (CHD) to that of age- and gender-adjusted controls. We also intended to identify clinical characteristics associated with maximum oxygen uptake (VO2max ) in this population. Methods We included in a cross-sectional multicentre study a total of 798 children (496 CHD and 302 controls) who underwent a complete cardiopulmonary exercise test (CPET). The association of clinical characteristics with VO2max was studied using a multivariate analysis. The study was approved by the South Mediterranean IV Ethics Committee (2009-A00423-54) and registered on ClinicalTrials.gov (NCT01202916). Informed consent was obtained from all parents. Results Mean VO2max in the CHD group and control represented 93 ± 20% and 107 ± 17% of predicted values, respectively. VO2max was significantly lower in the CHD group, overall (37.8 ± 0.3 vs. 42.6 ± 0.4 mL/kg/min, P < 0.0001) and for each group (P < 0.05) (Table 1). The mean VO2max decline per year was significantly higher in CHD than in the controls overall (−0.84 ± 0.10 vs −0.19 ± 0.14 mL/kg/min/year, P < 0.01), for males (−0.72 ± 0.14 vs. 0.11 ± 0.19 mL/kg/min/year, P < 0.01), and for females (−1.00 ± 0.13 vs. −0.55 ± 0.21 mL/kg/min/year, P = 0.05) (Fig. 1). VO2max was associated with body mass index, ventilatory anaerobic threshold, female gender, restrictive ventilatory disorder, right ventricle systolic hypertension, tricuspid regurgitation, the number of cardiac catheter or surgery procedures, and the presence of a genetic anomaly.
Investigation of T-box gene function in patterning second heart field progenitor cells C. Thellier 1 , C. De Bono 1 , S. Zaffran 2 , M. Theveniau-Ruissy 1,∗ , R. Kelly 1 1 IBDM, CNRS UMR7288 2 INSERM, GMGF UMR S910, Aix-Marseille université, Marseille, France ∗ Corresponding author. E-mail address: [email protected] (M. Theveniau-Ruissy) The heart is derived from two sources of progenitor cells: the first heart field giving rise to the left ventricle and atria, and the Second Heart Field (SHF) that progressively contributes to the right ventricle, outflow tract and parts of the atria. Perturbation of SHF cell addition leads to a spectrum of congenital heart defects, exemplified by conotruncal and atrioventricular septal defects observed in mouse embryos lacking the T-box transcription factor Tbx1, encoded by the major 22q11.2 deletion (DiGeorge) syndrome candidate gene. Tbx1 is expressed in the SHF where it regulates proliferation, differentiation and epithelial properties. Tbx1 is also required for the segregation of distinct anterior and posterior subpopulations of the SHF giving rise to arterial and venous pole myocardium, respectively. Here we show using genetic lineage tracing and immunofluorescence labeling that a second T-box gene Tbx5, implicated in Holt-Oram syndrome, is activated in Tbx1positive pharyngeal mesoderm in response to retinoic acid signaling at the onset of progenitor cell segregation. Loss of retinoic acid signaling results in failure to establish the posterior SHF domain and atrioventricular septal defects. SHF cells coexpressing Tbx1 and Tbx5 subsequently downregulate Tbx1 expression, in a Tbx1dependent manner, leading to the emergence of a transcriptional boundary between anterior and posterior SHF domains. Analysis of Tbx5 lineage and conditional loss of function implicate de novo activation of Tbx5 in boundary formation. Our results provide new insights into progenitor cell patterning during SHF deployment and the origins of common forms of congenital heart defects. Disclosure of interest The authors declare that they have no competing interest. https://doi.org/10.1016/j.acvdsp.2018.02.177
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Cardiopulmonary fitness in children with congenital heart diseases versus healthy children: A multicenter cross-sectional study M. Rola 1,∗ , A. Gavotto 1,2 , S. Guillaumont 1,2 , M. Vincenti 1,3 , C. Bredy 1 , G. De La Villeon 1,2 , M.C. Picot 4 , H. Bertet 4 , D. Vandenberghe 1 , O. Werner 1 , C. Ovaert 5 , P. Acar 6 , S. Matecki 3 , P. Amedro 1,3 1 Pediatric and Congenital Cardiology Department, M3C Regional Reference CHD Centre, Montpellier University Hospital, Montpellier 2 Pediatric Cardiology and Rehabilitation Unit, Saint-Pierre Institute, Palavas-Les-Flots 3 Physiology and Experimental Biology of Heart and Muscles Laboratory — PHYMEDEXP, UMR CNRS 9214 — INSERM U1046, Montpellier University 4 Epidemiology and Clinical Research Department, Montpellier University Hospital, Montpellier 5 Pediatric and Congenital Cardiology Department, M3C Regional Reference CHD Centre, La Timone University Hospital, Marseille 6 Pediatric and Congenital Cardiology Department, M3C Regional Reference CHD Centre, Toulouse University Hospital, Toulouse, France ∗ Corresponding author. Objective We aimed to compare the cardiopulmonary fitness of children with congenital heart diseases (CHD) to that of age- and gender-adjusted controls. We also intended to identify clinical characteristics associated with maximum oxygen uptake (VO2max ) in this population. Methods We included in a cross-sectional multicentre study a total of 798 children (496 CHD and 302 controls) who underwent a complete cardiopulmonary exercise test (CPET). The association of clinical characteristics with VO2max was studied using a multivariate analysis. The study was approved by the South Mediterranean IV Ethics Committee (2009-A00423-54) and registered on ClinicalTrials.gov (NCT01202916). Informed consent was obtained from all parents. Results Mean VO2max in the CHD group and control represented 93 ± 20% and 107 ± 17% of predicted values, respectively. VO2max was significantly lower in the CHD group, overall (37.8 ± 0.3 vs. 42.6 ± 0.4 mL/kg/min, P < 0.0001) and for each group (P < 0.05) (Table 1). The mean VO2max decline per year was significantly higher in CHD than in the controls overall (−0.84 ± 0.10 vs −0.19 ± 0.14 mL/kg/min/year, P < 0.01), for males (−0.72 ± 0.14 vs. 0.11 ± 0.19 mL/kg/min/year, P < 0.01), and for females (−1.00 ± 0.13 vs. −0.55 ± 0.21 mL/kg/min/year, P = 0.05) (Fig. 1). VO2max was associated with body mass index, ventilatory anaerobic threshold, female gender, restrictive ventilatory disorder, right ventricle systolic hypertension, tricuspid regurgitation, the number of cardiac catheter or surgery procedures, and the presence of a genetic anomaly.