We aim to understand the aetiology and treatment of Cardio-Vascular Disease, from a Developmental Biology, Genetics and physiology perspective, with Regenerative Medicine purposes.
For this purpose, we use ES Cells and mouse embryos as model systems using the most up to date technologies in molecular embryology. Those include generation and analysis of KO mouse lines, mouse and human ES cell differentiation and CRISPR/CAS9 technologies.
In the recent years, besides maintaining our interest in the L-R axis due to the role of Cerl2/DAND5, an important gene uncovered by our lab, we focus our studies on the induction and control of myocardium and coronary vasculature development, organogenesis and function. We demonstrated the importance of the Nodal/Wnt signaling in heart formation and the role of Cerl2/DAND5 in the control of cardiomyocyte proliferation. We are using mouse and human PS cells, and hiPS cells from cohorts of human patients to study the control of ES/PS cell differentiation towards cardiogenic tissue.
We have also firstly identified the gene CCBE1 and found it to be crucial for the generation of ES cell derived cardiomyocytes and uncover its role in the establishment of the coronary vessels network in the developing heart. We are thus studying the role of this gene in the specification of cardiogenic mesoderm and of the coronary vasculature aiming to develop novel approaches/methods for possible applications for Regenerative Medicine.
Coronary heart disease is one of the most common causes of death globally. Therefore, we need novel agents that stimulate angiogenesis to restore blood flow in patients with ischemic diseases.CCBE1 is a secreted protein emerged as a crucial regulator of VEGFC signaling. More recently, we have unveiled that CCBE1 is also crucial for proper coronary vasculature formation. In both processes, CCBE1 exerts its function by enhancing VEGFC signaling, being required for the maturation of VEGFC into its active form.Besides its role in coronary vasculature formation, we demonstrated that CCBE1 is required for cardiac mesoderm formation and multipotent cardiovascular progenitors’ differentiation in mouse ESCs. Using our knockout mouse models, we observed that loss of Ccbe1 leads to defect in coronary plexus development and thinner ventricular compact myocardium.The main aims of this project are:
Cardiovascular disease is responsible for unhealthy ageing, impaired quality of life for the patient and caretakers, and high health resources consumption. This project is an integrated approach to study and develop new therapeutic approaches for heart diseases, accounting for the increase of morbidity and decrease in life quality.Our laboratory demonstrated that DAND5 is the only member of the Cerberus/DAN family of secreted antagonists of Nodal and Wnt signaling cascades with expression in the heart. By binding to the signaling ligands, DAND5 prevents agonist-receptor interaction inhibiting the signaling cascade events.We have been recently driving a study with a cohort of human patients with congenital heart disease from which we identified a variation in the Cerl2 human homologue, DAND5. We are now using the iPS cell technology after generating iPS cell lines for some of these patients and performing studies of patient specific disease modeling on the study of cardiomyocyte formation and most importantly, proliferation.We verified an increase in the proliferation index of CMs by modulating DAND5 levels. Our preliminary data indicate that reduced levels of DAND5 lead to increased cardiovascular progenitors’ numbers and, in addition, extend their progenitor state for a longer period.
The main aims of this project are:
As project co-leader & collaborator
José Manuel Inácio, João von Gilsa Lopes, Ana Mafalda Silva, Fernando Cristo, Sara Marques, Matthias E. Futschik, José António Belo (2021). DAND5 inactivation promotes cardiac differentiation in mouse embryonic stem cells. Front. Cell Dev. Biol. doi: 10.3389/fcell.2021.629430.José M. Inácio, Micael Almeida, Fernando Cristo and José A. Belo (2019). Generation of gene-corrected human induced pluripotent stem cell line derived from a patient with laterality defects and congenital heart anomalies with a c.455G>A alteration in DAND5. Stem Cell Research. doi.org/10.1016/j.scr.2019.101677.Bover O, Justo T, Pereira PNG, Facucho-Oliveira J, Inácio JM, Ramalho JS, Domian IJ, Belo JA (2018). Loss of Ccbe1 affects cardiac-specification and cardiomyocyte differentiation in mouse embryonic stem cells. PLoS One. 2018 Oct 3;13(10):e0205108. doi: 10.1371/journal.pone.0205108. eCollection 2018.Tavares AT, Jacinto A and Belo JA. (2018). Identification of chick Lefty2 asymmetric enhancer. Matters Select. 2018 Jul 19. doi: 10.19185/matters.201807000006Bonet F, Pereira PNG, Bover O, Marques S, Inácio JM, Belo JA (2018). CCBE1 is required for coronary vessel development and proper coronary artery stem formation in the mouse heart. Dev Dyn. 247:1135–1145. 2018 Sep 11. doi: 10.1002/dvdy.24670.Silva MM, Gomes-Alves P, Rosa S, Simão D, Inácio JM, Peixoto C, Serra M, Belo JA, Alves PM. (2018). Full-length human CCBE1 production and purification: leveraging bioprocess development for high quality glycosylation attributes and functionality. J Biotechnol. 2018 Aug 27;285:6-14. doi: 10.1016/j.jbiotec.2018.08.015.Selin Pars, Fernando Cristo, José M. Inácio, Graça Rosas, Isabel Marques Carreira, Joana Barbosa Melo, Luís Pereira de Almeida, Patrícia Mendes, Duarte Saraiva Martins, José Maio, Rui Anjos and José A. Belo (2018). Generation and characterization of a human iPS cell line from a patient-related control to study disease mechanisms associated with DAND5 p.R152H alteration. Stem Cell Research 29:202-206. DOI: 0.1016/j.scr.2018.04.015.José A. Belo, Sara Marques and José M. Inácio (2017). The Role of Cerl2 in the Establishment of Left-Right Asymmetries during Axis Formation and Heart Development. J. Cardiovasc. Dev. Dis. 2017, 4, 23; Doi:10.3390/jcdd4040023.Fernando Cristo, José M. Inácio, Graça Rosas, Isabel Marques Carreira, Joana Barbosa Melo, Luís Pereira de Almeida, Patrícia Mendes, Duarte Saraiva Martins, José Maio, Rui Anjos and José A. Belo (2017). Generation of human iPSC line from a patient with laterality defects and associated congenital heart anomalies carrying a DAND5 missense alteration. Stem Cell Research 25:152-156. DOI: 10.1016/j.scr.2017.10.19.Furtado J, Bento M, Correia E, Inácio JM, Belo JA (2014) Expression and Function of Ccbe1 in the Chick Early Cardiogenic Regions Are Required for Correct Heart Development. PLoS ONE 9(12): e115481. doi:10.1371/journal.pone.0115481Ana Carolina Araújo, Sara Marques and José António Belo (2014). Target inactivation of cerl-2 leads to left ventricular cardiac hyperplasia and systolic dysfunction in mouse. PLoS One. 9(7):e102716. DOI: 10.1371/journal.pone.0102716).Ana Rubina Perestrelo, Ana Grenha, Ana M. Rosa da Costa and José António Belo (2014). Locust Bean Gum as an alternative polymeric coating for embryonic stem cell culture. Mater Sci Eng C Mater Biol Appl. 40:336-44. doi: 10.1016/j.msec.2014.04.022.Ana Rubina Perestrelo, Fouzi Mouffouk, Ana M. Rosa da Costa and José António Belo (2013). Novel triblock copolymer nanofiber system as an alternative support for embryonic stem cells growth and pluripotency. T. Eng. Reg. Med. 2016 Oct;10(10):E467-E476. DOI: 10.1002/term.1838.Vinhas M, Araújo AC, Ribeiro S, Brás Rosário L and Belo JA (2013). Transthoracic echocardiography reference values in juvenile and adult 129/Sv mice. Cardiovascular Ultrasound 11:12 (doi:10.1186/1476-7120-11-12).Inácio JM, Marques S, Nakamura T, Shinohara K, Meno C, Hamada H, and Belo JA (2013). The Dynamic Right
There is an open call for applications for a Post-Doctoral Research Grant (BIPD), under reference SAI/2022/03, in the scope of the project EXPL/CCI-BIO/1650/2021-CARDIOMiogênese In Silico: Um quadro computacional para o estudo da diferenciação de células estaminais em cardiomiócitos (CARDIOMyogenisis In Silico: A computational framework for the study of stem cell differentiation towards cardiomyocytes), at the institution Faculdade de Ciências Médicas|NOVA Medical School (FCM|NMS) from Universidade NOVA de Lisboa (UNL), supported by income from the above mentioned project financed by the Fundação para a Ciência e Tecnologia, I.P. (FCT, I.P.).
Application deadline: June 16 (until 5:00 PM), 2022.
Professors José Belo and Gabriela Silva were selected to participate in the staff training "e_Desk - Digital & Entrepreneurial Skills for European teachers", within the scope of the European project e-DESK.
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