Technician: ing. Dorien Ward-van Oostwaard
Main Research Themes:
• Human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) as cardiac disease models
• hPSC-CMs platforms for drug screening and safety pharmacology
• Three-dimensional (3D) cardiac microtissues
We use human pluripotent stem cells to model and study the genetic causes of cardiovascular diseases, in particular channelopathies. Long-QT syndrome (LQTS) is an arrhythmogenic disorder characterised by prolongation of the QT interval on the surface electrocardiogram, which can lead to sudden cardiac death. We have demonstrated that patient-specific hPSC-CMs are able to recapitulate the autosomal dominant forms of LQTS type 1 and type 2 and the rare recessive form Jervell and Lange-Nielsen syndrome.
Genome-engineering tools enable us to directly test the cellular consequences of precise genetic changes. We are applying efficient methods to edit hPSCs to generate isogenic lines. Investigating the electrophysiolgical phenotype of isogenic hPSC-CMs is helping us to explain the molecular and cellular basis of inherited cardiac arrhythmia. By leveraging these specific and isogenic disease lines we are also developing platforms to screen and identify cardio-active molecules that could revert pathological phenotypes.
The heart is a complex tissue composed by several cell types including cardiomyocytes, endothelial cells, smooth muscle cells, fibroblasts and other connective tissue cells. We are using hPSCs to develop 3D-cardiac microtissue constructs comprising both cardiomyocytes and non-myocyte cells to more accurately reproduce the multicellular organization and the dynamic function of native heart. These constructs will assist cardiovascular disease modelling and drug screening.
·ZonMw - More knowledge with fewer animals: Diseased cardiomyocytes from human stem cells for drug-repurposing and safety pharmacology (ongoing)
·H2020: ERA-CVD - Transnational Research Projects on Cardiovascular Diseases: Cardiomyocyte - non myocyte interplay as a novel platform for mechanistic insights and therapeutic approaches in ACM heart failure (ACM-HF) (ongoing)
· EU FP7 Marie Curie Intra-European Fellowship for Career Development (IEF) - HPSCLQT (concluded)
Milena Bellin was awarded the FEBS Anniversary Prize 2016:
Giacomelli E, Bellin M, Orlova VV, Mummery CL. Co-Differentiation of Human Pluripotent Stem Cells-Derived Cardiomyocytes and Endothelial Cells from Cardiac Mesoderm Provides a Three-Dimensional Model of Cardiac Microtissue. Curr Protoc Hum Genet. 2017 Oct 18;95:21.9.1-21.9.22. doi: 10.1002/cphg.46.
Giacomelli E, Bellin M, Sala L, van Meer BJ, Tertoolen LG, Orlova VV, Mummery CL. Three-dimensional cardiac microtissues composed of cardiomyocytes and endothelial cells co-differentiated from human pluripotent stem cells.
Development. 2017 Mar 15;144(6):1008-1017. doi: 10.1242/dev.143438.
Sala L, Ward-van Oostwaard D, Tertoolen LGJ, Mummery CL, Bellin M. Electrophysiological Analysis of human Pluripotent Stem Cell-derived Cardiomyocytes (hPSC-CMs) Using Multi-electrode Arrays (MEAs). J Vis Exp. 2017 May 12;(123). doi: 10.3791/55587.
Sala L, Yu Z, Ward-van Oostwaard D, van Veldhoven JP, Moretti A, Laugwitz KL, Mummery CL, IJzerman AP, Bellin M. A new hERG allosteric modulator rescues genetic and drug-induced long-QT syndrome phenotypes in cardiomyocytes from isogenic pairs of patient induced pluripotent stem cells. EMBO Mol Med. 2016 Sep 1;8(9):1065-81.
Birket MJ, Ribeiro MC, Verkerk AO, Ward D, Leitoguinho AR, den Hartogh SC, Orlova VV, Devalla HD, Schwach V, Bellin M, Passier R, Mummery CL.
Expansion and patterning of cardiovascular progenitors derived from human pluripotent stem cells. Nat Biotechnol. 2015 Sep;33(9):970-9.
Zhang M, D'Aniello C, Verkerk AO, Wrobel E, Frank S, Ward-van Oostwaard D, Piccini I, Freund C, Rao J, Seebohm G, Atsma DE, Schulze-Bahr E, Mummery CL, Greber B, Bellin M. Recessive cardiac phenotypes in induced pluripotent stem cell models of Jervell and Lange-Nielsen syndrome: disease mechanisms and pharmacological rescue. Proc Natl Acad Sci U S A. 2014 Dec 16;111(50):E5383-92.
Bellin M, Casini S, Davis RP, D'Aniello C, Haas J, Ward-van Oostwaard D, Tertoolen LG, Jung CB, Elliott DA, Welling A, Laugwitz KL, Moretti A, Mummery CL. Isogenic human pluripotent stem cell pairs reveal the role of a KCNH2 mutation in long-QT syndrome. EMBO J. 2013 Dec 11;32(24):3161-75.
Moretti A, Bellin M, Welling A, Jung CB, Lam JT, Bott-Flügel L, Dorn T, Goedel A, Höhnke C, Hofmann F, Seyfarth M, Sinnecker D, Schömig A, Laugwitz KL. Patient-specific induced pluripotent stem-cell models for long-QT syndrome. N Engl J Med. 2010 Oct 7;363(15):1397-409.
Reviews and other
Giacomelli E, Mummery CL, Bellin M. Human heart disease: lessons from human pluripotent stem cell-derived cardiomyocytes. Cell Mol Life Sci. 2017 Oct;74(20):3711-3739. doi: 10.1007/s00018-017-2546-5. Epub 2017 Jun 1. Review.
Bellin M, Mummery CL. Inherited heart disease - what can we expect from the second decade of human iPS cell research? FEBS Lett. 2016 Aug;590(15):2482-93. doi: 10.1002/1873-3468.12285. Review.
Bellin M, Mummery CL. Stem cells: The cancer's gone, but did chemotherapy damage your heart? Nat Rev Cardiol. 2016 Jul;13(7):383-4.
Veerman CC, Kosmidis G, Mummery CL, Casini S, Verkerk AO, Bellin M. Immaturity of human stem-cell-derived cardiomyocytes in culture: fatal flaw or soluble problem? Stem Cells Dev. 2015 May 1;24(9):1035-52. Review.
Bellin M, Marchetto MC, Gage FH, Mummery CL. Induced pluripotent stem cells: the new patient? Nat Rev Mol Cell Biol. 2012 Nov;13(11):713-26. Review.
A full publication list can be found here: http://www.ncbi.nlm.nih.gov/pubmed/?term=bellin+milena