Anatomy and Embryology 1

Molecular Cardiovascular Developmental Biology

Principal investigators

Prof.Dr C.L.Mummery, Prof.Dr R.E.Poelmann, Dr S.M. Chuva de Sousa Lopes, Dr R. Passier, Prof Dr M.C. de Ruiter, Dr M.R.M. Jongbloed, Dr M.M. Bartelings

Aim and focus

The heart is the first organ to form during embryonic development. Growth and differentiation of its component cells, its morphogenesis and proper connection to the vasculature are controlled by a complex interplay of multiple signalling pathways. Maladaption of these pathways leads not only to congenital heart and vascular defects but also to late onset cardiovascular disease. Conversely, recapitulating normal use of these pathways can direct differentiation of pluripotent stem cells so that human cardiovascular derivatives can be produced for various biomedical applications, including disease modeling, drug discovery and regenerative medicine. This research programme aims to define molecular and biomechanical mechanisms (i) used by progenitors to form the heart and vasculature, (ii) that support cardiovascular cell maturation to fully functional phenotypes and (iii) that cause deregulation in cardiovascular disease. We use pluripotent (embryonic and induced) stem cells and chicken, mouse and human embryos to identify functional signalling pathways and a range of classical (embryo culture, histology, gross morphology, electrophysiology) and modern molecular techniques (imaging, functional genomics, proteomics and epigenomics, high content analysis, genetic disease models) for this purpose.

Position in international context

The department has many international collaborators that have resulted in joint publications in high impact journals (Nature Medicine, Nature Biotech, Nature Methods, Circulation Res.), invitations to provide commentaries (NEJM, Cell Stem Cell, Nature Biotech) and reviews (TMM, Nature, TIPS) and invitations to speak at international meetings (Keystone, ISSCR, Weinstein).  The research profile stem cells, early embryonic development and cardiovascular disease is supported by grants from NWO, ZonMW, the Netherlands Heart Foundation (three), the Netherlands Proteomic Centre, Rembrandt Institute (two), Bsik-NL (NIRM) and the European Community (three), the latter involving multiple laboratories from different European countries. Clinical anatomy research is supported by STW and congenital heart research by ZonMW.

Content/highlights/achievements

• Generic methods for efficient gene transduction, targeting by homologous recombination and cardiomyocyte differentiation of human pluripotent stem cells.
• Drug screening platforms based on human (stem cell derived) cardiomyocytes.
• Novel use of Thalidomide as a vascular disease drug
• Developmental origins of cardiac arrhythmias in neonates and adults
• Role of the second heart field in myocardial and epicardial development.
• Cilia as sensors for endothelial shear stress in development and disease.

Future themes

Links with clinical departments will be strengthened to recruit patients of interest for deriving pluripotent stem cells bearing (cardiovascular and metabolic) disease genes for pathophysiology and cardiotoxicity analysis in combination with drug discovery. Lineage tracing in mice will be used to track formation of the conduction system. Electrophysiology and advanced/high content imaging will be used increasingly to characterize cardiomyocytes from stem cells and in situ, in slices from chicken and (mutant) mouse heart.

Cohesion within LUMC

Our stem cell research programme participates in the thematic research area Regenerative Medicine and is part of a multitude of collaborative projects within the LUMC (Molecular Cell Biology, Human Genetics, Cardiology). Aspects of molecular imaging and vascular biology are in collaboration with Radiology, Molecular Cell Biology, Human Genetics, Immunohematology and the Einthoven lab. The cardiac development programme is in collaboration with Cardiology, Pediatric Cardiology and Thoracic Surgery.  

Key publications

Beqqali A, Monshouwer-Kloots J, Monteiro R, Welling M, Bakkers J, Ehler E, Verkleij A, Mummery C, Passier R. (2010). CHAP is a newly identified Z-disc protein essential for heart and skeletal muscle function. J Cell Sci. 123:1141-50. IF 6.29

Braam S, Denning C, van den Brink S, Kats P, Hochstenbach R, Passier R, Mummery CL (2008), Improved genetic manipulation of human embryonic stem cells. Nature Methods  5(5):389-92. IF 13.65

Chuva de Sousa Lopes SM*, Hayashi K*, Tang F, Surani MA (2008). Heterogeneous expression of Stella reveals a unique epigenetic and developmental state of pluripotent embryonic stem cells. Cell Stem Cells, 3, 391-401. IF 23.6

Egorova AD, Khedoe PP, Goumans MJ, Yoder BK, Nauli SM, ten Dijke P, Poelmann RE, Hierck BP. (2011) Lack of primary cilia primes shear-induced endothelial-to-mesenchymal transition. Circulation Research;108(9):1093-101. IF 9.99

Elliott DA, Braam SR, Koutsis K, Ng ES, Jenny R, Lagerqvist EL, Biben C, Hatzistavrou T, Hirst CE, Yu QC, Skelton RJ, Ward-van Oostwaard D, Lim SM, Khammy O, Li X, Hawes SM, Davis RP, Goulburn AL, Passier R, Prall OW, Haynes JM, Pouton CW, Kaye DM, Mummery CL, Elefanty AG, Stanley EG. NKX2-5(eGFP/w) hESCs for isolation of human cardiac progenitors and cardiomyocytes. Nature Methods. 2011 Oct 23;8(12):1037-40. doi: 10.1038/nmeth.1740. IF 20.7

International stem cell initiative, Amps K.....Mummery CL,.....Ward-van Oostwaard D. Screening ethnically diverse human embryonic stem cells identifies a chromosome 20 minimal amplicon conferring growth advantage.  Nat Biotechnol. 2011 Nov 27;29(12):1132-1144. doi: 10.1038/nbt.2051. IF 31.1

Lebrin F, Srun S, Raymond K, Martin S, van den Brink S, Freitas C, Bréant C, Mathivet T, Larrivée B, Thomas J-L, Arthur HM, Westermann CJJ,  Disch F,  Mager JJ,  Snijder RJ, Eichmann A, Mummery CL. Thalidomide stimulates vessel maturation and reduces epistaxis in Hereditary Hemorrhagic Telangiectasia patients. Nature Medicine (2010) doi: 10.1038/nm 2131 16(4):420-8. IF 25.4

Van Hoof D, Muñoz J, Braam SR, Pinkse MW, Linding R, Heck AJ, Mummery CL, Krijgsveld J. (2009) Phosphorylation dynamics during early differentiation of human embryonic stem cells. Cell Stem Cell. 5(2):214-26. IF 23.6

Van Laake LW, Passier R, Doevendans PA, Mummery CL (2008) Human embryonic stem cell derived cardiomyocytes and cardiac repair in rodents.  Circulation Research 102: 1008-1010. IF 9.99

R. Vicente-Steijn, R. Passier, L.J. Wisse, M.J. Schalij, R.E. Poelmann, A.C. Gittenberger-de Groot, M.R.M. Jongbloed. The funny current channel HCN4 delineates the developing cardiac conduction system in the chicken heart. Heart Rhythm. 2011 Aug;8(8):1254-63. IF 4.6

Winter EM, Grauss RW, Hogers B, Tuyn J van, Geest R van der, Lie-Venema H, Vicente Steijn R, Maas R, DeRuiter MC, Vries AAF de, Steendijk P, Doevendans PA, Laarse A van der, Poelmann RE, Schalij MJ, Atsma DE, Gittenberger-de Groot AC. Preservation of left ventricular function and attenuation of remodeling after transplantation of human epicardium-derived cells into the infarcted mouse heart. Circulation 2007;116:917-927. IF 13.54