Prof C. Mummery PhD: Understanding cardiovascular disease through human pluripotent stem cells

christine mummeryHead of the group:  Prof Christine Mummery
Researcher scientists: Dr. C. Freund, Dr. R. Davis, Dr. M. Bellin, Dr. V. Orlova, B. van Meer
Research technician: D. Ward

Main Research Themes: 

  • Understanding cardiovascular disease through human pluripotent stem cell models
  • Quantitative bioassays development for cardiac and vascular disease phenotype
  • Heterotypic Organ-on-Chip models of healthy and diseased human tissue

Primary interests of the Mummery group concern cardiac and vascular development and differentiation of human pluripotent stem cells to cells of the cardiovascular system. The interest derives from a long-standing fascination on how differentiation choices are made in development and the roles played by growth factors, particularly members of the TGFß superfamily. The Mummery group discovered an important function in controlling vasculogenesis in development and later showed through experiments co-culturing human pluripotent embryonic stem cells with yolk sac endoderm-like cells, that together with wnt signaling, this growth factor family also induced mesoderm differentiation and subsequent cardiomyogenesis. Biophysical methods, most importantly electrophysiology, have became central in characterizing the electrical and contractile properties of these PSC-derived cardiomyocytes and their potential use in modelling cardiac and vascular disease. With the development of human iPS cells by reprogramming somatic cells from patients, the potential clinical applications in understanding disease and in particular, in using these cells to identify drug targets and sensitivities and ways correct disease phenotypes. The group moved to Leiden University Medical Centre in 2008 to put basic research in a clinical context and collaboration with clinical cardiologists continues to expand. An iPS cell core facility was established in collaboration with the department of Molecular Cell Biology. In addition, other mesodermal derivatives, endothelial cells and vascular smooth muscle cells take a central role in the research, again in a clinical setting where a hemorrhaging disease (Hereditary Hemorrhagic Telangiectasia, HHT) caused by mutations in TGFß receptors is studied. Clinical collaborators discovered that Thalidomide reduced the incidence of hemorrhage in HHT patients and by combining this with knowledge of vasculogenesis in development we revealed one important mechanism underlying the therapeutic effect of Thalidomide. This is now being prescribed to patients and research is ongoing to identify safer alternatives using hiPSC from HHT patients as a test model system. Through collaboration with engineers in the Universities of Twente, Delft and Harvard, we are currently implementing methods for creating synthetic 2-D and 3-D vascularized/myocardial tissue to create new models to understand mechanisms underlying cardiac and vascular disease and discover new methods of treatment. New methods for directed differentiation of hPS cells have been established based on the principles of development so that it is now possible to generate all cardiomyocyte subtypes in the heart and multiple non-cardiomyocyte populations which make up 60% of the adult heart. 

Present aims include:
  1. Generation of multicellular (heterotypic) cardiac microtissues that support cell maturation and lead to better cardiac and vascular disease models
  2. Implementation of new disease models based on hPSC for cardiac arrhythmias, fibrosis and hypertrophy and vascular disease for drug and target discovery.
  3. Refinement of quantitative biophysical and biochemical assays as end points in Organ-on-Chip models of normal and diseased tissues based on hPSC.  These are being used to obtain new insights into disease and relevant targets for therapy.

Grants (selection)  
  • ERC Advanced Grant (STEMCARDIOVASC)
  • Netherlands Heart Foundation (CVON-HUSTCARE)
  • Moller Foundation
  • SWORO (HHT Foundation)
Key publications

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), 16(4):420-8.   

Davis RP, Casini S, van den Berg CW, Hoekstra M, Remme CA, Dambrot C, Salvatori D, Oostwaard DW, Wilde AA, Bezzina CR, Verkerk AO, Freund C, Mummery CL. Cardiomyocytes derived from pluripotent stem cells recapitulate electrophysiological characteristics of an overlap syndrome of cardiac sodium channel disease.Circulation. 2012 Jun 26;125(25):3079-91.

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.

V.V. Orlova, F.E. van den Hil, S. Petrus-Reurer, Y. Drabsch, P. ten Dijke, C.L. Mummery. Endothelial Cells and Pericytes from human Pluripotent Stem Cells: methods for efficient generation, expansion and examination of functional competence. Nature Protocols 2014 9, 1514-1531

  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. Nature Biotechnol. 2015 33(9):970-9

  Reviews and books

  Bellin M, Marchiotti C, Gage F, Mummery CL. Induced pluripotent stem cells: the new patient? Nature Rev Mol Cell Biol., 2012. 13(11):713-26

  Mummery CL, Zhang J, Ng ES, Elliott DA, Elefanty AG, Kamp TJ. Differentiation of human embryonic stem cells and induced pluripotent stem cells to cardiomyocytes: a methods overview. Circ. Res. 2012 111:344-58

  Mummery C, H. Clevers, A van de Stolpe, BAJ Roelen Stem Cells. Scientific Facts and Fiction .   Elsevier ISBN 978-0-12-381535-4. (2011; 2nd edition 2014)

  Passier R, Orlova VV, Mummery CL Complex Tissue and Disease Modeling using hiPSCs. Cell Stem Cell. 2016 Mar 3;18(3):309-21.