- A detailed description of our main research aim and focus, including our international context, highlights and achievements can be found here : Anatomy-molecular-cardiovascular-developmental-biology
- You can find more about specific research lines in the subgroup links on the right
- Our Key publications can be found here : Key-publications
- You can also find a more complete list of publications here, but it takes more time to load: All publications
The heart is the first organ to form during embryonic development and its proper connection to the vasculature and blood circulation are controlled by a complex interplay of multiple signalling pathways. Maladaption of these pathways not only leads to congenital heart and vascular defects but also to late onset cardiovascular disease. Conversely, recapitulating normal use can support directed differentiation of stem cells so that human derivatives of the cardiovascular lineages can be produced for a multiplicity of biomedical applications ranging from disease modelling and drug discovery to regenerative medicine. This research programme aims to define molecular and biomechanical mechanisms that : 1. are used by progenitors to form cellular components of the heart and vasculature, 2. support cardiovascular cell maturation to fully functional phenotypes and 3. cause deregulation in cardiac and vascular disease. We use (pluripotent) stem cells, embryos and foetuses of chicken, mouse and human origin to identify functional signalling pathways in combination with a range of classical (embryo culture, histology, gross morphology, electrophysiology) and modern molecular techniques (molecular imaging, functional genomics, proteomics and epigenomics, high content analysis, gene editing techniques) for this purpose.
Collaboration with clinical departments is an ongoing basis for deriving pluripotent stem cells bearing (cardiovascular and brain) disease genes for pathophysiology analysis in combination with drug discovery. A human fetal database and tissue bank has been established as a research resource for the community. A joint appointment in the department of Cardiology provides a clinical link to research on the developmental origin of congenital heart defects and long-term outcomes of childhood surgery. Development and pathomorphology of bicuspid aortic valves, cardiac conduction and innervation is explored in both genetic animal models and human tissues. The earliest stages of oocyte development and maturation in the context of infertility (as a result of cancer therapy in young females) and placental development in the context of repeated miscarriage provides underlying basic research that support clinical innovation in the department of Obstetrics and Gynaecology.
A new “organ on chip” research programme developing human tissue and disease modelling technology (hDMT) in microfluidic and biomechanical/electrical devices was initiated in 2015 as a collaboration between the three technical universities, seven general universities and university medical centres, the Hubrecht Institute and pharma/biotech (Galapagos, GenMab). Synthetic human tissues derived from stem cells are incorporated in devices to provide complex models for drug discovery and safety pharmacology. In the first instance cardiac and vascular diseases and cancer were modelled on chip formats with neural (in collaboration with Erasmus MC) and skin (in collaboration with the AMC) in 2016.
Research is organized in two main themes
1. (Ab)normal cardiovascular development and disease. The primary goal is to obtain new insights into heart disease and heart development with view to developing new treatment strategies that range from (repurposing) drugs and risk profiling to surgical intervention.
2. Differentiation and Organ development. This embraces the primary competencies of the department and includes in depth knowledge of human embryo development through morphological, pathological, genetic and epigenetic analysis of an extensive collection of human fetal tissue. This forms the Centre for Human Development with links to a human fetal database (“Keygenes”) in which different organs at different developmental stages can be examined/compared (www.keygenes.nl).
These themes are lead by three senior (C.L. Mummery, S.M. Chuva de Sousa Lopes, M.C. DeRuiter) and three junior (M. Bellin, R.P. Davis, V.V. Orlova) Principal Investigators; PI M.R.M. Jongbloed has shared appointments in the depts. of Anatomy&Embryology and Cardiology, combining basic and clinical research with clinical activities. Senior PI R. Passier is also Professor of Applied Stem Cell Biology at the University of Twente since 2015 and C.L. Mummery also holds a part-time chair of Vascular Microfluidics at the same university, part of a strategic collaboration between the LUMC and UT. M.C. DeRuiter is responsible for the organization, execution and development of the anatomy and developmental biology teaching programme (0.7fte) in addition to research (0.3fte). Human (patient-derived) induced pluripotent stem cells used in multiple research lines are produced by the LUMC iPSC core facility (joint ANA/MCB).
Position in international context
The department is internationally leading in the area of cardiovascular disease modelling using human pluripotent stem cells. This is reflected in the large number of invitations to speak (including plenary) and be part of the programme committee of premier international conferences on stem cells (ESHRE, ISSCR, EMBO, New York Stem Cell Foundation), cardiology (eg ESC, AEPC, EuroEcho, ESHG, Dutch/German meeting, Keystone), pharmaceuticals/ safety pharmacology (eg SelectbioSciences, British Society Pharmacology, as well as more general international conferences (FEBS, Gordon conference).
Members of the department hold several individual prestigious international and national grants including three from the ERC (ERC-AdG, ERC-CoG, ERC-StG), VIDI, Marie Curie and Gisela Their fellowships.
Most PIs have multiple international collaborations that include joint publications (with eg Germany, US, Australia, UK, Sweden, Belgium, Japan); in some cases, these are funded by competitive international grants (eg EU FP7 and H2020, Marie Curie, NC3R/GSK, HFSP). Editorial board or editor-in-chief functions in multiple high profile journals (Stem Cell Reports, Scientific Reports, Cell Stem Cell, Cardiovascular Research) are testimony of the strong international position of several staff members in their respective fields.
Current research grants (selection)
- EU FP7 2013-2017 Plurimes. Mesodermal tissue repair using pluripotent stem cells (450k€)
- CVON (Cardiovascular Onderzoek Nederland) NHS. HUSTCARE 2013-2018. Cardiac repair. Co-PI (350k€).
- European Research Council Advanced Grant 2013-2018. Human pluripotent stem cells: the new heart patient. Personal grant/PI (2.5 M€)
- Muller Foundation (2014-2019). hiPSC models for vascular disease. PI (750k€)
- ERARE-CVD: CPVT heart disease models co-PI (350k€).
- ZonMW MKMD (2017-2020) hIPSC as models for cardiac disease. PI (350k€)
- Interreg: Biomat microfluidic chips (2018-2020).PI (450k€).
- TK-LSH (2018-2020):hiPSC model of arrhythmia. PI (90k€)
- Ministry of Education, Culture and Science NWO Gravity Grant 2017 (2017-2027) Netherlands Organ on Chip Initiative. PI (18.8 mlj €)
Most important scientific publications in the past six years
1. Davis, R. P., Casini, S., Hoekstra, M., Remme, C. A., Dambrot, C., Salvatori, D…Mummery C.L. Cardiomyocytes derived from pluripotent stem cells recapitulate electrophysiological characteristics of an overlap syndrome of cardiac sodium channel disease. Circulation, 2012; 125(25), 3079–3091. IF 19.3 Cite 154
2. Bellin M, Davis RP, Casini S, D’Aniello C, Haas J, Ward-van Oostwaard D, Tertoolen LGJ, 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 32, 3161–3175. IF 9.8; Cit 68
3. 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 doi:10.1038/nprot.2014.102 IF 10.0; Cit 43
4. Zhang M, D’Aniello C, Verkerk A, Wrobel E, Frank S, Ward-van Oostwaard D, Piccini I, Freund C, Rao J,
Seebohm G, Atsma D, Schulze-Bahr E, Mummery CL, Greber B, Bellin M. Recessive cardiac phenotypes in iPS cell models of Jervell and Lange-Nielsen Syndrome: disease mechanisms and pharmacological rescue. Proc Natl Acad Sci U S A. 2014; 111(50):E5383-92. IF: 9.7; Cit: 46
5. 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; 33(9):970-9. IF: 41.5; Cit: 52
6. Devalla HD, Schwach V, Ford JW, Milnes JT, El-Haou S, Jackson C, Gkatzis K, Elliott DA, Chuva de Sousa Lopes SM, Mummery CL, Verkerk AO, Passier R. EMBO Mol Med. 2015 Apr;7(4):394-410. IF 9.2; Cit: 49
7. Takasato M, Er PX, Chiu HS, Maier B, Baillie GJ, Ferguson C, Parton RG, Wolvetang EJ, Roost MS, Chuva de Sousa Lopes SM, Little MH. Kidney organoids from human iPS cells contain multiple lineages and model human nephrogenesis. Nature. 2016 Aug 11;536(7615):238. doi: 10.1038/nature17982. IF 40.1; Cit 131
8. Passier, R., Orlova, V., Mummery, C., 2016. Complex Tissue and Disease Modeling using hiPSCs. Cell Stem Cell 18, 309–321 IF 23.1 Cit 24
9. 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. IF 9.2 Cit 11
10. Roost MS, Slieker RC, Bialecka M, van Iperen L, Gomes Fernandes MM, He N, Suchiman HED, Szuhai K, Carlotti F, de Koning EJP, Mummery CL, Heijmans BT, Chuva de Sousa Lopes SM. DNA methylation and transcriptional trajectories during human development and reprogramming of isogenic pluripotent stem cells.
Nat Commun. 2017 Oct 13;8(1):908. doi: 10.1038/s41467-017-01077-3. IF 12.1 Cit 0
Five most important societal publications and/or other societal outputs in the past six years
1 ''Stem Cells: Scientific Fact and Fiction'' Elsevier 2014: general guide to stem cells for clinicians, ethicists, lawyers patients and lay public
2 EUROSTEMCELLS Consortium: Promoting stem cell knowledge and collaboration in Europe
3 Ergo Sum: Science, Art and Stem cells (2015): BioArt exhibition Boerhave Museum (iPSC lab and Charlotte Jarvis, UK)
4 Lowlands University 2015: Public lecture pop festival: Stem cells: healthy aging or immortality?
5 NEMO Science Museum Amsterdam: Public lecture on cloning and future health
6 Host high school students (10-15) annually for Profile Work Project (PWS) and ''Design Thinking Thesis''
7 Honours Academy, University of Leiden
Further information (in depth - subgroups - key publications - all publications)
For a further and more detailed description of our main research aim and focus, including our international context, highlights and achievements please browse to can be found here : Anatomy-molecular-cardiovascular-developmental-biology. You can find more about specific research lines in the subgroup links on the right. Our Key publications can be found here: Key-publications You can also find a more complete list of publications here, but it takes more time to load: All publications