Prof. Dr Christine L.Mummery: Pluripotent stem cells and differentiation to cardiovascular cells

Head of the group:  Prof Christine Mummery
Researcher scientists: Dr. C. Freund, Dr. R. Davis, Dr B. Hierck, S. Braam, R. Nauw.
Research technician: D. Ward

Main research themes:

• Self renewal and pluripotency of human embryonic stem cells
• Differentiation of pluripotent stem cells to cardiomyocytes and vascular cells
• Generation and characterization of patient-derived induced pluripotency stem cells
• Development of cardiovascular disease models in mouse and humans

We use both human and mouse embryonic stem cells to study self renewal and differentiation using genomics/proteomics approaches to identify signaling pathways that control these processes. Using defined growth conditions, genetic modification of the human cells is now feasible so that specific cell lineages can be marked by selectable fluorescent reporter genes using homologous recombination. 
We derive human and mouse induced pluripotent stem cells from mutant mice and patients with different genetic cardiac diseases. 
The vascular disease of interest is Heriditary Hemorrhagic Telangiectasia, caused by mutations in receptors for transforming growth factor β. Mice with deletions in any components of the TGF β signaling pathway show defective vasculogenesis in the developing yolk sac at mid-gestation.
Patients likewise have weak walled vessels that hemorrhage easily giving chronic nose bleeds. We are creating disease models based on iPS cells derived from these patients to study development of the disease and methods to treat it.
The cardiac diseases investigated are primarily channelopathies, caused by mutations in ion channels. Cardiomycocytes from human pluripotent stem cells beat spontaneously.

Their electrical  properties are characterized by the Electrophysiology Facility using microelectrode arrays and patch clamp with microelectrodes.

Key publications

Passier R, van Laake LW, Mummery C.L. Stem-cell-based therapy and lessons from the heart (2008) Nature 453:322-9. 

van Laake LW, Passier R, Doevendans PA, Mummery CL (2008). Human embryonic stem cell derived cardiomyocytes and cardiac repair in rodents. Circ. Res. 102:1008-1010. 

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. 5:389-92. 

Wu S, Chien KR, Mummery C.L (2008). Cardiac progenitor cells. Cell, 132:537-43. 

Adewumi et al (2007) Characterization of human embryonic stem cell lines by the International Stem Cell Initiative. Nat Biotechnol.  25(7):803-16. 

Daley et al (2007)  Ethics. The ISSCR guidelines for human embryonic stem cell research. Science. 315:603-4. 

van Laake LW, Passier R, Monshouwer-Kloots J, Verkelij A, Lips D, Freund C, den Ouden K, Ward-van Oostwaard D, Korving J, Tertoolen L, van Echteld CJ, Doevendans PA, Mummery CL. (2007) Human embryonic  stem cell-derived cardiomycoytes survive and mature in the mouse heart and transiently improve function after myocardial infarction. Stem Cell Res. 1:9-24. 

van Laake LW, Passier R, Monshouwer-Kloots J, Nederhoff MG, Ward-van Oostwaard D, Field LJ, van Echteld CJ, Doevendans PA, Mummery CL. Monitoring of cell therapy and assessment of cardiac function using magnetic resonance imaging in a mouse model of myocardial infarction. (2007) Nat Protoc.2:2551-67. 

van Laake, L., van den Dreische S., Post S., Feijen A., Jansen M., Driessens M., Mager J., Snijder R., Westermann C., Doevendans PA., van Echteld C., ten Dijke P., Arthur H., Goumans M-J., Lebrin F., Mummery CL.(2006) Endoglin has a crucial role in blood cell-mediated vasacular repair. Circulation 114:2288-97. 

Beqqali A, Kloots J, Ward-van Ooostward D, Mummery C.L., Passier R. Genome-wide transcriptional profiling of human embryonic stem cells differentiating to cardiomyocytes.  Stem Cells (2006) 24: 1956-1967. 

Chuva de Sousa Lopes SM, van den Driesche S, Carvalho RLC, Larsson J, Eggen B, Surani MA, Mummery CL. Altered primordial germ cell migration in the absence of transforming growth factor β signaling via ALK5. Dev. Biol. (2005) 284:194-203.

Mummery CL, Davis RP, Krieger JE. Challenges in using stem cells in cardiac repair. ScienceTranslationalMedicine 14 April 2010 Vol2 Issue 27 27ps17 1-5.  Reprint /  Full text.