Human stem cells for cardiac repair Applications of human stem cells for cardiac repair.

1. Human stem cells for cardiac repair Applications of human stem cellsforcardiacrepair Prof Pieter A. Doevendans (UMCU) Prof TranslationalCardiology 2004 Prof Hans Clevers (KNAW, Hubrecht lab)

2. Consortium Consortium Christine Mummery LUMC Eric Duckers Erasmus MC Vincent Christoffels AMC Jeroen Bakkers KNAW, (Hubrecht) Joost Sluijter UMCU ICIN (KNAW, Dir. Wiek van Gilst) Wanted: immunology

3. Health Care problem Aim: reduce the number of pts with symptomatic cardiac failure Unravelling the mechanisms behind the beneficial effects of stem cell therapy will allow us to improve the cardiac regenerative capacity of the human heart.

4. Research questions Whatroles do neovascularization, paracrine factors, microRNAsplay in cardiacregenerationandrepair? Why do patients post-MI or withchronic angina respondpositivelyto stem celltransplantationandothers do not? Do cardiovascular risk factors (Gender, smoking, diabetes, high bloodpressure, high cholesterol DM) have an impact on stem cellbehaviour or host response? Do endogenousprogenitorscontributetocardiacrepair in response to stem celltransplantation? Can we boost endogenousregenerativecapacity of the heart?

5. Intramyocardial Delivery of Bone Marrow-Derived c-kit+ Cells after MI Stimulates Endogenous CM Regeneration. Loffredo et al. Cell stem cell 2011

6. Cardiogenesis and Regeneration Large animal models CVON Clinical trials Variations in individual response

7. WP 1 Cardiogenesis andregeneration (Bakkers, Christoffels, Clevers, Mummery, Sluijter) ESC: cardiogenesis, compound screening Zebrafish: regeneration, genetic screening Lineagetracing (mouse) : cardiogenesis andregeneration Alternative stem cell sources andproducts

8. Hippo Pathway Inhibits Wnt Signalingto Restrain CardiomyocyteProliferation and Heart Size Todd Heallen,1 Min Zhang,1 Jun Wang,1 Margarita Bonilla-Claudio,1 Ela Klysik,1 Randy L. Johnson,2 James F. Martin1* Science April 2011

9. WP 2 Individualvariation (Mummery, Sluijter, Bakkers) GENDER differences Role of risk factors (age, metabolism)

10. WP 3 Preclinical trials (Doevendans, Duckers) Delivery Function Imaging

12. WP 4 Clinical trials (Doevendans, Duckers) MSC ATMNC CSC Delivery

13. Basic Science: Cardiogenesis Translation (Pre) clinical trials

14. Focus areas Netherlands Heart Foundation Individualvariation: G,A,M Hartfalen, Hartstilstand, GENDER, Aangeboren Hartafwijkingen Females respond differently to heart attacks than males. In addition, the electrophysiological responses of freshly isolated human primary cardiomyocytes differ in males and females. We will investigate the responses of human stem cell derived cardiomyocytes in culture to male and female hormones. Inclusion females preclinical and clinical.

16. Europa

17. FP6 Eugene

18. FP6,7 CardiacRepairCHeart (Moorman)

19. FP7 Bioscent

20. In preparation: FP 7 with Australia