1. Stem cell therapy: what a cardiologist needs to know Robert Roberts MD Chief of Cardiology Baylor College of Medicine Houston, Texas Piero Anversa MD Director, Cardiovascular Research Institute New York Medical College Valhalla, New York Seigo Izumo MD Professor of Medicine Harvard Medical School Boston, Massachusetts

2. Stem cell therapy The basics stem cells  are primitive cells  can renew themselves  can develop into different cell types  have the potential to become more differentiated cells in vitro fertilized embryo multiple embryos produced in vitro for clinical purposes donated surplus embryos used to culture embryonic stem cells Source: University of Wisconsin

3. Stem cell therapy Embryonic stem cells derived from the early embryo are totipotent (can differentiate into all cell types of all organs) used to create gene knockout (KO) animal models for CVD study KO mouse (©Taconic)

4. Stem cell therapy Adult stem cells reside in adult tissue are multipotent (differentiating capacity is more limited)  satellite cells in skeletal muscle regenerate muscle after injury  stem cells in bone marrow replenish blood cells and have potential to become cardiovascular cells

5. number of cells in the human body: 200 trillion number of unique cell types all derived from an estimated 20–30 stem cells: 200 Stem cell therapy Body cells

6. plasticity of adult stem cells much greater than suspected shown to generate cell lineages different from the organ they reside in Stem cell therapy Plasticity

7. adult hematopoietic stem cells show potential to regenerate myocardium — both myocytes and coronary vessels injection of this cell in the region bordering infarct in mice improved ventricle function embryonic stem cells shown in vitro to differentiate into cardiomyocytes Stem cell therapy New myocardium Orlic D, et al. Nature 2001;410(6829):701-705 Kocher AA, et al. Nat Med 2001;7(4):430-436

8. “It is very clear that at this early stage there are some promising signs that some of the adult stem cells may in fact be able to turn into other cells with appropriate stimulation. Whether these cells will really become true functioning liver or brain cells on their own when they are put into a human being remains to be determined.” Stem cell therapy Promising signs Robert Roberts MD Chief of Cardiology Baylor College of Medicine Houston, Texas

9. Embryonic stem cells can form any 1 of the 200 different cell types obtained from 2 sources  miscarried/aborted fetus  unused fetus from in vitro fertilization Adult stem cells have a potential and have been successfully used in the treatment of leukemia Stem cell therapy Summary

10. different from stem cell research prohibited in the US but approved in the UK nucleus is taken out of one cell and transplanted into another recipient cell then adopts the identity of the donor Stem cell therapy Cloning by nuclear transfer Dolly, cloned by nuclear transfer (©Roslin Institute)

11. Stem cell therapy Applications of stem cells Robert Roberts MD Chief of Cardiology Baylor College of Medicine Houston, Texas “This is very early in the game, and if we had as many embryonic stem cells as we wanted tomorrow, there is a lot of research to be done in terms of what are the appropriate stimuli, what could turn these cells into liver or heart cells. Discovering what the particular stimuli are may take 2 or 3 years, even if stem cell research is approved and stem cells become available from embryonic form.”

12. embryonic stem cells could be used to grow cardiomyocites in vitro to be transplanted into MI patients adult stem cells  could generate cardiomyocytes in culture, or  could be injected directly into the MI animal cells home to area of damage and generate new myocardium, including electrically coupled myocytes and coronary arterials and vessels Stem cell therapy Cardiomyocytes Piero Anversa MD Director, Cardiovascular Research Institute New York Medical College Valhalla, New York place picture here

13. “I think that there is a potential in the adult stem cell…. Bone marrow-derived stem cells have the capacity to go to areas of damage in the myocardium and generate new myocardium, composed of myocytes and vessels.” Stem cell therapy A potential Piero Anversa MD Director, Cardiovascular Research Institute New York Medical College Valhalla, New York place picture here

14. embryonic stem cells used as in vitro model  to study cardiac growth  to investigate adverse effects of drugs on cardiac development Stem cell therapy In vitro

15. “I think that it is actually good to have this controversy…this is a central issue that we cannot avoid.” Seigo Izumo MD Professor of Medicine Harvard Medical School Boston, Massachusetts Robert Roberts MD Chief of Cardiology Baylor College of Medicine Houston, Texas Stem cell therapy Ethical debate “It was always intended by the NIH that, if this research is going to be funded, a set of rules has to be established for investigators to follow.”

16. Robert Roberts MD Chief of Cardiology Baylor College of Medicine Houston, Texas Stem cell therapy Adult stem cell research Seigo Izumo MD Professor of Medicine Harvard Medical School Boston, Massachusetts “The question is, can we get what we want by just funding research in the adult stem cell?” “There will be little ethical issue for the use of adult stem cells, in my opinion, particularly concerning those coming from bone marrow.”

17. how many adult stem cells lie in what organ is still unclear how to locate adult stem cells in the heart is still unknown more needs to be known about the characteristics of the cell surface answers may lie in the study of embryonic stem cells Stem cell therapy Location Robert Roberts MD Chief of Cardiology Baylor College of Medicine Houston, Texas

18. “We haven’t done any type of research to identify whether there are stem cells in the heart like there have found in the brain. I think the issue is more complex than just analyzing, identifying, characterizing, and understanding the biology of embryonic stem cells. We need to also look for stem cells in other organs which we always thought were not present. We might be surprised again, like we were a couple of years ago when we found out that neural stem cells do exist.” Stem cell therapy Complex issue Piero Anversa MD Director, Cardiovascular Research Institute New York Medical College Valhalla, New York place picture here

19. how to search for the adult stem cell  begin with markers used to isolate hematopoietic primitive bone marrow cells (c-kit, sca-1, mdr-1 etc) several approaches can be used initially to see whether there is a population of primitive undifferentiated cells in the heart or the kidney, to see whether there is a potential for regeneration in these organs, and to try to interfere with disease processes Stem cell therapy Search for stem cells Piero Anversa MD Director, Cardiovascular Research Institute New York Medical College Valhalla, New York place picture here

20. until recently, the heart was assumed to be terminally differentiated  no previous search for stem cells “Certainly that’s a line of research that should be pursued, and it is already showing some promising results.” Stem cell therapy The heart Robert Roberts MD Chief of Cardiology Baylor College of Medicine Houston, Texas

21. study of stem cells in mice and other species may help identify human adult stem cells taking advantage of evolutionary conservation in development, one can probably identify a number of markers for adult stem cells “The availability of human stem cells will probably hasten the research.” Stem cell therapy The future Seigo Izumo MD Professor of Medicine Harvard Medical School Boston, Massachusetts

22. Stem cell therapy Conclusions many fundamental uses for stem cells great potential for both embryonic and adult stem cell fields every effort should be made to pursue adult stem cells, regardless of what the future holds for embryonic stem cell research research with embryonic stem cells needs to be properly debated and formulated Robert Roberts MD Chief of Cardiology Baylor College of Medicine Houston, Texas