The Medical College of Wisconsin has been awarded a five-year, $8 million, multi-investigator Program Project Grant (PPG) from the National Institutes of Health to understand how human pluripotent stem cells, defined as cells which if left to their own designs can develop into any of the more than 200 cell types in the human body, can be channeled to exclusively become heart muscle cells.
"To date no one has been able to replace damaged heart tissue. If we can use pluripotent cells to produce cardiac myocytes, which constitute the contractile tissue of the human heart, in laboratory dishes, we could potentially transplant them into diseased hearts to compensate for the loss of muscle tissue," says John Lough, Ph.D., head of the investigative team and professor of cell biology, neurobiology and anatomy.
According to the American Heart Association, approximately 500,000 new cases of heart disease are reported each year, translating into a census of nearly five million patients with an annual death rate of 250,000. In most cases, heart disease is caused by interruption of the heart's blood supply, which causes the beating cells of the heart muscle - cardiac myocytes - to die. Because cardiac myocytes cannot regenerate, the injury is essentially irreversible; hence these cells are a primary candidate for cell replacement therapy.
"Rapid discoveries in stem cell science are fueling a biomedical revolution. We are very pleased that this new grant confirms that our scientists are at the forefront of this research and competitive for obtaining programmatic funding in a very hot area," says Jonathan Ravdin, M.D., dean and executive vice president at the College.
The PPG is divided into sub-groups headed by Stephen A. Duncan, D.Phil., Marcus Professor in Human and Molecular Genetics, and professor of cell biology, neurobiology and anatomy; Paula E. North, M.D., Ph.D., professor of pathology; John Auchampach, Ph.D., professor of pharmacology and toxicology; and Stephen Dalton, professor and eminent scholar of biochemistry and molecular biology at the University of Georgia.
These investigators will pool their expertise to generate heart muscle from pluripotent stem cells. Pluripotent cells can be obtained from two sources. Induced pluripotent stem cells (iPSCs) are re-programmed from a patient's donor cells, which can therefore be transplanted without immune rejection. Embryonic stem cell (hESC) lines are derived from blastocysts obtained from in vitro fertilization clinics.
Specifically, the researchers will exploit the ability of stem cell-generated endoderm cells, the innermost of the three primary germ layers which induces the heart to develop in the embryo, to induce the pluripotent stem cells into cardiac myocytes, in numbers sufficient for remedial transplantation using animal models of heart disease. Therapeutic regeneration of diseased or damaged heart muscle with stem cells will depend on how efficiently the researchers can induce stem cells in culture dishes to develop into specialized endpoints of cardiac muscle maturation.
Success achieving these tasks will be promoted by synergy provided by the Medical College's many shared core facilities, and by the expertise of its world-class Cardiovascular Center and Human and Molecular Genetics Center to help meet these goals.
Ability to obtain this award was facilitated by local support from Advancing a Healthier Wisconsin, which provided grants to Drs. Duncan and Lough for preliminary aspects of the work.
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