Concepts of Cardiac Regeneration - a Pharmacologist´s View

Prof. Eschenhagen, Thomas. University Medical Center Hamburg-Eppendorf Department of Experimental and Clinical Pharmacology and Toxicology, Martinistr. 52, 20246 Hamburg, Germany.

Recently the concept evolved that stem cells exist ubiquitously in the adult organism and serve a regenerative role in situations of disease. Stem cell function could be either stimulated by therapeutic interventions or the cells themselves could be isolated and propagated and retransferred to the patient to serve replace diseased or lost cells. This concept of „regenerative medicine“ has gained much attention in neurology and cardiology, because brain and heart were previously considered as prototypic organs with postmitotic cells that are unable to regenerate. According to this dogma, any cell that dies is irreversibly lost and is replaced by scar. This process can be prevented or delayed, but not reversed. Cell therapy that induced or supported endogenous cardiac myocyte regeneration would therefore be a true “drug of the future”. However, the question whether endogenous regeneration occurs after myocardial infarction and whether stem cells with a true cardiac differentiation potential exist remains controversial. Bone marrow cells, skeletal myoblasts, and mesenchymal stem cells have been tested clinically and evidence exists for some positive effects of these cells on cardiac function when injected or infused into the heart. The mechanisms remain largely unknown. What appears quite clear is that the implanted cells do not or not to a relevant extent differentiate to cardiac myocytes. An alternative approach which we pursue in our laboratory is to generate force-generating cardiac muscle constructs from myocardial cells outside of the body and transplant them after myocardial injury. Proof-of-concept has been demonstrated in a rat model of permanent LAD ligation using constructs from neonatal rat heart cells. Open questions include the optimal cell source for a potential human application, means to increase the critical size, mechanisms of vascularization and electrical coupling after implantation. Potential solutions are being discussed.