MYOCARDIAL REGENERATION AND NEOANGIOGENESIS
Learning outcomes of the course unit
Basic knowledge on the mechanisms of cell diiferentiation, transdifferentiation and plasticity.
Indications on the role of stem cells in organ damage.
Clinical use of stem cells in regenerative medicine.
Stem cells and myocardial regeneration
a) Experimental observations
b)Actual clinical applications
Course contents summary
Basic mechanisms on the role of stem cells in tissue regeneration and on the clinical relevance of cell therapy in cardiolgy
The main concepts and underlying biological and clinical notions are the objects of the lectures of this course and are reported below.
Cardiovascular disease (CVD) continues to be one of the main causes of death in the western world. The high burden of disease and the high costs for the healthcare systems highline the need for novel therapeutic strategies besides conventional medical care. Current therapeutic modalities for the treatment of end-stage cardiac failure are limited and include medical therapy, mechanical left ventricular assist devices, and cardiac transplantation. The heart has little regenerative capacity after damage, thus the response to the injury is characterized by inadequate cardiomyocyte regeneration and excessive fibrosis resulting in significant impairment of tissue structure and function. Ventricular remodelling following acute myocardial infarction leads to ventricular dilatation and progressive heart failure. The evolution of cardiac failure appears to depend on two crucial factors responsible for deterioration of pump functions, that are the accumulation of old, poorly contracting cells and the formation of multiple foci of myocardial scarring. A severe reduction in cell number occurs acutely after ischemic injury and results in scar formation in the heart. For this reason, efforts in understanding the factors required to produce new cardiac myocytes have been intensified.The static view of the myocardium implies that myocyte death and regeneration have little role in cardiac homeostasis and that cells enter a physiological state from which they cannot be rescued by an appropriate stimulus, are unable to duplicate DNA and increase in number, regardless of the disease process and the magnitude of myocardial mass. However, the concept that myocytes cannot divide originated from the difficulty to identify mitotic figures in the cells and not from estimation of myocyte cell volume and number. The presence or absence of cell proliferation can be determined only by counting the number of cells. Data from nuclear arms testing in the middle of the 20th century provide evidence for post-natal human cardiac myocyte turnover. Myocytes generation during the adult life-span was observed, thus supporting the notion that the mammalian heart has conserved some capacity for cardiac myocyte turnover. The evidence that the human heart harbours a population of primitive undifferentiated cells derives from studies able to identify in humans primitive cells that expressed the stem cell surface antigens c-kit. Thus, the identification of cardiac progenitor cells has suggested that the heart is not a terminally differentiated, post-mitotic organ but an organ regulated by a stem cell compartment. The failure of significant levels of regeneration in the adult human heart following MI, or other forms of injury, may not be due to the absence of resident cardiac stem cells or the failure of mobilization, recruitment, and transdifferentiation of circulating stem cells from other tissues. It may be a consequence of the inability or the efficiency of a damaged myocardium to provide the appropriate molecular signals to activate and promote the differentiation of resident cardiac stem cells, or to recruit circulating stem cells in sufficient numbers to mediate the repair of large infarcts. The ability of adult stem cells to transdifferentiate according to environment has culminated in the characterization and isolation of bone marrow MSCs, HSC and EPCs. The BMCs consist of different subpopulations like BM-hematopoietic stem cells (BM-HSCs 2-4%), mesenchymal stem cells (BM-MSCs 0.1%), BM-endothelial progenitor cells (BM-EPCs) or side population cells. Both multipotent precursor cell populations are self-renewing, grow clonogenic, and can be induced to differentiate into a cardiomyocyte phenotype in vitro.BMCs have an important therapeutic impact for cardiac diseases in humans; in fact, human BMCs have the ability to transdifferentiate in cardiac muscle cells, smooth muscle cells, and endothelial cells in vitro and in vivo and this cell population can also induce endogenous neovascularization and cardiomyogenesis . Thus these ﬁndings support the notion that BMCs adopt the cardiac phenotype and potentiate the growth reserve of the adult heart.
The field of regenerative medicine is on continuous evolution so that no specific texts are available. Students should consult NIH web site for the educational on stem cells. Moreover, essential references of scientific articles are provided.
Lectures, seminars and laboratory training
Assessment methods and criteria