PIERO ANVERS A Is a distinguished investigator in the field of cardiovascular applications of stem cell research. His work contributed to a paradigm shift about cardiac physiology, strengthening the position that conceives of the heart as a self-renewing organ. He was born in Parma, Italy, in 1940. He gained his medical degree at the University of Parma in 1965, where he worked as assistant professor of pathology until 1980. In the early 1980s, he started his collaboration with the New York Medical College, where he was appointed professor of medicine in microbiology, immunology, and pathology. In 1985 Dr. Anversa permanently moved to United States, where he currently holds the office of director of the New York Medical College Cardiovascular Research Institute and vice chairman of the Department of Medicine.
Piero Anversa made a great effort to change the widespread conception of the heart as a terminally differentiated postmitotic organ, incapable of any sort of regeneration. One of the first observations that opened the way to such a deep revision of cardiac cellular homeostasis was the finding of male cells, endowed with a XY karyotype, in female hearts transplanted into male recipients. A deeper investigation of this heart chimerism phenomenon subsequently demonstrated a group of c-kit-posi-tive cells, which can differentiate into myocytes, endothelial cells, and smooth muscle cells. This multipotent, clonogenic, and self-renewing cell population was proven to be a primitively cardiac sort of stem cell. Cardiac stem cells (CSCs) have been isolated from different species of mammalian hearts, including human ones. They are distributed into the myocardium along with supporting cells, forming stem cell niches. Such a peculiar micro-environment significantly interacts with CSCs, regulating their proliferative potential through junctional proteins and soluble mediators in a mostly unidentified manner. The origin of these stem cell pools has been a debated issue ever since the first observations of heart chimerism were made: A scrupulous analysis of mouse embryonic heart made by Eberhard and Jockusch provided the evidence that all resident CSCs are formed during embryonic life, whereas heart chimerism in sex-mismatched transplants can be explained by the migration of host cells from atrial remnants to the donor heart.
REGENERATIVE CARDIOLOGY
Piero Anversa and his cardiovascular research team played a major role in regenerative cardiology not only in trying to figure out cardiac stem cell compartment features but also in attempting to translate such basic information regarding stem cell physiology into a novel and promising therapeutic strategy. The possibility of regenerating cardiac tissue through a cellular therapy has been first explored in mice by Dr. Anversa using lineage negative bone marrow cells (BMCs), a mixed population of cells composed of hematopoietic and mesenchymal stem cells, along with endothelial progenitors. In 2001 his team demonstrated that the injection of BMCs into infarcted myocardium can mend the ischemic lesion, and many following clinical trials performed on humans corroborated such beneficial effects, which have been interpreted as the consequence of a novel proliferation of myocytes and vascular structures mediated by BMCs’ differentiation or the effect of a paracrine stimulation of CSCs mediated by the graft.
After the identification of CSCs, a new and better source for cellular therapy seemed to appear. In contrast to exogenous cells, CSCs should better carry out the regenerative task because they are physiologically involved in myocardial homeo-stasis. In addition, every exogenous cell type used (BMCs, skeletal myoblasts, embryonic myo-cytes, and endothelial cells), although capable of enhancing cardiac function, behaved as a passive graft acquiring a rather immature aspect and enhanced overall cardiac function modifying the biomechanical properties of the scarred portion of the heart. Embryonic stem cells, which have also been proposed as exogenous progenitor cells, have tumorigenic properties and would represent a het-erologous source: Because they express HLA class I antigens in discrete quantities, they could induce an immune response. Myocardial regeneration has been demonstrated to happen in humans after infarction through the activation of resident CSCs, and the reason why such a phenomenon does not lead to a complete restitutio ad integrum, but to a scar formation, is one of the most challenging issues involving Dr. Anversa’s research.
According to Dr. Anversa, enhancing such physiological regenerative properties could be the best regenerative approach suitable for ischemic and nonischemic heart failure. This goal may be achieved by isolating CSCs directly from the patient, expanding them to therapeutically employable quantities, and injecting them back to the diseased heart. The complex ex vivo stem cell harvesting process and the lack of expansion protocols are significant difficulties that will need to be solved before this therapy becomes available as a standard treatment. To restore cardiac function, CSCs need to migrate, divide, and differentiate properly; nevertheless, Dr. Anversa determined that the stem cell pool is modified by many factors such as age, gender, and myocardial overload. All these conditions induce CSCs to acquire a senescent phenotype, characterized by specific molecular alterations (e.g., telomere dysfunction), which could reduce their therapeutic potential if not corrected.
To increase myocardial regeneration, many improvements have currently been tested: Dr. Anversa proposed the use of bioengineered scaffolds loaded with CSCs, together with growth factors to promote a better interaction between CSCs and the surrounding environment. The New York Medical College Cardiovascular Research Team is presently collaborating with Louisville University on a myocardial regeneration phase I trial, which is going to assess the safety and the feasibility of intracoronary autologous CSC transplantation in patients with ischemic cardiomyopathy. More than 200 patients worldwide have already undergone such procedure with BMC infusion, and none reported any adverse events. From a clinical perspective, only comparative tests will be able to clarify in the future whether undifferentiated CSC transplant has a better clinical outcome than other kinds of techniques.
