Читать книгу The SAGE Encyclopedia of Stem Cell Research - Группа авторов - Страница 102

Anversa, Piero

Anversa, Piero

53

54

Anversa, Piero

Physician and scientist Dr. Piero Anversa was born in Parma, Italy, where he earned his doctorate in medicine. His interest in cardiovascular research began in his final years in medical school, and his commitment to science has remained intact in the last 50 years. Shortly after graduation, he obtained a NATO fellowship and moved to the United States in 1971. Although he lived most of his life in the United States and considers New York his real home, he maintains strong bonds with his country of origin. Myriad of fellows have been mentored by Dr. Anversa throughout his career.

The research conducted in Dr. Anversa’s laboratory has questioned the paradigm that the heart is a post-mitotic organ characterized by a predetermined number of parenchymal cells, which is defined at birth and is preserved throughout life. The work that Dr. Anversa conducted in the last 30 years has led to the recognition that the heart is an organ permissive for myocardial regeneration, which can be mediated by exogenous progenitor cells, endogenous progenitor cells, or both. Historically, the foundations for the notion that the heart is a static organ incapable of regeneration were established in the mid-1920s. The impact of this research was enormous, leading generations of pathologists and cardiovascular scientists to adhere to the concept that replicating myocytes are not to be found in the adult myocardium. Dr. Anversa’s critical analysis of the published data resulted in the development of a simpler and more convincing hypothesis of the cellular mechanisms regulating cardiac growth. If the assumption is made that cardiomyocytes lack the ability to reenter the cell cycle and replicate, differences in myocyte size would be expected to reflect comparable differences in the size of the organ. Dr. Anversa observed that changes in heart mass and cardiomyocyte volume rarely coincide, challenging the notion that the number of myocytes is an entity that remains largely constant throughout the organ lifespan, physiologically and pathologically. He demonstrated that hearts varying in weight can be composed of myocytes of similar volume, pointing to cell number as a crucial determinant controlling the size of the organ. Based on this work, numerous laboratories worldwide have demonstrated that the adaptive plasticity of the adult myocardium could not be equated to myocyte hypertrophy any longer.

Dr. Anversa introduced the concept of cardiomyocyte death as a cellular process strictly interrelated to myocyte formation in the control of cell number and heart homeostasis. Although the critical interaction of cell death and cell renewal is not unique to the myocardium, the concept that myocyte death is inevitably accompanied by the generation of new myocytes remains highly controversial. However, the fundamental observations obtained by Dr. Anversa and others impose a reexamination of cardiac biology in an attempt to provide novel information for a better understanding of the processes involved in the manifestations of severe ventricular dysfunction.

As stated by Angelini and Markwald, “almost single-handedly, Anversa and colleagues have raised new interest in the capacity of adult cardiac myocytes to replicate naturally. These investigators have proposed the innovative concept that, contrary to previous assumptions, the adult human heart is not terminally differentiated but has a significant population of stem cells capable of reproducing and differentiating into myocytes.”

To define whether cardiomyocyte renewal derives from endogenous and/or exogenous progenitors, Dr. Anversa studied initially sex-mismatched human cardiac transplants, a condition that offers the unique opportunity to determine whether host male cells develop within the female donor heart. This research provided the first evidence in support of the notion that the heart is a stem cell–regulated organ. Male cardiomyocytes and coronary vessels were detected and quantified in transplanted female hearts. Although discrepancies exist among groups in terms of the magnitude of cardiac chimerism, these results documented that male stem cells likely colonize the donor heart and differentiate into cardiovascular structures.

In numerous following publications, Dr. Anversa has shown that the heart belongs to the group of constantly renewing organs, where the capacity to replace cells depends on the persistence of a stem cell compartment. These findings have formed the basis of a new paradigm of the heart in which multipotent cardiac progenitor cells (CPCs) are implicated in the physiological turnover of myocytes, endothelial cells, smooth muscle cells, and fibroblasts. The recognition that the heart possesses a stem cell compartment that can regenerate myocytes and coronary vessels has raised the unique possibility to reconstitute dead myocardium after infarction; to repopulate the hypertrophic decompensated heart with new, better functioning myocytes and vascular structures; and perhaps to reverse ventricular dilation and wall thinning, restoring the physiological and anatomical characteristics of the normal heart. However, the field of regenerative cardiology is in its infancy and great caution has to be exercised in the implementation of this form of cellular therapy in human beings. Although there is no good animal model that can be employed to obtain this information, experimental evidence has been collected in Dr. Anversa’s laboratory in favor of the efficacy of CPCs for the repair of the damaged heart. Currently, cardiac-derived cells are utilized in clinical trials with encouraging results.

A fundamental discovery that has influenced the treatment of cardiac diseases in the world concerned the identification of a pool of bone marrow progenitor cells (BMPCs) capable of transdifferentiating into cardiomyocytes and coronary vascular cells. These findings have been furiously criticized, but they opened a new field of research in clinical cardiology. The therapeutic potential of BMPCs has been tested in several trials, which have documented that intracoronary and intramyocardial infusion of BMPCs is feasible and improves functional recovery in patients with acute myocardial infarction. Negative results have also been published. The substantial disparity among studies was analyzed by designing meta-analyses that involved subgroups of trials, in which one or more unifying parameters were identified: route of delivery, type of cardiac disease, age and gender of the patients, and presence of co-morbidities. Intracoronary injection of BMCs in patients with acute myocardial infarction was found to be safe and effective, with an average 3.79% increase in ejection fraction.

Dr. Anversa’s research has inspired generations of scientists.

Annarosa Leri

Harvard Medical School/Brigham & Women’s Hospital

See Also: Clinical Trials, U.S.: Heart Disease; Heart: Current Research on Isolation or Production of Therapeutic Cells; Heart: Development and Regeneration Potential; Heart: Existing or Potential Regenerative Medicine Strategies; Heart: Stem and Progenitor Cells in Adults; Heart Disease.

Further Readings

Angelini, Paolo and Roger R. Markwald. “Stem Cell Treatment of the Heart. A Review of Its Current Status on the Brink of Clinical Experimentation.” Texas Heart Institute Journal, v.32/4 (2005).

Anversa, Piero, Mark A. Sussman, and Roberto Bolli. “Molecular Genetic Advances in Cardiovascular Medicine. Focus on the Myocyte.” Circulation, v.109 (2004).

Orlic, Donald, et al. “Bone Marrow Cells Regenerate Infarcted Myocardium.” Nature, v.410 (April 5, 2001).