Cardiovascular Regeneration and Stem Cell Therapy
Annarosa Leri, Piero Anversa, and William H. Frishman, eds.
229 pp. Oxford, UK: Blackwell Publishing; 2007. $134.95. ISBN 1-4051-4842-9
The past decade has witnessed extraordinary medical and scientific discovery: The human genome is now sequenced, human embryonic stem cells can be cultured, and the existence of endogenous tissue repair systems is newly appreciated. Technologically, our ability to image biological systems both in the intact organism and at microscopic levels also has advanced at a breathtaking pace. Many of these advances were difficult to imagine 10 to 15 years ago and, in many instances, have forced reappraisal of long-held biological paradigms. One of the most important examples of this is the concept of chronic irreversible damage to adult organs.
The totality of discoveries has challenged and overturned the long-held paradigmatic view that (with few exceptions) the parenchyma of adult organs comprises terminally differentiated cells that must function for our entire lives. Wound healing and the ability of the liver to regenerate (myth of Prometheus is must reading) were considered exceptions that proved the rule.
In the past several years, we have seen discoveries indicating that bone marrow and other sites harbor stem cells capable of differentiation into various lineages, including cardiac myocytes, and that the heart itself contains a pool of stem or precursor cells. Similar biology has emerged for other organ systems, notably the brain, long thought to lack these endogenous repair mechanisms. With regard to the cardiovascular system, the discovery has occurred so rapidly that translational preclinical and clinical work already offers the promise of revolutionary new therapies for damaged hearts. As far as the heart is concerned, the underpinning of the number 1 killer in Western society was rooted in the belief that the loss of a cardiac myocyte was an irreversible phenomenon. Importantly, serial loss of cells throughout life not only was the basis for chronic diseases but also led to the aging of organs.
Now, with the discovery that bone marrow harbors cells that can traffic to the injured heart and stimulate its repair and the fact that the heart itself has a reservoir of stem or precursor cells, the paradigm of irreversible and progressive damage to the heart requires revision. The new book Cardiovascular Regeneration and Stem Cell Therapy by Drs Annarosa Leri, Piero Anversa, and William Frishman beautifully outlines these developments in a series of well-organized sections and chapters.
The book, divided into 5 sections comprising 22 chapters, outlines the series of major discoveries that have given us a new view of the biology of the heart under both physiological and pathophysiological conditions. Covered in detail by a series of contributors are chapters on the variety of bone marrow and embryonic preparations of cells with cardiac differentiation capacity. The bulk of the book is appropriately devoted to the heart itself, with descriptions of cardiac precursor cells in the adult heart and the role they play in the diseased heart.
The book outlines the key biological principles that are cornerstones of this emerging new field. The first section on stem cell biology covers the broad array of cells that have cardiomyogenic and vasculogenic capacity. These include bone marrow–derived mesenchymal stem cells, endothelial precursor cells, and embryonic stem cells. The important property that stem cells home or traffic from their site of origin to a site of injury is discussed, which is a key principle in this emerging field.
A second section is devoted to the extremely exciting discovery that the heart itself contains stem cells, and attention is paid to some of the various ways in which these cells are isolated and expanded, whether through the ability to efflux dyes such as Hoechst 33342 or on the basis of cell surface markers such as the c-Kit receptor. In addition, another critically important concept is outlined: The stem cells within the heart are, in all likelihood, organized into units known as stem cell niches. Niches are structural and functional units that organize and regulate stem cell function. Within the niche, stem cells either self-replicate into identical daughter cells or begin the process of differentiation into 3 potential lineages: endothelial cells, smooth muscle cells, or cardiac myocytes. The niche serves to regulate and control this process, in large part through cell-cell interactions. Accordingly, the niche serves to maintain a pool of multipotent precursor cells important for organ homeostasis and regulates the initiation of the differentiation process in response to cues that remain, at present, incompletely characterized. Thus, cellular regeneration or replacement is a regulated process, so loss or damage of niches contributes to disease pathophysiology.
A subsequent section introduces the concept of therapy, with chapters devoted to embryonic stem cells, bone marrow, and endothelial precursor cells. Another important approach covered is the activation of endogenous cell reservoirs with cytokines such as granulocyte-colony stimulating factor or insulin-like growth factor-1.
A second major new idea to which a fourth section is devoted is that the stem cell may play a key role in disease pathophysiology and aging. Thus, the cardiac stem cell and its niche may be viewed not only as a potential therapeutic agent, endogenous repair, or homeostatic cell but also the source of disease. As we now begin to view the heart as an organ in homeostasis with lifelong cell loss balanced by replacement, we can begin to understand how dysfunction of the replacement limb of that balance can be primary in disease. Two specific examples of pathophysiological states in which stem cell dysfunction plays a role—diabetes and aging—are presented. This concept is absolutely revolutionary, is highly plausible, and has widespread implications. As clinicians are well aware, so-called idiopathic dilated cardiomyopathy is a widespread and important clinical problem, and variability in response to injury among different hosts can be extraordinary. Potential explanations for these phenomena can now be sought by examining dysfunction in endogenous regenerative pathways.
There are some points not addressed in the book. Importantly, there have been several additional approaches to cardiac stem cell identification, including the demonstration that cardiac precursor cells can be cultured from heart tissue and form cardiospheres similar to neurospheres, as well as other antigen panning techniques such as the Sca-1 receptor and the islet-1 transcription factor. A key issue for scientists in the field is to understand the interrelationship between the cells prepared by these varying methods. Additionally, the translation of this science into clinical trials has proceeded at an extremely rapid pace, and coverage of this aspect of the field is limited.
Despite the few limitations, the book is well organized and easy to read. Each chapter is beautifully illustrated, with schematics and abundant confocal micrographs displaying the biology of cardiac regeneration. This book covers the key new biological principles of this extremely exciting and rapidly evolving new field and is must reading for both veterans and newcomers at all levels.
Dr Hare receives grant funding from Osiris Therapeutics, Inc.