Potential of stem-cell-based therapies for heart disease
Deepak Srivastava1 and Kathryn N. Ivey1
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The use of stem cells to generate replacement cells for damaged heart muscle, valves, vessels and conduction cells holds great potential. Recent identification of multipotent progenitor cells in the heart and improved understanding of developmental processes relevant to pluripotent embryonic stem cells may facilitate the generation of specific types of cell that can be used to treat human heart disease. Secreted factors from circulating progenitor cells that localize to sites of damage may also be useful for tissue protection or neovascularization. The exciting discoveries in basic science will require rigorous testing in animal models to determine those most worthy of future clinical trials.
Rarely has anything so energized scientists and the lay public alike as the enormous potential of stem-cell biology to treat human disease. The ability to mobilize endogenous progenitor cells in organs or to introduce and differentiate exogenous stem cells for tissue repair could have an impact on many diseases, including those affecting the brain, skeletal muscle, pancreas and heart. Regenerative therapies could be particularly beneficial for heart disease — the number one killer in adults and the leading non-infectious cause of death in children1. Cardiomyocytes do not seem to enter the cell cycle after birth, and consequently the heart has almost no regenerative capacity after injury. The long-held dogma has been that the heart cells with which you are born are the ones with which you die.
However, exciting new findings in the past 5 years have caused us to re-evaluate the potential of protective or regenerative cardiac therapies. Like the brain, the heart seems to have reservoirs of progenitor cells that may not be sufficient to replace the acute loss of a large number of cells, but may be able to replace a slow apoptotic loss of cells over a lifetime. Here, we examine the current basic and clinical science that is forming the foundation of future approaches to cardiac regeneration.
Cardiac and ES-cell-derived progenitor cells
Throughout the myocardium, pools of cardiac progenitor cells (CPCs) may participate in the continual replacement of apoptotic cardiomyocytes at a low basal level. Unlike terminally differentiated cardiac cells, CPCs are small cells that do not express cardiac markers and that can self-renew and proliferate. Several seemingly different but overlapping populations of progenitor cells (such as Sca-1- (ref. 2), c-Kit- (ref. 3) and Abcg2- (ref. 4) expressing side populations) can be induced to activate cardiomyocyte-specific genes in vitro; however, this effect has been also observed in mesenchymal stem cells, which do not fully differentiate into functional heart cells5. In addition, Sca1- or c-Kit-expressing cells may differentiate into cardiomyocytes in vivo, contributing to repair of the damaged heart after acute myocardial infarction, but their potential is limited, in part, by the small number of endogenous CPCs. Attempts to mobilize and to expand endogenous progenitor cells by introducing growth factors hold promise but remain controversial6. It is likely that the activity of endogenous CPCs will have to be augmented, through knowledge of the mechanisms of normal progenitor expansion and determination during embryonic development, before these cells will contribute substantially in the extreme setting of infarcted hearts.
Because embryonic stem (ES) and progenitor cells resemble early fetal cells that are adopting discrete lineages, elucidating the early developmental events of cardiogenesis has been instructive for understanding and manipulating CPCs. Pluripotent stem cells maintained through transcriptional regulators (such as NANOG, OCT4 and SOX2; ref. 7) are directed to differentiate into the mesoderm lineage by key transcription factors, including MESP and the T-box protein brachyury8,9 (Fig. 1). Subsequent determination of mesoderm progenitors mimics the embryonic developmental potential of two distinct fields of cells that give rise to the heart. Often referred to as the first and second heart fields, cells in these regions express unique markers of progenitor cells10. For example, the LIM-domain-containing transcription factor islet1 (ISL1) is involved in the differentiation of second heart field cells11, whereas the homeodomain-containing transcription factor NKX2.5 is a marker of both heart fields10. Most interestingly, remnant second heart field cells may not only be able to differentiate into many cell types, but also persist in the postnatal heart12 (Fig. 1). The pool of potential CPCs might be involved in continual maintenance of the heart by differentiating into several types of cardiac cell, including muscle, conduction and vascular cells, although the precise lineage potential of distinct subtypes remains to be determined (Fig. 2). It will be important to identify specific markers of the primary heart field to locate progenitor cells postnatally and even into adulthood.
作者:admin@医学,生命科学 2011-08-31 17:14