Sci. Aging Knowl. Environ., 4 September 2002
Vol. 2002, Issue 35, p. pe13
[DOI: 10.1126/sageke.2002.35.pe13]

PERSPECTIVES

Auto Repair on the Aging Stem Cell Superhighway

Jay M. Edelberg

The author is in the Department of Medicine at the Weill Medical College of Cornell University, New York, NY 10021, USA. E-mail: jme2002{at}med.cornell.edu

http://sageke.sciencemag.org/cgi/content/full/sageke;2002/35/pe13

Key Words: cardiovascular disease • ischemic heart disease • stem cells • bone marrow • endothelial precursor cells

Introduction

Vascular disease is epidemic among aging members of the population. Clinical research has demonstrated increased rates of cardiovascular disease and related complications in older patients as compared to their younger counterparts. Population-based studies have revealed that the incidence of ischemic heart disease--which is caused by obstructed blood flow to the heart and the resulting lack of oxygen--increases with age, so that over 80% of those with coronary artery disease are over age 65 (1). Older patients have poorer clinical outcomes and are associated with higher myocardial infarction-related mortality rates (2, 3). Whereas ischemic preconditioning, or brief periods of low oxygen, can protect the myocardium against ischemic damage, studies in both people and animals have demonstrated that this protective role is depressed in the senescent heart (4, 5). Moreover, aged individuals who survive initial cardiac events are more likely to develop congestive heart failure (6), which suggests that aging-associated changes in the cardiovascular system might predispose older individuals to increased vascular pathology. The incidence of stroke is also markedly higher in older people; over two-thirds of strokes occur in people over age 65 (1). Indeed, the risk of stroke doubles with each decade after age 60 (1), further demonstrating the importance of developing new therapeutic strategies optimized for older adults.

Stem cell therapy offers a novel approach for restoring the functions of tissues compromised by vascular diseases. Recent studies have demonstrated that adult bone marrow is a source for generating an array of nonhematopoietic cells, including specialized cells of the heart and brain. Like hematopoietic stem cells, bone marrow precursors of peripheral organ tissues respond to systemic signals that induce mobilization and to environmental cues that govern local cell differentiation patterns. Bone marrow-derived cardiac myocytes populate the heart after heart transplantation (7) and myocardial infarction (8-10). Similarly, bone marrow cells can generate new neurons in both the central (11, 12) and peripheral (13) nervous systems. In experimental systems, genetically marked stem cells can be transplanted from total bone marrow or from subpopulations of sorted blood-borne stem cells into irradiated hosts, and the migration and differentiation patterns of these marked cells can be followed. Subsequent induction of vascular injury in the heart or nervous system of these animals has been shown to induce the peripheral recruitment of the marked cells and their differentiation into locally specialized cells. Moreover, these bone marrow-derived cells can improve end-organ activity, resulting in significant increases in cardiac (14, 15) and sensory and motor (16, 17) function. Harnessing the clinical potential of these cells might yield substantial improvements in the treatment of older people.

Potholes in the Stem Cell Highway

Stem and precursor cells in the bone marrow are activated and mobilized into the circulation by systemic growth factors. The increased end-organ pathology associated with vascular diseases, however, can impair the peripheral recruitment of bone marrow stem cells. Previous studies have demonstrated that exogenous granulocyte-macrophage colony-stimulating factor leads to the generation of bone marrow-derived cardiac myocytes and results in improved cardiac function after myocardial infarction (15). In murine models, however, bone marrow stimulatory cytokines are present in the blood at lower concentrations than normal after myocardial infarction and after the development of congestive heart failure after coronary occlusion (18). In addition, bone marrow function (hematopoiesis; see Fuller Perspective) is decreased after myocardial infarction (19). Together, these changes might further contribute to the increased severity of vascular diseases associated with advanced age.

Changes in aging blood vessels might also impair the delivery of stem cells to peripheral organs. The peripheral vascular blood supply is maintained by complex cellular and enzymatic activities that regulate blood flow by modulating several processes, including (i) vascular constriction and dilation, (ii) the induction of coagulation and the subsequent dissolution of clots by fibrinolytic cascades, and (iii) angiogenesis (the growth of new vessels). Unfortunately, many of these functions are altered with increasing age. For example, blood vessels are lined with a layer of epithelial cells, the endothelium, and aging-associated changes in endothelial function limit the capacity of older blood vessels to regulate local blood flow dynamically, in such a way that both coronary and peripheral vascular beds display impaired vasodilation (20, 21). Moreover, increased coagulation activity and decreased endothelial fibrinolytic potential (22-24) can amplify senescence-associated changes in vascular integrity, and they suggest a potential basis for the increased predisposition of older individuals to coronary and cerebrovascular diseases. Angiogenic vascular repair mechanisms, which are critical for maintaining organ viability in a setting of impaired blood flow, are also less active in the senescent vasculature, as demonstrated in both clinical and animal models of oncologic (25), cardiac (26), and peripheral vascular (27, 28) angiogenesis. The results of these aging-associated changes in endothelial function might lead to more profound organ damage from vascular injury and decreased delivery of restorative stem cells to damaged regions of the body.

Damage Control

Bone marrow cells might provide the means to restore the delivery of stem cells as well as committed precursor cells, such as endothelial precursor cells (EPCs), through the aging blood vessels. Bone marrow cells directly contribute to the peripheral vascular endothelium and thus offer a means by which to restore senescent vascular function and the delivery of bone marrow-derived stem cells to injured tissues. Recent studies have demonstrated that EPCs, and cardiac myocyte and neuron precursor cells, all from the bone marrow, migrate to the appropriate regions of the body and generate or regenerate critical cell populations in hearts (EPCs and myocytes) and brains (neurons) (8, 11, 15). Indeed, bone marrow-derived EPCs are mobilized after myocardial infarction, in part through increases in systemic concentrations of vascular endothelial growth factor (29). Impairment of this process, either through decreased numbers of cells or reduced cytokine-mediated migration, correlates with increased risk factors for coronary artery disease (30). Aging is associated with reduced production of angiogenic growth factor in response to hypoxia (31), and EPCs that are generated by the aging bone marrow manifest impairment in critical vascular endothelial growth factor and platelet-derived growth factor pathways (30, 32). Intramyocardial injection of platelet-derived growth factor greatly reduces the extent of myocardial infarction in the older heart [Fig. 1 and (26)]. Moreover, bone marrow-derived EPCs derived from young adult mice can also reconstitute platelet-derived growth factor expression and rescue cardiac angiogenic function in older animals. Transplantation of bone marrow cells from older mice, however, fails to restore senescent vascular function, suggesting that strategies specifically targeted at promoting the angiogenic capacity of the aging bone marrow might allow the recruitment of stem cells to damaged peripheral organ beds.



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Fig. 1. Restoration of cardiac angiogenic pathways by intramyocardial injection of platelet-derived growth factor promotes cardioprotection and reduces the extent of myocardial necrosis (blue stain) in the aging rat heart (26).

 
Grasping the Ravages of Aging

An understanding of the molecular and cellular biology of age-associated changes that specifically affect the function of endothelial cells and bone marrow-derived EPCs should lead to the development of approaches that restore function to the senescent vascular system. Aging is associated with increases in oxidative stress caused, in part, by mitochondrial dysfunction and changes in the activity of enzymes such as superoxide dismutase (33) (see also the Nicholls Perspective and "The Two Faces of Oxygen"), which can promote enhanced endothelial apoptosis (34). Moreover, oxidative stress results in decreased telomere length (35) and might exacerbate senescence-associated decreases in bone marrow plasticity and angiogenic potential. Aging-associated impairment in proangiogenic growth factor pathways (26, 28, 30, 31), which is not fully understood, coupled with associated increases in tumor necrosis factor {alpha} (TNF-{alpha}) concentrations (36, 37) and a senescence-associated shift to proapoptotic TNF receptor pathways (38, 39), can alter the balance of angiogenic and apoptotic signals to promote the loss of critical endothelial cell populations and further impair senescent vascular function, diminishing the recruitment of bone marrow-derived stem cells.

Strategies aimed at promoting the delivery of endogenous stem cells should be focused on overcoming aging-associated vascular dysfunction, potentially through restoration of the function of senescent bone marrow-derived endothelial precursor cells. Indeed, whereas direct injection of bone marrow cells into target organs might lead to transient restoration of local vascular and stem cell function, systemic approaches are required to promote the long-term restoration of the stem cell pathways through the aging vasculature. One such approach is to transplant young genetically matched bone marrow to restore vascular angiogenic function (32), but this procedure might not fully restore the senescence-associated decrease in telomere length, as serial transplantation studies in mice demonstrate (40). To this end, telomere length might be preserved through genetic engineering (41) of telomerase function or cloning techniques that can extend chromosomal telomeres (42) in order to provide prolonged reconstitution of bone marrow-derived endothelial precursor cell activity. Alternatively, optimal therapeutic approaches might be aimed at reversing the effects of certain aging-related processes to promote vascular function. For example, lowering concentrations of oxidized lipoproteins, which are present in increased amounts in aged individuals, improves endothelial function and promotes angiogenic activity (43), in part through an increase in bone marrow-EPC mobilization (44). This can be accomplished with 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, which block cholesterol biosynthesis and thus decrease the accumulation of oxidized lipids that directly and indirectly impair vascular function. Similarly, restoration of estrogen levels can decrease oxidative stress (45), increase EPC telomere length (46), and promote EPC mobilization (47), which might contribute to the improved vascular effects attributed to estrogen replacement therapy (48).

Overall, targeting the aging-associated impairment in vascular function might have profound implications for the treatment of older people. Such strategies might not only decrease the end-organ dysfunction related directly to vascular disease but also could allow the delivery of bone marrow stem cells in order to restore cell populations in tissues damaged as a result of vascular pathology (Fig. 2).



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Fig. 2. Auto repair on the stem cell superhighway. Vascular diseases, including coronary heart disease and stroke, have their greatest impact on older people. Age-associated vascular dysfunction, which includes a combination of enhanced atherosclerosis and thrombosis, as well as depressed vasodilation and angiogenesis, impairs endogenous tissue repair mechanisms in such a way that there is diminished delivery of bone marrow-derived stem cells to peripheral organ beds. Restoration of senescent vascular function, particularly through rejuvenation of bone marrow-derived endothelial precursor cell function, might promote the recruitment of stem cells to damaged organs and decrease the severity of vascular diseases.

 


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Citation: J. M. Edelberg, Auto Repair on the Aging Stem Cell Superhighway. Science's SAGE KE (4 September 2002), http://sageke.sciencemag.org/cgi/content/full/sageke;2002/35/pe13








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