Stem cells and regeneration of the cardiovascular system: facts, fictions, and uncertainties

The data reviewed here support the view that bone marrow (BM) stem cells can migrate to infarcted myocardium and differentiate into mature, functional cardiomyocytes. Cytokines can mobilize BM stem cells from marrow leading to homing of progenitor cells to infarcted myocardium. Interestingly, contractile performance in these studies appears greater than the capacity of the regenerated cell mass and its biomechanial organization predict, suggesting that the function of the regenerated cell per se may not alone account for global functional recovery.     

Stem cells for cardiovascular repair - the challenges of the aging heart

The discovery of extracardiac progenitor cells and resident cardiac stem cells in recent years has led to a great deal of interest in the development of therapeutic strategies that target these endogenous cell sources for promotion of cardiovascular repair mechanisms in the diseased heart. Cardiovascular risk increases with age and among many factors, the age-associated decline in cardiac and vascular regenerative capacity may contribute to the progressive deterioration of cardiovascular health. Thus, understanding the mechanisms which underlie the dysregulation of cardiac stem and progenitor cells may lead to the identification of novel targets and approaches to reverse this decline. In this review, we outline the current knowledge about cardiac stem and progenitor cells, their contribution to cardiovascular regenerative processes and factors that may affect their decreased function in aging individuals. Moreover, we describe the therapeutic strategies that are currently being tested in clinical trials as well as potential new avenues of investigation for the future.     

Stem cells and myocardial regeneration.

The belief that organs such as the heart could only undergo hypertrophy but not hyperplasia has been challenged with the discovery that differentiated cells can be constantly regenerated by stem cells (SCs). The dogma considering the heart as a post-mitotic organ has been questioned by the demonstration of continuous renewal of cardiomyocytes produced by cardiac SC differentiation and by bone marrow SCs. Several experimental models for transplantation of SCs into damaged myocardium have been developed. This new strategy is known as cellular cardiomyoplasty (CCM). CCM may be beneficial in improving cardiac function using various SC types, although many questions remain unanswered. Nonetheless, it is expected that their clinical potential will radically modify the therapeutic approach to certain cardiac diseases. In this review, we will focus on the different types of SCs tested in the heart, their advantages and limitations, and their potential therapeutic applications.     

Stem cells for myocardial regeneration

Stem cells are being investigated for their potential use in regenerative medicine. A series of remarkable studies suggested that adult stem cells undergo novel patterns of development by a process referred to as transdifferentiation or plasticity. These observations fueled an exciting period of discovery and high expectations followed by controversy that emerged from data suggesting cell-cell fusion as an alternate interpretation for transdifferentiation. However, data supporting stem cell plasticity are extensive and cannot be easily dismissed. Myocardial regeneration is perhaps the most widely studied and debated example of stem cell plasticity. Early reports from animal and clinical investigations disagree on the extent of myocardial renewal in adults, but evidence indicates that cardiomyocytes are generated in what was previously considered a postmitotic organ. On the basis of postmortem microscopic analysis, it is proposed that renewal is achieved by stem cells that infiltrate normal and infarcted myocardium. To further understand the role of stem cells in regeneration, it is incumbent on us to develop instrumentation and technologies to monitor myocardial repair over time in large animal models. This may be achieved by tracking labeled stem cells as they migrate into myocardial infarctions. In addition, we must begin to identify the environmental cues that are needed for stem cell trafficking and we must define the genetic and cellular mechanisms that initiate transdifferentiation. Only then will we be able to regulate this process and begin to realize the full potential of stem cells in regenerative medicine.     

Stem cells and regeneration of human myocardium

A concept of impossibility of appearance of novel cardiomyocytes in the heart of adult men in exchange for those lost due to cardiovascular diseases had dominated medicine and biology for many long decades. However ability of human myocardium to regenerate was demonstrated during recent years in multiple studies. This dictated necessity to reconsider previously generally accepted concept. At present researchers and practicing physicians actively discuss possibility of the use of transplantation of bone marrow stem cells, proper cardiac stem cells, skeletal muscle myoblasts or precursors of endothelial cells in patients with myocardial infarction and heart failure in order to restore normal cardiac structure and function. Another potential method of restoration of the myocardium in patients with cardiovascular diseases is the use of cytokines which stimulate migration of stem cells into myocardium and their differentiation into cardiomyocytes.     

干细胞移植与心血管疾病

干细胞是一类具有自我复制和分化潜能的早期未分化细胞。本综述着重介绍干细胞移植技术在基础及临床心血管领域的研究现况 ,并对干细胞技术的进一步临床应用前景作了初步讨论     

Normal and abnormal aging of cardiovascular system

Studies of normal aging in the cardiovascular system in humans are affected by the study population. Besides intrinsic biological aging, extrinsic factors including overt or latent cardiovascular diseases as well as life style variables such as physical activity, diet, alcohol and smoking may influence the age-related changes of cardiovascular function. We have recruited "normal" elderly subjects from community-dwelling volunteers by extensive health screening procedures including treadmill maximum exercise tests. Some of their cardiovascular functions, such as various cardiovascular regulatory functions, were altered compared to normal young subjects, while others such as resting hemodynamics were not. Interrelationships among various autonomic functions in the elderly were not recognized. Although general effects of life styles on circulatory regulatory functions were not clearly indicated, variables such as sodium intake or body mass index appeared to affect some of the sympathetic nervous functions. Furthermore, hypertension in the elderly had much less impact on cardiovascular functions than is generally expected, based on the results from young or middle-aged subjects. To identify factors which either modify (accelerate) or do not affect the aging of the cardiovascular functions is important not only to achieve a good aging process but also to establish therapeutic goals in elderly subjects.     

Endothelial progenitor cells for cardiovascular regeneration

Endothelial progenitor cells (EPCs) are peripheral blood mononuclear cells that can differentiate into mature endothelial cells. Adult EPCs were first discovered in human peripheral blood in 1997. Since then, the potency of EPCs for cardiovascular regeneration has been demonstrated in several preclinical studies; and investigators are beginning to evaluate the therapeutic utility of EPCs in early-phase clinical trials. This review summarizes the progression of basic, preclinical, and clinical research into the potential use of EPC therapy for cardiovascular regeneration.     

Stem cells for heart failure in the aging heart

Despite a wide range of therapeutic interventions, the prognosis for most patients with heart failure remains poor. The identification of stem cells with the ability to generate cardiomyocytes and vascular cells and promote local repair and survival pathways has highlighted the ability of the heart to undergo regeneration and potentially provides a new therapeutic strategy for treatment of the failing heart. In recent years, however, clinical trials aimed at exploiting the beneficial effects of stem and progenitor cells to treat patients with cardiovascular disease have resulted in mild improvements at best, suggesting that these cells and/or the conditions in which they find themselves are not conducive to cardiac repair. Heart failure is most prevalent among older individuals, and a growing body of evidence suggests that with increasing age, cardiac stem and progenitor cells undergo senescent changes that impair their regenerative capacities. Moreover, environmental alterations over time appear to impact the capacity of these cells to improve cardiac function. Understanding these senescent changes may lead to the development of new and improved approaches to exploit the potential of stem cells to repair the aging heart. In this review, age-associated alterations in cardiac stem cell function are discussed, as well as strategies that are being investigated to promote cardiac regeneration in the patient with heart failure.     

Hematopoietic stem cells and the aging hematopoietic system

The etiology of the age-associated pathophysiological changes of the hematopoietic system including the onset of anemia, diminished adaptive immune competence, and myelogenous disease development are underwritten by the loss of normal homeostatic control. As tissue and organ homeostasis in adults is primarily mediated by the activity of stem and progenitor cells, it has been suggested that the imbalances accompanying aging of the hematopoietic system may stem from alterations in the prevalence and/or functional capacity of hematopoietic stem cells (HSCs) and progenitors. In this review, we examine evidence implicating a role for stem cells in the aging of the hematopoietic system, and focus on the mechanisms suggested to contribute to stem cell aging.     

Growth hormone,insulin-like growth factor-1 and the aging cardiovascular system

There is a large body of evidence that biological aging is related to a series of long-term catabolic processes resulting in decreased function and structural integrity of several physiological systems, among which is the cardiovascular system. These changes in the aging phenotype are correlated with a decline in the amplitude of pulsatile growth hormone secretion and the resulting decrease in plasma levels of its anabolic mediator, insulin like growth factor-1 (IGF-1). The relationship between growth hormone and biological aging is supported by studies demonstrating that growth hormone administration to old animals and humans raises plasma IGF-1 and results in increases in skeletal muscle and lean body mass, a decrease in adiposity, increased immune function, improvements in learning and memory, and increases in cardiovascular function. Since growth hormone and IGF-1 exert potent effects on the heart and vasculature, the relationship between age-related changes in cardiovascular function and the decline in growth hormone levels with age have become of interest. Among the age-related changes in the cardiovascular system are decreases in myocyte number, accumulation of fibrosis and collagen, decreases in stress-induced cardiac function through deterioration of the myocardial conduction system and beta-adrenergic receptor function, decreases in exercise capacity, vessel rarefaction, decreased arterial compliance and endothelial dysfunction leading to alterations in blood flow. Growth hormone has been found to exert potent effects on cardiovascular function in young animals and reverses many of the deficits in cardiovascular function in aged animals and humans. Nevertheless, it has been difficult to separate the effects of growth hormone deficiency from age-related diseases and associated pathologies. The development of novel animal models and additional research are required in order to elucidate the specific effects of growth hormone deficiency and assess its contribution to cardiovascular impairments and biological aging.     

Mitochondria and cardiovascular aging

Old age is a major risk factor for cardiovascular diseases. Several lines of evidence in experimental animal models have indicated the central role of mitochondria both in lifespan determination and in cardiovascular aging. In this article we review the evidence supporting the role of mitochondrial oxidative stress, mitochondrial damage and biogenesis as well as the crosstalk between mitochondria and cellular signaling in cardiac and vascular aging. Intrinsic cardiac aging in the murine model closely recapitulates age-related cardiac changes in humans (left ventricular hypertrophy, fibrosis and diastolic dysfunction), while the phenotype of vascular aging include endothelial dysfunction, reduced vascular elasticity, and chronic vascular inflammation. Both cardiac and vascular aging involve neurohormonal signaling (eg, renin-angiotensin, adrenergic, insulin-IGF1 signaling) and cell-autonomous mechanisms. The potential therapeutic strategies to improve mitochondrial function in aging and cardiovascular diseases are also discussed, with a focus on mitochondrial-targeted antioxidants, calorie restriction, calorie restriction mimetics, and exercise training.     

Tracking stem cells in the cardiovascular system

Stem cells are a promising approach to cardiovascular therapeutics. Animal experiments have assessed the fate of injected stem cells through ex vivo methods on sacrificed animals. Approaches are needed for in vivo tracking of stem cells. Various imaging techniques and contrast agents for stem cell tracking will be reviewed.     

Chromatin methylation and cardiovascular aging

DNA and histone methylation are well characterized epigenetic marks that are altered during the aging process. In aged cells and tissues, DNA cytosine tagging by methylation undergoes the so-called “epigenetic drift”, in parallel with a change in the methylated histone profile. Despite the large body of knowledge regarding age-dependent epigenetic changes, there are few reports related to this topic in the cardiovascular field. This review summarizes age-dependent changes in DNA and histone methylation with a specific focus on age-related cardiovascular diseases (CVDs).     

衰老细胞相关信号传递系统

细胞信号传递系统是一个复杂的调控网络。激素、神经递质、细胞(生长 )因子等生物信息通过ｃＡＭＰ(α受体 )、磷脂酰肌醇 (β受体 )、丝氨酸 /酪氨酸蛋白激酶 (ＴＰＫ)、及离子通道、离子泵等途径发挥生物效应。β受体通过激活Ａ激酶而诱导细胞分化 ,抑制生长增殖 ;α受体及ＴＰＫ则通过激活Ｃ激酶、Ｇ激酶、Ｃａ2 + ＣａＭ激酶 ,并通过酪氨酸蛋白激酶的激活 ,诱导核内多种生长调控因子 ,如ｆｏｓ、ｍｙｃ基因表达 ,从而促进细胞生长增殖。衰老对细胞信号传递系统的影响主要表现在对细胞周期进程及与细胞生长增殖相关的转录调控因子功能的…     

Sympathetic nervous system as a target for aging and obesity-related cardiovascular diseases

GeroScience - Chronic sympathetic nervous system overactivity is a hallmark of aging and obesity and contributes to the development of cardiovascular diseases including hypertension and heart...