Current Pharmaceutical Design - Volume 17, Issue 30, 2011

During the last 15 years, three pioneer discoveries have changed our common understanding on vascular regeneration, cardiac repair, and cell re-differentiation/programming. In 1997, Asahara et al. [1] discovered the so called “endothelial progenitor cells”. This finding changed the paradigm that during postnatal life vascular remodeling and regeneration exclusively occurs through proliferation and subsequent migration of mature endothelial cells derived from pre-existing vessel walls (angiogenesis). In 2003, Quaini et al. [2] provided the first unequivocal documentation of the existence of primitive cells able to generate all the different component structures of the myocardium in adult human life in the setting of sex mismatched cardiac transplantation. In 2006, Takahashi and Yamanaka [3] were the first to show that somatic cells could be reprogrammed to embryonic stem cell-like pluripotent cells by the expression of only four transcription factors. These discoveries not only gave us further insights in the pathology of cardiovascular disease, they also triggered the extensive research in analyzing the potential of stem cell therapy for the treatment of cardiac disorders. The review articles included in this issue of Current Pharmaceutical Design aim to provide an overview on the novel insights regarding “endothelial progenitor cells”, cardiac resident stem cells, and inducible pluripotent stem cells. With respect to stem cell trafficking and homing, the role of chemokines, cytokines, and adhesion molecules is reviewed. Furthermore, this issue summarizes the current knowledge on the potential of stem cell therapy for the treatment of different cardiac disorders, including inflammatory cardiomyopathy, chronic ischemic myocardial disease, myocardial infarction, and diabetic cardiomyopathy. Among others, hurdles in stem cell therapy, advantages of one stem cell over the other, and the importance of the route of administration are discussed. Finally, the clinical experience with cardiac surgical cell therapy is summarized. The first review by Dirk Strunk [4] intends to critically outline aspects of terminology, origin and applicability of the so called “endothelial progenitor cells”, the somatic progenitors which are thought to maintain integrity and support regeneration of the inner lining of vessels through proliferation. With respect to cardiac resident stem cells, the review of Frati et al. [5] addresses the potential role of cardiac stem progenitor cells in the onset and development of congestive heart failure and its reversal by regenerative approaches aimed at the preservation and expansion of the resident pool of progenitors. Thorrez and Sampaolesi [6] give an overview of the current applications of inducible pluripotent stem cells in cardiovascular drug development and highlight active areas of inducible pluripotent stem cell research towards functional repair of the damaged heart. Furthermore, they discuss the results obtained from adult stem cells in clinical trials in light of the hurdles which have to be taken to move inducible pluripotent stem cells to the clinic......

A constantly growing body of research has been performed mainly over the past decade and a half, aiming to facilitate our still limited understanding of the biology and function of various different cell types which collectively have been termed endothelial progenitor cells. This review intends to critically outline aspects of terminology, origin and applicability of the somatic progenitors which are thought to maintain integrity and support regeneration of the inner lining of vessels through proliferation. Despite reasonable progress in the field, we are still not confident regarding the precise phenotype and function of endothelial progenitor cells. Model systems that have been developed to study the vascular regenerative potential of human endothelial progenitor cells in animal models in vivo present principle tools for testing new agents that modulate vascular homeostasis and regeneration.

The introduction of stem cells in cardiology provides new tools in understanding the regenerative processes of the normal and pathologic heart and opens new options for the treatment of cardiovascular diseases. The feasibility of adult bone marrow autologous and allogenic cell therapy of ischemic cardiomyopathies has been demonstrated in humans. However, many unresolved questions remain to link experimental with clinical observations. The demonstration that the heart is a self-renewing organ and that its cell turnover is regulated by myocardial progenitor cells offers novel pathogenetic mechanisms underlying cardiac diseases and raises the possibility to regenerate the damaged heart. Indeed, cardiac stem progenitor cells (CSPCs) have recently been isolated from the human heart by several laboratories although differences in methodology and phenotypic profile have been described. The present review points to the potential role of CSPCs in the onset and development of congestive heart failure and its reversal by regenerative approaches aimed at the preservation and expansion of the resident pool of progenitors.

The field of stem cell research was revolutionized with the advent of induced pluripotent stem cells. By reprogramming somatic cells to pluripotent stem cells, most ethical concerns associated with the use of embryonic stem cells are overcome, such that many hopes from the stem cell field now seem a step closer to reality. Several methods and cell sources have been described to create induced pluripotent stem cells and we discuss their characteristics in terms of feasibility and efficiency. From these cells, cardiac progenitors and cardiomyocytes can be derived by several protocols and most recent advances as well as remaining limitations are being discussed. However, in the short time period this technology has been around, evidence emerges that induced pluripotent stem cells may be more prone to genetic defects and maintain an epigenetic memory and thus may not be entirely the same as embryonic stem cells. Despite the lack of a complete fundamental understanding of stem cell biology, and even more of ways how to coax them into defined cell types, the technology is quickly adopted by industry. This paper gives an overview of the current applications of induced pluripotent stem cells in cardiovascular drug development and highlights active areas of research towards functional repair of the damaged heart. Adult stem cells have already been taken to clinical trials and we discuss these results in light of potential and hurdles to be taken to move induced pluripotent stem cells to the clinic.

Although definition and mechanistic understanding of pro-angiogenic progenitor cells remains unsatisfactory, general agreement highlights their role in regenerative process following tissue injury and ischemia. Furthermore, stem-cell based therapy represents a hot topic of cardiovascular medicine. Recent studies provide new insights on the signalling pathways that modulate stem/progenitor cell mobilization from bone marrow, homing to ischemic area and participation in vascular remodelling and tissue healing. This review focuses on current knowledge and emerging concepts on stem cell/progenitor cell trafficking in relation to changes in surrounding environment and epigenetic modifications caused by risk factors and comorbidities.

Cardiovascular disease remains the leading cause of morbidity and mortality in the developed countries. This review summarizes current pre-clinical and clinical evidence for the potential role and mechanisms of action of stem and progenitor cells in vascular and cardiac repair and regeneration. Apart from cell transplantation strategies, approaches to maintain stem cell niche function and targeting mobilization/recruitment of specific stem/progenitor cell populations may aid in preserving vascular and cardiac function. Moreover, with the use of patient-derived induced pluripotent stem cells, the field of regenerative medicine is entering a new era. Potential applications of induced pluripotent stem cells and direct reprogrammed cells as well as recent developments in tissue engineering are discussed.

Inflammatory cardiomyopathy is associated with a diffuse inflammation in the heart accompanied with cardiac fibrosis, cardiomyocyte apoptosis, and reduced capillary density. On the other hand, mesenchymal stromal cells (MSCs) have immunomodulatory, anti-fibrotic, anti-apoptotic, and pro-angiogenic features, making them attractive candidates for the treatment of inflammatory cardiomyopathy. The potential of MSC application for the treatment of myocarditis is supported by their beneficial effects in experimental models of acute and chronic inflammatory cardiomopathy. This review summarizes the cardioprotective features of MSCs and describes how MSCs are primed by the inflammatory environment to exert their protective effects. In view of clinical translation, searching for the optimal source of MSC and delivery route, allowing efficient and non-invasive cell application, the differences between MSCs of distinct origin and between diverse routes of application are outlined.

Over the last decade, much was learned about the biology of several types of stem and progenitor cells. It has become apparent that various cell sources may have the capacity to promote cardiomyogenesis and new blood vessel formation through different mechanisms, forming the rationale for cell-based therapy in patients with chronic ischemic heart disease. After initial clinical studies have provided evidence for safety of cell administration, larger randomized trials demonstrated variable effects on myocardial perfusion and contractile performance. Although cell-based therapy is a promising strategy for the treatment of myocardial disease, many questions remain to be answered with respect to the optimal cell type, delivery route and mechanism of action in order to improve the outcome of cardiac cell therapy. This paper aims to provide an overview of the methods available to apply cell-based therapy in chronic ischemic myocardial disease. The different cell types that have been tested in (pre)clinical trials and their proposed mechanism of action will be discussed, along with the possible routes of cell delivery. Furthermore, the experience from experimental and clinical studies will be summarized, and innovative strategies to enhance the efficacy of cell therapy, for example by improving cell retention and survival, will be reviewed.

Despite timely reperfusion and subsequent optimal postinfarct pharmacotherapy and device-based treatment, the outcome in patients with severe myocardial infarction remains unfavourable. Myocardial salvage is incomplete, resulting in adverse left ventricular remodeling with concomitant morbidity and mortality. The combined risk of recurrent myocardial infarction, death or readmission for heart failure amounts to 25 % within the first year, highlighting the need for additional treatment strategies. Recent and rapidly evolving insights in cardiac biology, recognizing endogenous repair capabilities of the adult human heart, paved the path towards progenitor or stem cell based cardiac protection and repair strategies following ischemic injury. We critically report on the major randomized controlled clinical trials published so far concerning intracoronary transfer of autologous bone marrow cells in the setting of acute myocardial infarction. Moreover, underlying mechanisms, practical aspects, remaining questions and future challenges are highlighted. Taken together, these trials confirm the safety and feasibility of intracoronary progenitor cell transfer in the setting of myocardial infarction. Efficacy data suggests its potential to improve left ventricular function recovery beyond current state of the art therapy, but results are mixed, modest at best and do not support true cardiomyogenesis. Hence, due to its complexity, costs and remaining uncertainties, it is still too early to implement progenitor cell therapy in its current form in standard treatment strategies for ischemic heart disease. Future studies on strategies for cardiomyocyte regeneration in combination with myocardial protection are needed.

Diabetic cardiopathy includes a specific cardiomyopathy, which occurs in the absence of coronary heart disease under diabetes mellitus. Hallmarks of diabetic cardiomyopathy are besides others, interstitial inflammation, cardiac oxidative stress, interstitial and perivascular fibrosis, cardiac apoptosis, intramyocardial microangiopathy, endothelial dysfunction, abnormal intracellular Ca2+-handling, cardiomyocyte hypertrophy, and impaired cardiac stem cells. Since mesenchymal stromal cells have been shown to have anti-diabetic as well as cardioprotective features, we summarize in this review how they can indirectly affect diabetic cardiomyopathy via their influence on the metabolic trigger hyperglycemia, and how they can directly influence the cardiac cellular consequences typical for diabetic cardiomyopathy via their immunomodulatory, anti-oxidative, anti-fibrotic, anti-apoptotic, pro-angiogenic, and endothelial-protective features, and their ability to activate cardiac progenitor cells. Furthermore, the dysfunctionality of (bone marrow-derived) mesenchymal stromal cells under diabetes mellitus and potential strategies to overcome this impairment in cell functionality are outlined.

More than 10 years ago, the first clinical application of cardiac cell therapy was performed in a patient undergoing coronary bypass grafting (CABG). Ever since, catheter-based cell delivery approaches have dominated the field, but surgical cell therapy continues to provide important information on safety and efficacy of various cell therapy strategies. The open chest offers unrivalled simplicity and precision of intramyocardial cell injection, and the cardiac surgical patient population includes those with very advanced heart disease who are in greatest need of innovative regeneration concepts. In this review, the clinical experience with cardiac surgical cell therapy is summarized and critically appraised.