Endothelial Progenitor Cells A New Real Hope?

Chronic inflammatory diseases, such as cardiovascular diseases (CVDs), diabetes, Alzheimer’s disease (AD) and cancer, have a disproportionate prevalence with advancing age owing to the continuous growth in the aging population. This condition determines several medical, economic and social problems due to the dramatic increase in the number of affected individuals, who are not autonomous. Thus, research efforts are centred around reducing and/or delaying the onset and progression of these diseases by researching new strategies for early prevention and diagnosis. In this context, understanding the mechanisms involved in the tissue, organ protection and repair are imperative for the development of new preventive treatments. Accordingly, medical research is pursuing new ways of trying to face this imposing challenge, i.e. regenerative medicine with stem cells and progenitors, such as endothelial progenitor cells (EPCs). Since their discovery, EPCs have rapidly caught the attention of researchers for their ability to facilitate vascular repair in different ischemic tissues, by contributing to neovascularization in several tissue injury models. Interest has also heightened dramatically after evidence about their capacity to counteract related CVD endothelium dysfunction. In addition, recent studies, using different animal models of cancer, suggested the importance of bone marrow-derived EPCs (i.e. postnatal vasculogenesis) in tumor vascularization and growth. EPCs are present in the peripheral blood; their levels are increased in response to certain signals/cytokines; and they home into the neovascular bed of malignant tissues. Furthermore, at the clinical level, evidence is emerging that changes in EPC levels might predict the efficacy of anticancer drug combinations, such as anti-angiogenic agents. On the basis of these observations, EPCs have attractive potential diagnostic and therapeutic applications for malignant diseases. Additional recent evidence also suggests the possibility to adopt EPCs as prognostic biomarkers for AD. It has been observed that patients with AD have reduced circulating EPCs, suggesting that an anomalous capacity to regenerate endothelium is associated with AD. In the case of diabetes, numerous groups have detected decreased EPC numbers and functionality in affected patients, confirmed by decreased numbers of colony-forming units, decreased adhesion and migration and decreased tubule formation. In addition, it has been found that strategies based on ix the administration of statins, angiotensin converting enzyme inhibitors, angiotensin receptor blockers and peroxisome-proliferator-activating-receptor-c agonists, up-regulate and enhance both the EPC number and functionality. Emerging evidence also indicates that transplantation of EPCs is beneficial for the recovery of ischemic cerebral injury. EPC-based therapy could open a new avenue for ischemic diseases. Currently, clinical trials for evaluating EPC transfusion in treating ischemic stroke are underway. However, much of the increasing evidence implicating progenitors in these diseases is contrasting. Thus, their real role remains uncertain. This is compounded by the necessity for a standardization of the different methodologies and protocols for characterizing, identifying and defining these cells, or their subsets. This problem represents one of the major consequences of the large heterogeneity that exists in data from the literature. In this monograph, some of these aspects are discussed using research to give clear indications regarding EPC functions and definitions, as well as evidence to support the problem of their characterization. In addition, recent findings on their role as disease biomarkers and exogenous or autologous cell therapy are provided. Certainly, limitations are also stressed. Based on these observations, this monograph, structured in 3 chapters, will describe, in the first chapter, the relevance of translational medicine (TM) as a new research approach to counteract the imposing challenge of age-related diseases. In particular, a considerable emphasis will be given to regenerative medicine (RegMed), a new branch of TM. RegMed can be used to improve health and quality of life, by restoring, maintaining or enhancing tissue and functions of organs. Of the diverse RegMed approaches, a particular focus will be given to stem/progenitor cell-based therapies, their benefits and disadvantages, as well as to the description of types of stem and progenitor cells considered for regenerative cell therapies, such as EPCs as emerging candidates for RegMed applications. To understand the value and potentiality of EPCs in this field, as well as the related limitations, in Chap. 1, the biological features, origins, sources and endogenous functions of EPCs will be reported. In addition, a critique of EPCs, namely relating to their characterization and definition, will be put forward, because they represent the real cause of the extensive heterogeneity of existing data in the literature on this topic, which creates more confusion than comprehension. Chapter 2 outlines the clinical relevance of EPCs as both potential predictors, and diagnostic and prognostic biomarkers of age-related diseases and therapeutic agents, by discussing the advantages, disadvantages and the conflicting data. To conclude, Chap. 3 will propose a potential roadmap for revising the findings obtained to date, reordering them and creating a clear puzzle of the valid data. It can facilitate understanding of important aspects, including firstly defining, isolating and characterizing EPCs by establishing a standardized criteria for EPC research, discrimination of appropriate sub-populations for cell therapy, timing, dosing, priming of cells, and delivery mode for different applications. Furthermore, influencing factors might also be identified with the aim to focus resources and efforts, and the problems linked to the local retention and fate of cells in the therapeutic target zone might be resolved. Finally, an overview of innovative strategies will be reported, which might improve x Preface the efficacy of cell therapy at all levels, including cell priming, bio-nanotechnology, and tissue engineering. They might be used as emerging tools, and, in particular, their combination might produce very advantageous results. Such descriptions and discussions address an extensive audience, including students, health care professionals, biologists, physicians and diverse scientific community. In particular, it will be a valuable resource for clinical scientists, researchers, university professors, health practitioners, gerontologists and geriatricians, students, and for all those who wish to broaden their knowledge in the allied field. Policy makers and agencies involved in implementing preventive policies might also use this monograph as an updated integral resource. All government and private organizations, including libraries at the college level, academic universities, and research institutions might benefit from it as resource for its current references. Palermo, Italy Carmela Rita Balistreri July 2016