Stem Cells

The following sections are included:

• Dedication
• Contents
• About the Editor
• Preface

Pluripotent stem cells offer tremendous potential for the treatment of various diseases, including cardiovascular disease. Myocardial infarction results in the almost irreversible loss of over 1 billion cardiomyocytes, with little endogenous replacement from the damaged heart. Subsequently, the quality of life of patients recovering from myocardial infarction is significantly reduced and is, to date, without an effective cure. Pluripotent stem cell-derived cardiomyocytes bring exciting potential for use in regenerative medicine therapies by replacing the damaged cells with healthy, lab-grown cardiomyocytes. However, safety concerns regarding the purity and maturity of pluripotent stem cell-derived heart muscle is currently still a significant barrier to the successful translation of lab-grown cells into patients. This chapter will review the current status of embryonic and induced pluripotent stem cell strategies to generate heart muscle, as well as discuss the currently remaining obstacles which must be overcome for the safe clinical application of stem cell therapy.

Myocardial infarction is the leading cause of chronic heart failure, an ominous disease entity with a wide prevalence in many countries. The morbidity and mortality of chronic heart failure remains high, despite recent pharmacologic advances and cardiac resynchronization therapy. After acute coronary occlusion, the necrotic area triggers a cascade of pathophysiologic events that may lead to structural and electrophysiological left ventricular remodeling, and eventually to progressive chronic heart failure. Therapeutic strategies targeting the repair of the infarcted myocardium aim at interrupting this vicious cycle and constitute an etiological and, as such, promising approach. However, after the initial enthusiasm accompanying early reports, subsequent preclinical and clinical studies unveiled several challenges associated with cell survival and proliferation, as well as abnormal electrophysiological responses after engraftment. In this chapter, we review the main cell sources that hold promise for clinical use, either alone or combined with growth factors and biomaterials, focusing on the acute and medium-term electrophysiological effects of cardiac regeneration approaches.

Real-time monitoring of stem cells has been a growing area of interest over the past decade because of new regenerative medicine approaches. Also, the effect of culture composition on stem cell metabolic pathways and their regulation of cellular fate are of increasing importance. In this chapter, non-destructive methods for cell monitoring in vitro are reviewed, including recent developments enabling metabolomics monitoring using LC-MS and GC-MS. Finally, the application of metabolomics in the examination of stem cell differentiation is discussed, suggesting the potential of metabolomic profiling as a powerful tool for regenerative medicine approaches.

In spite of the current notable advances in surgical management of critical limb ischemia (CLI), the most severe form of peripheral artery disease, it is still associated with the high frequency of amputations, lethality and low quality of life. Although the compensatory opportunities are mainly exhausted in the treatment of CLI, an efficient medical intervention remains possible. The purpose of this intervention is to eliminate a pronounced imbalance between the blood supply of the ischemic tissues and their metabolic needs. The physiological compensatory arteriogenesis, which actively proceeds at the initial stages of limb ischemia, almost ceases to the beginning of its transition into the final stages. Therefore, research efforts are focused on those technologies for tissue repair which are directed at the activation and expansion of the microvascular bed (angiogenesis) in the affected limb. Cell therapy, having been actively studied from the beginning of 2000s, is one of such approaches. This review discusses in-depth the advantages of different cell types for the CLI therapy, including peripheral bone marrow-derived mononuclear cells (BMMNCs) and mesenchymal stem cells (BMMSCs). The results of the most important pre-clinical and clinical studies, including the ongoing clinical trials, involving cell-based approach for CLI therapy have also been discussed besides optimization of the cell delivery techniques with or without the use of biomaterials as cell carriers.

Heart disease is the primary cause of mortality and morbidity in the world. Existing therapies limit the extent of injury without structural restoration of the lost myocardial tissue. Consequently, injured myocardial tissue continues to remodel that ultimately leads to cardiac failure. Cell therapy provides a promising alternative for enhancement of cardiac structure and function, yet the mechanism explaining salutary effects remain elusive. Ability of the transplanted stem cells to adopt cardiac cell morphology dubbed as the “Transdifferentiation Hypothesis” is widely believed to be the mechanism for cell therapy. Recently, however multiple studies provide evidence that challenges the transdifferentiation hypothesis, thereby questioning the ability of transplanted stem cells to differentiate into tissue cell types. Alternatively, stem cells secrete growth factors, proteins and extracellular vesicles including exosomes that possess cardioprotective and regenerative properties, thereby forming the “Paracrine Hypothesis”. This chapter aims to summarize the cell therapy and its applications for cardiac repair and regeneration including mechanisms explaining beneficial effect of the transplanted stem cells. A particular focus will be on the emerging importance of the paracrine hypothesis and its future implication for cardiac tissue repair after injury.

Cancer Stem Cells (CSCs) are a small population of cells within tumors holding stemness properties that sustain cancer progression, such as enhanced capacities for self-renewal, growing, metastasizing, homing, and reproliferating. CSCs show remarkable organizing capacities as they can educate neighboring cells to provide nutrients and collaborate in the elusion from the immune system, creating an environment favorable for tumor growth. In particular, tumor-specific microenvironments comprise stromal cells, immune cells, networks of cytokines and growth factors, hypoxic regions, and the extracellular matrix. The contribution of the microenvironment in this picture is crucial: it is now accepted that the “cancer” scenario is not simply composed of transformed cells working together in isolated and strictly autonomous machinery. Tumor microenvironment actively collaborates with neoplastic cells at different levels: promoting proliferation while evading growth suppression and immune surveillance, overcoming cell death, modulating cell metabolism, activating angiogenesis and invasion/metastasis programs. Also, the interactions between CSC and microenvironment help in their survival of common anti-cancer therapies thus being partly responsible for disease recurrence. Further studies regarding CSC/microenvironment seem to be promising for new CSC-targeting therapies, which may represent an innovative strategy for the cure of lung cancer.

Mesenchymal stem cells (MSCs) can be isolated from many different tissue sources and have several superior characteristics that render them more ideal for therapeutic application compared to other types of stem cells. MSCs have excellent immune-modulatory properties for reducing local and systemic inflammation. MSCs modulate the immune system by secreting paracrine factors and direct cell-to-cell contact with immune cells. MSCs interact with multiple immune cells, including T-cells, B-cells, natural killer cells, macrophages and dendritic cells to modulate the host immune response. Due to their ability to suppress inflammation, preclinical and clinical studies have investigated MSCs extensively for treating autoimmune and inflammatory diseases such as multiple sclerosis, systemic lupus erythematosus, diabetes mellitus, graft-versus-host disease, and graft rejection. Thus far, most studies have reported that MSC therapy yields positive results in ameliorating immune-mediated diseases. Both autologous and allogeneic MSCs can be transplanted into humans safely without eliciting the host immune response and with minimal risk of tumor formation. However, a few limitations such as dosage, route, number, and timing of transplantation require more extensive study to derive the maximum therapeutic effect.

In the past decade, several major breakthroughs and groundbreaking discoveries have been reported from medical science researchers involved in the areas of hematology and oncology, due to improved understanding of the human immune system. Novel amongst these discoveries is the biopharmaceuticals such as monoclonal antibodies and immune checkpoint regulators that have revolutionized our options of therapeutic interventions for patients with diseases once considered untreatable. Autologous/allogeneic/mesenchymal stem cells are collected by Apheresis machines and are used in regenerative medicine by physicians to treat previously considered incurable diseases. Eventually, it has all progressed to the reprogramming of somatic cells by genetic engineering techniques. Chimeric Antigen Receptor (CAR) T-cells are reprogrammed cells with the capacity to kill malignant cells via binding of their new, synthetic and specific receptors to their targets on tumor cells. Some of the CAR T-cell preparations are currently approved by the Food and Drug Agency for the treatment of refractory acute lymphocytic leukemia and diffuse large B cell lymphoma. Their potentials are under investigation in treating chronic lymphocytic leukemia, acute myeloid leukemia, multiple myeloma, and other lymphomas. After constructing a CAR gene and transferring it into patients’ own T-cells’ DNA via a vector, genetically modified CAR T-cells are created. Currently, CAR T-cells are more popular and effective than dendritic cell-based tumor vaccines. Development and usage of CAR T-cells in clinical studies have also been reviewed.

Recent years have observed the development of stem cell therapy, which appeared as promising treatment strategies for various disease conditions. Cell therapies employ stem cells, or cells grown from stem cells, to replace or rejuvenate damaged tissue. Numerous findings have suggested a significant therapeutic advantage with the utilization of cell therapeutic approaches in various neurological disorders including amyotrophic lateral sclerosis, various heart disorders involving endstage ischaemic heart diseases, myocardial infarction, or preventing vascular restenosis. Various bone fractures are also reported to benefit from cell therapy including osteogenesis imperfecta. Nonetheless, cell therapy has its drawbacks, which include the risk of tumorigenesis or immune rejection. The therapy also faces ethical and political controversies besides scientific challenges. Consequently, efforts are made towards the development of stem cell secretome which are the secreted factors produced by the stem cells that are responsible for mediating and modulating stem cells effects in the disease condition. The secretome holds various added advantages: it can be manufactured, freeze-dried, packaged, and transported more easily which is some of the numerous advantages of using secretome over the use of stem cells. Besides, as secretome is free from cells, there is no need to match the donors and recipients to avoid the risk of rejection. For that reason, stem cell-derived secretome is a promising possibility to be used as pharmaceuticals for regenerative medicine. Up till now, there have have been limited clinical trials utilizing secretome in certain disease conditions.

The following section is included:

• Index