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With approximately 130 million babies born worldwide every year umbilical cord blood represents perhaps the largest potential source of stem cells for regenerative medicine. Between 1972 and 2008, it is estimated that over 10,000 patients would have been treated by cord blood cells for over 80 different clinical conditions. Cord blood stem cells are used clinically mostly to support patients suffering from haematological and immunological diseases but they also provide emerging therapeutic solutions for limited cases of type 1 diabetes or infant cerebral injuries. Cord blood samples are collected after birth and bio-processed before cryopreservation in either public biobanks for unrelated allogenic use or private family biobanks for related allogenic and autologous uses. Regenerative medicine research demonstrated the existence of multipotent stem cells with embryonic characteristics in cord blood, which can produce over 20 tissue types including liver, neural or insulin-secreting cells. Cord blood stem cells not only offer therapeutic benefits at present but also show real potential for the advancement of regenerative medicine.

The provision of central resources of human stem cell lines will be an important element in enabling progress in stem cell research and the development of safe and effective cell therapies. These resource centres, commonly referred to as "stem cell banks", could promote advances in the field of stem cell research, by providing access to well-characterised and quality controlled seed stocks of human stem cell lines that have been checked for appropriate ethical provenance. Such banks can also deliver benefits for the field through establishing international collaboration and standardisation between the developing national stem cell banking centres. This chapter will review the key issues that centres banking and distributing stem cells must address to support the research community in the development of exciting cell therapies for the future.

Despite the enormous advances in tissue engineering, several challenges still prevent the widespread clinical application of tissue engineering products, such as how to acquire adequate number of cells, and how to engineer complex vascularized tissues that mimic the complexity and function of native tissues. The merger of bio-materials and microscale technologies offer new opportunities to overcome the challenges in tissue engineering to fabricate scaffolds and direct stem cell differentiation. In this chapter, various applications of microscale technologies have been illustrated in controlling stem cell fate and building complex artificial tissues. It is envisioned that with the rapid growth of this burgeoning research field, microscale technologies will transform the conventional tissue engineering approaches and greatly contribute to the therapeutic potential of tissue engineering.

Congenital abnormalities, trauma, infection, and cancer can all necessitate reconstructive surgery in the genitourinary tract. Currently, such surgeries may be performed with native non-urologic tissues, homologous tissues from a donor, heterologous tissues or substances, or artificial materials. However, these materials often lead to complications after reconstruction, including rejection of the implanted tissue. The field of tissue engineering may soon allow replacement of lost or deficient urologic tissues with anatomically and functionally equivalent ones that are derived from a small sample of the patient's own tissue. This would improve the outcome of reconstructive surgery in the genitourinary system and lead to new methods of treating these disorders.

The lack of appropriate regenerative capacity of the heart has been the spur to early clinical trials using autologous stem cells (bone marrow-derived and skeletal myoblast) for cardiac repair. Associated in vivo and in vitro laboratory experiments have been essential in advancing understanding of mechanism of benefit or harm from these cells, and in suggesting other sources of stem cells for cardiac application. Skeletal myoblasts have dangers, in that lack of integration with myocardium produces an arrhythmic substrate. Bone marrow-derived stem cells, while safer, do not generate significant new cardiac muscle as part of their beneficial actions, suggesting an angiogenic mechanism or paracrine protection of existing cardiomyocytes. Other adult stem cells, primarily from heart but also from organs such as testis, are currently being characterised as source of new cardiac tissue. Embryonic stem cells reliably produce contracting cardiac muscle, and are a likely candidate for future repair when problems of teratoma formation and immune response have been solved. They are also more suited to tissue engineering application, because of their ready availability and potential for expansion. Study of the biology of stem cells is also generating new paradigms for understanding the intrinsic regenerative capacity of the heart.

Cardiovascular disease is a major problem worldwide, and remains the leading cause of death within Europe. Clinical trials of stem cells have been conducted in the setting of acute myocardial infarction and chronic heart disease. At the time of writing there have been a number of different cell types, preparation and doses delivered by a number of different delivery routes to a variety of patients in small, mostly uncontrolled trials, generally with positive outcomes. Larger placebo-controlled trials are ongoing and we eagerly await their results. The challenges currently facing the field are to define the optimal target patient population, cell source, preparation, dose, delivery and retention of cells within the myocardium and the appropriate assays to detect meaningful clinical changes. Clearly not all of these questions can be answered in the clinical trial setting and it is imperative that basic science and translational research are conducted simultaneously to help guide clinical research. At present there appears to be no clear steer in answering these questions but we attempt to discuss the evidence to date and the future of stem cells in the management of cardiovascular disease.

Recent advances in stem cell biology provide the conceptual framework for the development of cell-based therapies for life-threatening diseases affecting many organs, including the lung. Because of its complexity and structure, cell-based therapy for the lung faces significant technical challenges. Therapeutic goals span a spectra of expectations that might include: (1) regeneration of functional lung tissue, (2) replacement of specific cells affected by inherited or acquired diseases with genetically altered progenitor cells, (3) provision of cells capable of enhancing repair or influencing oncogenesis directly or indirectly, and (4) introduction of cells capable of expressing therapeutic molecules for local or systemic delivery. The technical hurdles required for accomplishing each of these goals are distinct and of various heights. None are trivial. Knowledge of the cellular and molecular basis for specification and differentiation of stem/progenitor cells will be required for the successful application of cell-based therapies for the lung. This chapter reviews concepts derived from study of lung morphogenesis and repair as well as stem cell biology that will be relevant to the development of novel therapies for pulmonary diseases in the future.

Human fibrocytes exhibit mixed phenotypic characteristics of haematopoietic stem cells, monocytes and fibroblasts, and originate from a precursor of the monocyte lineage. They constitutively produce chemokines and growth factors that are known to modulate inflammatory reactions or promote angiogenesis and the deposition of extracellular matrix molecules. Upon exposure to transforming growth factor-β₁ and endothelin-1, fibrocytes produce large quantities of extracellular matrix components and acquire a contractile phenotype. Such differentiation of fibrocytes into myofibroblast-like cells occurs at the tissue sites during repair processes and has been found to contribute to wound healing in vivo. Fibrocytes and fibrocyte-derived myofibroblasts are also involved in the pathogenesis of lung disorders characterised by chronic inflammation and extensive remodelling of the bronchial wall, like asthma, or progressive fibrosis with destruction of the pulmonary architecture, like idiopathic pulmonary fibrosis. They participate in tumour-induced stromal reactions and may either promote or inhibit the metastatic progression of cancers. Prevention of excessive extracellular matrix deposition and detrimental tissue remodelling in pulmonary diseases may be achieved by inhibiting the accumulation of fibrocytes in the lungs. Moreover, in vitro expanded fibrocytes may serve as vehicles for the delivery of gene constructs to improve ineffective lung repair or be used in anti-cancer cell therapy.

Demonstrating that a cell therapy can directly contribute to functional recovery of a diseased organ is made difficult by experimental methods that are liable to introduce false-positive data. In this chapter we analyze the methods used to prove that a transplanted cell has grafted into the target organ and highlight the potentials for producing misleading results. Furthermore, we discuss the advantages and pitfalls of supporting graft data by quantifying improvement of organ function. We conclude that a multi-tiered experimental approach is required to thoroughly dispel the notion that engraftment and functional improvement are artefactual. Because of the relative immaturity of the field of lung cell therapy, we draw many of our examples from tissues with related challenges, such as cardiomyocyte cell therapy.

Lung cancer is the most common cause of death from cancer. It is estimated that every 15 minutes in the UK, one person dies of lung cancer¹ and in both the UK and USA more people die of it than any other type of cancer,^2,3 it being responsible for about one quarter of all deaths from cancer. Its high mortality rate is also reflected on a global scale, with lung cancer accounting for more than 1 million deaths per year.⁴ Lung cancer is usually sub-divided into three types: small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), and mesothelioma — a rare type of cancer that affects the pleura. Stem cells and cancer are inextricably linked; the perceived wisdom is that the process of carcinogenesis initially affects normal stem cells or their closely related progenitors, and then at some point, neoplastic stem cells are generated that propagate and ultimately maintain the process. Many, if not all cancers contain a population of self-renewing stem cells; the so-called cancer stem cells (CSCs) that are entirely responsible for sustaining the tumour as well as giving rise to proliferating but progressively differentiating cells that contribute to the cellular heterogeneity typical of many solid tumours. Thus tumours, like normal cell populations, may have a hierarchical structure. Adherents of the CSC hypothesis believe that the bulk of the tumour is therefore not the clinical problem, and so the identification of CSCs and the factors that regulate their behaviour are likely to have an enormous bearing on the way we treat neoplastic disease in the future. This chapter summarises 1) the histogenesis and molecular pathogenesis of lung tumours that probably take origin from normal pulmonary stem cells; 2) the evidence for the existence of CSCs in neoplastic lung tissue; and 3) illustrates some of the cellular pathways, often related to stem cell behaviour, that are frequently aberrant in lung cancer and may represent druggable targets.

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.

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.

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.

Stem cell therapy offers a promising frontier in veterinary regenerative medicine, providing novel approaches for addressing various disorders in both livestock and companion animals. From musculoskeletal injuries to degenerative diseases, stem cell therapy emerges as a versatile and effective approach for improving animal health and overall well-being. Despite its potential, the clinical application of stem cells in the veterinary sector faces challenges, with ongoing exploration needed to understand the precise mechanisms of action and long-term benefits post-application. This chapter delves into the advantages and limitations of stem cells from diverse sources and species, shedding light on their regenerative potential. Further, it highlights the current landscape of stem cell banking and explores the scope of stem cells in targeted drug delivery and assisted reproductive technologies.

Over the last decade, a number of studies have provided evidence of the existence of stem cells with pluripotency properties either in fresh bone marrow or following in vitro culture. Numerous groups have isolated non-hematopoietic cell populations from bone marrow, umbilical cord blood, amniotic fluid or fetal tissue via in vitro culture, which possess some molecular and biological properties comparable to embryonic stem cells. Due to their differentiation capacity into cells with features of the three germ layers, they are a novel cellular source for tissue regeneration. Because such stem cells of greater potency can be expanded for prolonged periods ex vivo without evidence of senescence and can be easily genetically manipulated, they can also be considered good candidates for gene therapy approaches.