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Bone marrow (BM) is a source of various stem and progenitor cells in the adult, and it is able to regenerate a variety of tissues following transplantation. In the 1970s the first BM stem cells identified were hematopoietic stem cells (HSCs). HSCs have the potential to differentiate into all myeloid (including erythroid) and lymphoid cell lineages in vitro and reconstitute the entire hematopoietic and immune systems following transplantation in vivo. More recently, nonhematopoietic stem and progenitor cells have been identified that can differentiate into other cell types such as endothelial progenitor cells (EPCs), contributing to the neovascularization of tumors as well as ischemic tissues, and mesenchymal stem cells (MSCs), which are able to differentiate into many cells of ectodermal, endodermal, and mesodermal origins in vitro as well as in vivo. Following adequate stimulation, stem and progenitor cells can be forced out of the BM to circulate into the peripheral blood, a phenomenon called “mobilization.” This chapter reviews the molecular mechanisms behind mobilization and how these have led to the various strategies employed to mobilize BM-derived stem and progenitor cells in experimental and clinical settings. Mobilization of HSCs will be reviewed first, as it has been best-explored—being used extensively in clinics to transplant large numbers of HSCs to rescue cancer patients requiring hematopoietic reconstitution—and provides a paradigm that can be generalized to the mobilization of other types of BM-derived stem and progenitor cells in order to repair other tissues.

Mobilization and recruitment of bone marrow-derived progenitor cells (BMDPCs) play an important role in postischemic tissue repair. Patients with coronary artery disease (CAD) or peripheral vascular disease (PVD) exhibit endothelial dysfunction, and as a result are likely to have a reduced number of progenitor cells mobilized in their peripheral circulation following ischemic injury. Identification of eNOS independent pathways for BMDPC mobilization may have important therapeutic value in this patient population. To identify such mechanisms we investigated the effect of granulocyte-colony stimulating factor (GCSF) and stem cell factor (SCF) in eNOS-KO mice with and without surgical hind-limb ischemia. Our results suggest that BMDPC mobilization can be achieved via activation of NO-independent pathways.

Isolated from simple bone marrow aspirates, mesenchymal stromal cells (MSCs) can be easily expanded ex vivo and differentiated into various cell lineages. Because they are present in humans of all ages, are harvested in the absence of prior mobilization and preserve their plasticity following gene modification, MSCs are particularly attractive for cell-based medicine. One of the most fascinating properties of ex vivo expanded MSCs is their ability to suppress ongoing immune responses, both in vitro and in vivo. Although not fully understood, the immunosuppressive properties of MSCs have been reported to affect the function of a broad range of immune cells, including T cells, antigen-presenting cells, natural killer cells and B cells. Whereas successful harnessing of these immunosuppressive properties might one day open the door to the development of new cell-based strategies for the control of graft-versus-host and other autoimmune diseases, recent studies suggest that the immune-modulating properties of MSCs are far more complex than first thought. Reminiscent of the dichotomy of function of dendritic cells (DCs), which can act as potent activators or potent suppressors of immune responses, new studies including our own work has shown that MSCs in fact possess the dual ability to suppress or activate immune responses. In this review, we summarize the different biological properties of MSCs and discuss the current literature on the complex mechanism of immune modulation mediated by ex vivo expanded MSCs.

During the course of an entire lifespan, tissue repair and regeneration is made possible by the presence of adult stem cells. Stem cell expansion, maintenance, and differentiation must be tightly controlled to assure longevity. Hematopoietic stem cells (HSC) are greatly solicited given the daily high blood cell turnover. Moreover, several bone marrow-derived cells including HSC, mesenchymal stromal cells (MSC), and endothelial progenitor cells (EPC) also significantly contribute to peripheral tissue repair and regeneration, including tumor formation. Therefore, factors influencing bone marrow-derived cell proliferation and functions are likely to have a broad impact. Aging has been identified as one of these factors. One hypothesis is that aging directly affects stem cells as a consequence of exhaustive proliferation. Alternatively, it is also possible that aging indirectly affects stem cells by acting on their microenvironment. Cellular senescence is believed to have evolved as a tumor suppressor mechanism capable of arresting growth to reduce risk of malignancy. In opposition to apoptosis, senescent cells accumulate in tissues. Recent evidence suggests their accumulation contributes to the phenotype of aging. Senescence can be activated by both telomere-dependent and telomere-independent pathways. Genetic alteration, genome-wide DNA damage, and oxidative stress are inducers of senescence and have recently been identified as occurring in bone marrow-derived cells. Below is a review of the link between cellular senescence, aging, and bone marrow-derived cells, and the possible consequences aging may have on bone marrow trans plantation procedures and emerging marrow-derived cell-based therapies.

Until recently, the adult neovasculature was thought to arise only through angiogenesis, the mechanism by which new blood vessels form from preexisting vessels through endothelial cell migration and proliferation. However, recent studies have provided evidence that postnatal neovasculature can also arise though vasculogenesis, a process by which endothelial progenitor cells are recruited and differentiate into mature endothelial cells to form new blood vessels. Evidence for the existence of endothelial progenitors has come from studies demonstrating the ability of bone marrow-derived cells to incorporate into adult vasculature. However, the exact nature of endothelial progenitor cells remains controversial. Because of the lack of definitive markers of endothelial progenitors, the in vivo contribution of progenitor cells to physiological and pathological neovascularization remains unclear. Early studies reported that endothelial progenitor cells actively integrate into the adult vasculature and are critical in the development of many types of vascular-dependent disorders such as neoplastic progression. Moreover, it has been suggested that endothelial progenitor cells can be used as a therapeutic strategy aimed at promoting vascular growth in a variety of ischemic diseases. However, increasing numbers of studies have reported no clear contribution of endothelial progenitors in physiological or pathological angiogenesis. In this chapter, we discuss the origin of the endothelial progenitor cell in the embryo and adult, and we discuss the cell’s link to the primitive hematopoietic stem cell. We also review the potential significance of endothelial progenitor cells in the formation of a postnatal vascular network and discuss the factors that may account for the current lack of consensus of the scientific community on this important issue.

Anincreasing number of patients living with cardiovascular disease (CVD) and still unacceptably high mortality created an urgent need to effectively treat and prevent disease-related events. Within the past 5 years, skeletal myoblasts (SKMBs) and bone marrow (or blood)-derived mononuclear cells (BMNCs) have demonstrated preclinical efficacy in reducing ischemia and salvaging already injured myocardium, and in preventing left ventricular (LV) remodeling, respectively. These findings have been translated into clinical trials, so far totaling over 200 patients for SKMBs and over 800 patients for BMNCs. These safety/feasibility and early phase II studies showed promising but somewhat conflicting symptomatic and functional improvements, and some safety concerns have arisen. However, the patient population, cell type, dose, time and mode of delivery, and outcome measures differed, making comparisons problematic. In addition, the mechanisms through which cells engraft and deliver their beneficial effects remain to be fully elucidated. It is now time to critically evaluate progress made and challenges encountered in order to select not only the most suitable cells for cardiac repair but also to define appropriate patient populations and outcome measures. Reiterations between bench and bedside will increase the likelihood of cell therapy success, reduce the time to development of combined of drug- and cell-based disease management algorithms, and offer these therapies to patients to achieve a greater reduction of symptoms and allow for a sustained improvement of quality of life.

The success of therapies targeting acute myocardial ischemia and the aging of the population due to improved general medical care has resulted in an increasing population of patients with chronic myocardial ischemia and congestive heart failure who remain symptomatic despite having exhausted the currently available therapeutic options. In this chapter we review the scientific underpinnings of autologous bone marrow-derived cell therapy and the early clinical experience that has fuelled interest in this approach.

The isolation of endothelial progenitor cells (EPCs) derived from adult bone marrow (BM) was an epoch-making event for the recognition of “neovessel formation” occurring as physiological and pathological responses in adults. The finding that EPCs home to sites of neovascularization and differentiate into endothelial cells (ECs) in situ is consistent with “vasculogenesis,” a critical paradigm well described for embryonic neovascularization, but proposed recently in adults, in which a reservoir of stem or progenitor cells contributes to vascular organogenesis. EPCs have also been considered as therapeutic agents to supply the potent origin of neovascularization under pathological conditions. Considering the regenerative implications, gene modification of stem cells has advantages over conventional gene therapy. Ex vivo gene transfection of stem cells may avoid administration of vectors and vehicles into the recipient organism. Stem cells isolated from adults may exhibit age-related, genetic, or acquired disease-related impairment of their regenerative ability. Transcriptional or enzymatic gene modification may constitute an effective means to maintain, enhance, or inhibit EPCs’ capacity to proliferate or differentiate. This chapter provides an update of EPC biology as well as EPCs’ potential use for therapeutic regeneration.

Until recently, the concept of treating the injured or failing heart by generating new functional myocardium was considered physiologically impossible. Major scientific strides in the past few years have challenged the concept that the heart is a post-mitotic organ, leading to the hypothesis that cardiac regeneration could be therapeutically achieved. Bone marrow-derived adult stem cells were among the first cell populations that were used to test this hypothesis. Animal studies and early clinical experience support the concept that therapeutically delivered mesenchymal stem cells (MSCs) safely improve heart function after an acute myocardial infarction (MI). MSCs produce a variety of cardio-protective signalling molecules, and have the ability to differentiate into both myocyte and vascular lineages. Additionally, MSCs are attractive as a cellular vehicle for gene delivery, cell transplantation or for tissue engineering because they offer several practical advantages. They can be obtained in relatively large numbers through standard clinical procedures, and they are easily expanded in culture. The multi-lineage potential of MSC, in combination with their immunoprivileged status, make MSCs a promising source for cell therapy in cardiac diseases. Here we provide an overview of biological characteristics of MSCs, experimental animal studies and early clinical trials with MSCs. In addition, we discuss the routes of cell delivery, cell tracking experiments and current knowledge of the mechanistic underpinnings of their action.

Neurodegenerative diseases are characterized by a progressive degeneration of selective neural populations. This selective hallmark pathology and the lack of effective treatment modalities make these diseases appropriate candidates for cell therapy. Bone marrow-derived mesenchymal stem cells (MSCs) are self-renewing precursors that reside in the bone marrow and may further be exploited for autologous transplantation. Autologous transplantation of MSCs entirely circumvents the problem of immune rejection, does not cause the formation of teratomas, and raises very few ethical or political concerns. More than a few studies showed that transplantation of MSCs resulted in clinical improvement. However, the exact mechanisms responsible for the beneficial outcome have yet to be defined. Possible rationalizations include cell replacement, trophic factors delivery, and immunomodulation. Cell replacement theory is based on the idea that replacement of degenerated neural cells with alternative functioning cells induces long-lasting clinical improvement. It is reasoned that the transplanted cells survive, integrate into the endogenous neural network, and lead to functional improvement. Trophic factor delivery presents a more practical short-term approach. According to this approach, MSC effectiveness may be credited to the production of neurotrophic factors that support neuronal cell survival, induce endogenous cell proliferation, and promote nerve fiber regeneration at sites of injury. The third potential mechanism of action is supported by the recent reports claiming that neuroinflammatory mechanisms play an important role in the pathogenesis of neurodegenerative disorders. Thus, inhibiting chronic inflammatory stress might explain the beneficial effects induced by MSC transplantation. Here, we assemble evidence that supports each theory and review the latest studies that have placed MSC transplantation into the spotlight of biomedical research.