Search

Due to lack of optimal inductive protocols, how to effectively improve chondrogenesis of adiposederived stem cells (ASCs) is still a great challenge. Our previous studies demonstrated that the culture media derived from chondrocyte-scaffold constructs (conditional media) contained various soluble chondrogenic factors and were effective for directing chondrogenic differentiation of bone marrow stem cells. Nevertheless, it remains unclear whether the conditional media can induce ASCs towards chondrogenic differentiation, especially for three-dimensional (3D) cartilage formation in a preshaped scaffold. In this study, it demonstrated that the conditional media derived from chondrocyte-scaffold constructs could promote ASCs to differentiate into chondrocyte-like cells, with similar expression of type II collagen to those induced by chondrogenic growth factors. Moreover, the expression level of chondrocyte-specific genes, such as SOX9, type II collagen, and COMP, was even higher in conditional medium group (CM) than that in optimized chondrogenic growth factor group (GF), indicating that the conditional media can serve as an effective inducer for chondrogenic differentiation of ASCs. Most importantly, the conditional media could also induce ASC-scaffold constructs to form 3D cartilage-like tissue with typical lacunae structures and positive expression of cartilage specific matrices, even higher contents of GAG and type II collagen were achieved in CM group compared to GF group. The current study establishes a simple, but stable, efficient, and economical method for directing 3D cartilage formation of ASCs, a strategy that may be more closely applicable for repairing cartilage defects.

Cardiovascular investigators are currently investigating adult bone marrow stem cells, cardiac stem cells, and adipose stem cells as potential new regenerative cell treatments for patients with acute myocardial infarctions and cardiomyopathies. The initial ten-year experience with autologous, unfractionated bone marrow aspirates, which contain hematopoietic and mesenchymal stem cells (MSCs), suggested that patients with myocardial infarctions who receive these cells demonstrate 2–3 % increases in the left ventricular (LV) ejection fraction of the heart, 4.8 ml decreases in the left ventricular end-systolic volume (LVESV), and approximately 5 % reductions in infarction size without experiencing significant side effects from these cells. The bone marrow stem cells are thought to act by releasing biologically active factors that limit myocardial inflammation, injury, and necrosis. The LateTIME, the TIME, and the Swiss Myocardial Infarction trials have recently addressed the questions of the optimal time for autologous, unfractionated bone marrow cell administration after acute myocardial infarction and coronary angioplasty and whether these cells limit myocardial damage in comparison with the patients treated with percutaneous coronary angioplasty and current medical care without cell transplantation. In these studies, the myocardial infarction sizes and the left ventricular ejection fractions (LVEFs) were not significantly different between the cell-treated patients with standard medical care and patients treated with standard medical care without bone marrow cells (BMCs). The lack of differences between treatments may have been due to the performance of coronary angioplasty within 4–5 h of the onset of patient’s symptoms of myocardial infarction, but may also have been due to heterogeneous patient bone marrow cell populations, red blood cell contamination of stem cells, heparin inhibition of stem cell migration, and expulsion of the stem cells from the contracting heart shortly after injection. Current trials of patients with myocardial infarction are examining specific bone marrow stem cells including MSCs and CD34+ endothelial stem cells. In addition, cardiac stem cells isolated from human hearts are being investigated in the treatment of patients with infarcted hearts. Cardiac stem cell treatments in patients with infarcted hearts have reportedly decreased left ventricular infarct scar sizes by 11.9–15.7 g and increased left ventricular viable mass by 17.9–22.6 g. Successful cell-based therapy for patients with heart disease requires the close cooperation and interaction of basic scientists and clinicians throughout the world. In this manner, the cell-based therapy in the twenty-first century will offer new hope to the millions of patients with heart disease throughout the world who would otherwise suffer from the inexorable downward progression of heart disease, heart failure, and death.

Stem cells are defined by their ability to self-renew and differentiate into mature cells (Keller 2005). They are responsible for tissue maintenance during homeostatic conditions and are able to respond to injury by adapting their ability to generate differentiated progeny according to the organism’s need. Knowing the biology of multiple tissue stem cells will allow treatment of diseases characterized by tissue failure. For example, novel approaches are needed for the treatment of degenerative diseases such as Parkinson’s disease, liver failure, leukemia, diabetes, osteoarthritis, and osteoporosis, for which there is currently no effective therapy. An emerging therapeutic approach for the management of these conditions is cell therapy or cellular therapeutics where organ functions are restored through transplanting healthy and functional cells. Administration of factors that stimulate regeneration by endogenous stem cells and transplantation of exogenous stem cells or engineered tissue derived from stem cells are the main approaches that regenerative medicine aims to develop. Moreover, gene therapy approaches are becoming a concrete possibility if stem cells are targeted.

Spinal cord injury is one of the main causes of disability in the young population. Based on the associated pathological changes, many modalities of treatments, including stem cells and non-stem cells transplantation have, been trialed with very promising results. The route of delivery and engraftment of these cellular transplants is an important determining factor in the functional outcome, and should be chosen as to be safe and efficacious on human patients. In this chapter we will discuss the pathology of spinal cord injury, the potential cellular therapy, and the routes of delivery.

Overtime, various modalities of spinal cord injury (SCI) treatment have been trialed. Of these, the most attractive is the cellular transplantation of neural and mesenchymal stem cells. Extensive experimental studies have been done to identify the safety and effectiveness of their transplantation in animal and human models. In this chapter, the different sources, isolation and transplantation of these multipotent stem cells, and associated outcomes will be discussed.

Hemophilia A (HA) is caused by mutations within the factor VIII (FVIII) gene, which leads to depleted protein production and inefficient blood clotting. Current therapies include fixes-dose FVIII prophylaxis, factor VIII replacement therapies, and most recently, gene therapy. Several attempts at gene therapy have failed for various reasons-including immune rejection. Liver is the primary site of FVIII synthesis; however, the specific cell types responsible for its synthesis remain controversial. Several reports have demonstrated the capacity of bone marrow stem cells (BMSCs) to transdifferentiate into hepatocytes and liver sinusoidal endothelial cells (LSECs). These findings created enormous interest because they uncovered a new property of BMCs and opened the possibility that these cells could be used in the treatment of liver injury and acute or chronic liver failure. We propose that the severity of the bleeding disorder could be ameliorated by partial replacement of mutated liver cells with healthy cells in HA mice. Our study showed that BM-derived hepatocytes and endothelial cells can synthesize FVIII in liver and correct bleeding phenotype in HA mice. Thus, BM-stem cell therapy is a potential alternative approach to managing HA.

Diabetes mellitus (DM) will affect the lives of 380 million people by 2025. Curative therapies mainly include diet, insulin, and oral hypoglycemic agents. However, these therapies fail to maintain blood glucose levels in the normal range all the time. Pancreas or islet-cell transplantation achieves better glucose control and substantially improves the quality of life. In this chapter, we summarize stem cell therapies for type 1 and type 2 DM and diabetic complications.

Reactive oxygen species (ROS) are a group of small molecules that regulate tissue redox status and oxidative stress. Redox regulation is an important determinant for cell development, activities, and function. ROS and oxidative stress also have a significant impact on the regulation of stem cells including bone marrow stem cells (BMSCs) and bone marrow-derived progenitor cells. ROS could regulate the self-renewal or proliferation of BMSCs, their mobilization, homing, migration, differentiation, and apoptosis or senescence. The effects of ROS and oxidative stress on BMSCs are complex and closely related to the ROS levels in the intracellular compartment and in the extracellular micro-environment. Oxidized low density lipoprotein (ox-LDL), a key contributor to the development of atherosclerosis in hyperlipidemic state, produces a significant amount of ROS spontaneously in vitro at clinically relevant concentrations. In the present review, the effects of ROS and oxidative stress on BMSCs and bone marrow-derived progenitor cells and related mechanisms are highlighted and discussed especially on the expression of stem cell marker Oct-4, self-renewal, mobilization, and differentiation. Specific efforts are made to discuss the role of ROS generated from ox-LDL in mediating the actions of ox-LDL on BMSCs and the potential impact on cell therapy with BMSCs.

Genetic liver diseases are the greatest challenge of modern health care that have no proven treatment. End-stage patients are advised for transplantation of liver. Unlike kidney, donor liver is difficult to obtain. Therefore, an alternate route of generating hepatocytes has been sought. BM-derived stem cells have been shown to differentiate into hepatocytes in culture and in vivo. It has been proposed that small increase in missing protein may cause significant improvement in the pathology of genetic liver diseases. Experimental findings from our and other groups heighten the scope for exploitation of this novel phenomenon of adult stem cells plasticity for the treatment of such disease. It has been presumed that BM-stem cell therapy not only helps for the synthesis of missing protein, it may protect liver from hepatocellular carcinoma or other adverse pathological changes of the liver.

Cell fusion is a natural process implicated in normal development, immune response, tissue formation, and with a prominent role in stem cell plasticity. The discovery that bone marrow stem cells fuse with several cell types, under normal condition or after an injury, introduces new possibilities in regenerative medicine and genetic repair. Cell fusion has been shown to be implicated in regeneration, and the complementation of recessive mutations affecting the liver, brain, muscle, lung and gut, under appropriate conditions. However, we should be cautious and better understand the mechanisms that govern cell fusion during regeneration before to consider it as clinically relevant. In this chapter, we will present the current evidences about the role of cell fusion in tissue regeneration and its future potential as therapy. Cell fusion is an exciting and promising research field. In addition, we will review the challenges that should face the fusion process to become therapeutically effective and safe., M.M-L. is a “Sara Borrell” postdoctoral from Institute Carlos III, Spanish Ministry of Health.

The bone marrow constitutes an unique microenvironment for cancer cells in three specific aspects. First, the bone marrow actively recruits circulating tumor cells where they find a sanctuary rich in growth factors and cytokines that promote their proliferation and survival. When in the bone marrow, tumor cells profoundly affect the homeostasis of the bone and the balance between osteogenesis and osteolysis. As a consequence, growth and survival factors normally sequestered into the bone matrix are released, further fueling cancer progression. Second, tumor cells actively recruit bone marrow-derived precursor cells into their own microenvironment. When in the tumors, these bone marrow-derived cells contribute to an inflammatory reaction and to the formation of the tumor vasculature. Third, bone marrow-derived cells can home in distant organs, where they form niches that attract circulating tumor cells. Our understanding of the contribution of the bone marrow microenvironment to cancer progression has therefore dramatically improved over the last few years. The importance of this new knowledge cannot be underestimated considering that the vast majority of cancer treatments such as cytotoxic and myeloablative chemotherapy, bone marrow transplantation and radiation therapy inflict a trauma to the bone marrow microenvironment. How such trauma affects the influence that the bone marrow microenvironment exerts on cancer is still poorly understood. In this article, the reciprocal relationship between the bone marrow microenvironment and tumor cells is reviewed, and its potential impact on cancer therapy is discussed.

Congestive heart failure (CHF) is a complex clinical syndrome resulting from myocardial dysfunction that impairs the cardiovascular system’s function. Both medical and surgical therapy still results in a large number of patients with very few options and persistent ventricular dysfunction. The major process to reverse ventricular remodeling would be the enhancement of regeneration of cardiac myocytes, as well as the stimulation of neovascularization within the affected area of the myocardium. This can be achieved by introducing progenitor cells that are capable of differentiating into cardiac myocytes or that promote neovascularization and restore the normal characteristics of myocardium environment. However a number of issues remain as to the type of cells, delivery, timing, and mechanisms involved. There have been a number of clinical trials based on very early small and large animal experiments that investigate stem cell therapy for heart failure, most of which have employed bone marrow stem cells or myoblasts. The majority of studies demonstrate an improvement in ventricular function, reduction in scar, or improvement in symptoms. There are a few trials that show no improvement at all. Here we present our surgical experience over the past 4 years with autologous and fetal liver stem cells in patients with heart failure.

When getting old, a lot of unpleasant events are developing in our organism. Here, we should mention the decline or gradual loss of function and potential and, ultimately, death of cells of different types. Many data exist about age-dependent deterioration of nervous and muscle cells as well as about many proliferating cell populations, such as epithelial, osteogenic, hemopoietic and others. These changes manifest themselves in a number of old age diseases like the Alzheimer’s disease, Parkinsonism, heart and brain infarction, osteoporosis, diabetes, immune deficiency, malignancies and others. So, it takes to elaborate some technologies and methods for improving the situation by stimulation or replacement of the impaired organs and tissues. The dream is to launch a medical revolution, in which failing organs and tissues might be repaired not with crude mechanical devices like insulin pumps or titanium joints, but with the living homegrown replacement. And great promises here make now the use of stem cell technologies.

The growth of new blood vessels is a critical factor in many human diseases including cancer, ischemic injury and wound healing. De novo vessel formation or vasculogenesis was thought to take place solely in the embryo from mesodermal progenitor cells, whereas the vasculature in postnatal life was considered to undergo remodeling through expansion of pre-existing endothelial cells, or angiogenesis. Current evidence suggests that endothelial progenitor cells (EPCs) also exist in adult organisms as circulating cells originating in the bone marrow. They can be mobilized after vascular trauma, myocardial infarction, tissue injury, or during peripheral vascular disease, by a number of growth factors and chemokines like VEGF, GM-CSF, G-CSF and SDF-1. EPCs do not appear to represent a distinct or homogeneous cell population, but they are defined as cells that can give rise to endothelial progeny under certain circumstances in culture or in vivo. EPCs enhance tissue revascularization by contributing to new vessels and stimulating local angiogenesis, thus offering novel ways to regulate vascular growth. Results from the first clinical studies using mostly bone marrow stem cells as a source of EPCs have been encouraging, emphasizing the therapeutic potential of endothelial progenitor cells. This review summarizes the role of EPCs in the formation of new blood vessels and provides an outline of their biological characteristics and potential use in the clinical setting

The main goal of experimental therapies for the treatment of degenerative neurological diseases ranges from the prevention of molecular events underlying neuronal death to the replacement of concrete damaged neuronal populations. Invasive therapeutic strategies such as grafting of embryonic neural cells or of adult bone marrow stem cells, the induction of trophic factor synthesis in brain cells by virus-mediated genetic transfer, and the electrical stimulation of the brain by the placement of electrodes into concrete brain circuits have accrued in the past decades. However, successful results obtained in experimental animals do not necessarily correlated with similar clinical advances. The rationale of these different invasive therapeutic strategies to treat brain damage and neurodegenerative processes is reviewed in this chapter. The discussion is focused on some noticeable discrepancies between experimental advances represented by the proposed therapies and their actual clinical benefits.

The designation ‘mononuclear phagocyte system’ has replaced the previous more comprehensive name of ‘reticuloendothelial system’, as this included non-phagocytic cells, such as fibroblast and endothelial cells, and cells which did not arise from the monocyte—macrophage progenitor, which also produces the granulocytic cell line. Recent studies have provided additional support for earlier conclusions on the derivation and function of monocytes and macrophages1,2. The bone marrow stem cells produce the committed progenitor which gives rise to the monoblast, promonocyte and monocyte in the bone marrow. The monocytes leave the bone marrow after their maturation, remain only a short time in the peripheral blood, migrate out into the tissues where they become macrophages.

Congenital immune deficiency (CID) diseases comprise a group of rare disorders of varied aetiology with either sporadic, autosomal recessive or sex-linked inheritance. They vary in severity but generally cause death in childhood from overwhelming opportunistic infection. There is also an increased risk of lympho-reticular malignancy. Table 1.1 lists major conditions considered in the chapter, giving details of their inheritance and the nature of the abnormality where known1. For practical purposes they can be separated into two groups: severe combined immune deficiency (SCID) syndromes and other less-severe immune deficiency (ID) syndromes. Figure 1.1 illustrates the development of immune competent cells from the pluripotent bone marrow stem cell precursor, and indicates (where it is known) the site of the defect associated with particular congenital immune deficiency states. Some disorders are best understood as a developmental arrest at a particular stage of lymphocyte maturation while in others a defined metabolic abnormality such as deficiency of adenosine deaminase (ADA) or nucleoside phosphorylase (NP) enzyme leads to functional as well as developmental abnormalities of the lympho-reticular system. In Di George syndrome2 cell-mediated immunity is impaired to a variable degree in association with defective embryogenesis of the third and fourth pharyngeal pouch causing thymic aplasia.

As an introduction to the workshop, Broerse reminded participants to the major studies performed in the 1950’s and 60’s to derive dose-response relationships for acute responses to ionizing radiations. There was now a need to re-examine these data with a view to comparing exposure conditions and to measuring biological endpoints other than death. This was particularly important in providing a scientific basis for clinical studies involving total body irradiations (TBI) followed by bone marrow transplantation. He stressed the need for standardized procedures in patients if the various centres using TBI wished to compare their results in terms of successful destruction of bone marrow cells and recovery following the injection of compatible donor cells.