Stem Cells and Ischemic Heart Disease. Left ventricular remodeling is a major cause of progressive heart failure and death after myocardial infarction [20]. Implantation of bone marrow stem cells into the human heart may restore tissue viability and induce angiogenesis, thus improving perfusion of the infarcted myocardium [21].
The formation of new blood vessels may occur by two processes: vasculogenesis and angiogenesis. Vasculogen­esis is the in situ differentiation of endothelial cells (ECs) from hemangioblasts and their organization into a primary capillary plexus. Angiogenesis is the formation of new vessels by sprouting from pre-existing blood vessels [22]. In the prenatal period, hemangioblasts derived from the human ventral aorta give rise to cellular elements involved in both vasculogenesis and hematopoiesis [20,23].
A subset of circulating human CD34+ cells have the capacity to differentiate into endothelial cells in vitro [23]. Hematopoietic stem and progenitor cells express markers, similar to those of endothelial cells, including VEGFR-1, CD34, platelet endothelial cell adhesion molecule (PECAM), Tie-1, Tie-2, and von Willebrand factor (vWF). The CD34+ cells occur in bone marrow, umbilical cord blood, fetal liver and cytokines such as granulocyte colony- stimulating factor (G-CSF) promote its mobilization from bone marrow to the peripheral blood [24]. These hematopoietic stem and progenitor cells express the early hematopoietic stem cell marker AC133. Human AC133+ cells can be considered to be pluripotent hematopoietic stem cells because they can repopulate sheep bone marrow [24]. Subsets of CD34+ cells that express AC133 are considered phenotypic, to be a functional marker of an immature population of hematopoietic stem/progenitor cells. This subpopulation of CD34+ cells co-expressing AC133 and VEGFR-2, express some other endothelial specific markers, including E-selectin and VE-cadherin. Incubation of nonadherent CD34+ cells co-expressing AC133 and VEGFR-2 with VEGF, fibroblast growth factor (FGF)-2 and collagen, results in their differentiation into adherent mature endothelial cells [24]. These data suggest that these CD34+ cells comprise a functional population of endothelial precursor cells that may play a role in post­natal vasculogenesis and angiogenesis [22,24,25]. The observation that the AC133+ cell population includes endothelial precursors might be of clinical relevance in the field of ischemic disorders [22].
Stem Cells and Diabetes Mellitus. Type 1 (insulin-dependent) diabetes is a chronic disease affecting genetically predisposed individuals, in which insulin-secreting b cells within the pancreatic islets of Langerhans are selectively destroyed by an autoimmune assault. For over 80 years insulin replacement was the main therapeutic approach to treat the symptoms of the disease [26].
Advances in stem cell biology and in cloning strategies raise the possibility of creation of immunologically autologous ES cells from which to generate functional pancreatic b cells for transplantation therapy. This involves taking the nucleus from a somatic cell from the patient, inserting it into an enucleated human egg, and allowing the new egg to develop into a blastocyst. Embryonic stem cells from the inner cell mass of the blastocyst are then used to generate ES cell lines, which can be expanded in vitro to produce plentiful cells as required for transplantation therapy. An alternative source of stem cell populations could be tissue stem cells isolated from a patient’s pancreas [27], liver [28] or bone marrow [29], and differentiated into insulin-producing cells for transplantation. Many aspects of this process are already possible. Human embryos have already been created using nuclei from somatic cells. Human ES cell lines from blastocysts have been generated, and the number of available cell lines is on the increase. Likewise, islet-like structures from b cell populations in vitro have been created.
However, vast numbers of replacement b cells are required in order to make a significant therapeutic impact. Replacement cells must be able to synthesise, store and release insulin when it is required, primarily in response to changes in the ambient blood glucose concentration and they must avoid destruction by the recipient’s immune system. The immune systems of patients with Type 1 diabetes are programmed to destroy primary b cells, they will thus target even the immunologically homologous b cell replacements derived by therapeutic cloning of ES cells. One possibility in avoiding this problem could be to generate populations of cells that possess the functional phenotype of b cells but are distinct developmentally and immunologically from primary b cells [26].
Stem Cells and Parkinson’s Disease (PD). The possibility of repairing the damaged human brain has been a dream of physicians and scientists for decades. The discovery that stem cells are present in, and can be isolated from, the developing and the adult mammalian brain make them an ideal candidate as therapeutic tools for neuro-degenerative disorders such as ParkinsonNs disease (PD) [30,31]. Parkinson’s disease is characterized by progressive degeneration and loss of neurons. The reason for selective degeneration of specific populations of neurons in PD is not known. Because most cases of idiopathic PD are sporadic, it has been suggested that the convergence of predisposing genetic factors and environmental factors such as pesticides or viruses may play an important role in producing the disease. Comparatively rare cases of familial PD suggest that mutations in the genes for a-synuclein and ubiquitin carboxyl terminal hydroxylase-L1 lead to autosomal dominant forms of PD, while mutations in the Parkin gene, lead to autosomal recessive juvenile PD.
A source of neural stem cells, suitable for cell replacement in PD, is human fetal mesencephalic tissue (which is rich in dopaminergic neurons) [31]. However, six-to-seven human fetuses are required to supply a sufficient number of cells for one PD patient. Practical and ethical issues limit the success of this therapy. Cell replacement strategies based on stem or progenitor cells offer several advantages over fetal mesencephalic cells. Firstly, since there is no need for embryonic or fetal material, practical and ethical concerns are removed. Secondly, unlimited numbers of dopaminergic neurons can be produced in vitro. Grown in monolayers (on substrate-coated tissue cultures plates), or as self-adherent complexes of cells known as neurospheres, in the presence of growth factors, such as FGF-2, EGF, lymphocyte inhibitory factor and neural survival factor-1, neural cells maintain the potential to produce neurons, astrocytes and oligodendrocytes [30,32]. Thirdly, it is possible for all these cells to be cryopre­served and expanded according to need. Thus, dopamine neurons derived from stem cells constitute one of the most promising tools for stem cell therapy in PD [30].
Stem Cells and Cancer. Cancer is increasingly being viewed as a stem cell disease [33]. The cancer stem cell (CSC) hypothesis suggests that neoplastic clones result from a rare fraction of cells with stem cell properties. Although the existence of CSCs in human leukemia is established, little evidence exists for CSCs in solid tumors, except for breast cancer [34].
Recently, a CD133+ cell subpopulation from human brain tumors has been isolated with stem cell properties in vitro. Injection of these cells in NOD-SCID (non-obese diabetic, severe combined immunodeficient) mouse brains resulted in growth of a tumor that is a phenocopy of the original tumor of the patient. These data support the hypothesis that CSCs might be the basis for other solid tumors [35].
The recently discovered polycomb group (PcG) proteins form a part of a gene regulatory pathway that determines cell fate during normal development. Deregulation of PcGs protein genes (Bmi1, Pc2, and Cbx7) has been associated with proliferation of cancer cells. These genes appear to regulate self-renewal of specific stem cells types, thus suggesting a link between the maintenance of cellular homeostasis and tumorigenesis [36].
Recent findings suggest that the tumor suppressor protein p53 plays an important role in maintaining genetic stability in ES cells by eliminating DNA-damaged ES cells. The p53 gene induces the differentiation of DNA- damaged ES cells by suppressing the expression of Nanog, that is very important for the self-renewal of ES cells. These new findings suggests that the p53 gene may play a similar role in AS cells, and thus suppress the development of CSCs [37].
Although stem cells are considered to hold great promise in treatment of a variety disorders, these cells may be the cellular origin of cancer. It has been suggested that bone marrow-derived cells are CSCs for the development of gastric tumors [38]. It is important to first test stem cells to see if they can give rise to cancer, before using them as cell therapy. Maybe there is a way to tame the tendency of stem cells to form cancers.