Vision loss may be caused by disease or damage to the retina of the eye. The retina consists of a specialized layer of cells at the back of the eye where light entering the eye is Sensed as an image. These cells normally respond to all aspects of the light emitted from an object and allow perception of color, shape and intensity. The types of cells located in the retina include retinal pigment epithelial (“RPE) cells, rod cells, cone cells, bipolar cells, amacrine cells, horizontal cells, Mueller cells, glial cells, and retinal ganglion cells. When normal retinal function is impaired, it may lead to a loss of color perception, blind Spots, reduced peripheral Vision, night blindness, photophobia, decreased Visual acuity or blindness. For example, acquired immunodeficiency virus (“AIDS”) patients may suffer cytomegalovirus retinitis which is caused by Spread of the cytomegalo virus to the retina. This and other infectious processes can lead to loss of Visual field, decreased visual acuity, and blindness. Uveitis is an inflammation of the eye which can affect the retina and can lead to decreased Visual acuity. Its effects on the retina include inflamed or leaking vasculature which may appear as perivascular exudation or haemorrhage, edema of the retina, chorioretinal lesions, neovascularization or inflammatory changes in the peripheral retina. Cancers of the retina also impair vision. One example is retinoblastoma, which is the most common childhood malignancy in eye. Other diseases like age-related macular degeneration can adversely affect retinal cell structures with age. Many different genetic diseases lead to retinal damage and blindness. A relatively common example is retinitis pigmentosa (“RP”), which affects one person in four thousand worldwide. Patients with RP have normal vision for one or more decades, and then experience progressive loss of Vision due to the premature death of rod or cone cells. Blindness may result afterwards. Other types of retinal degenerations and retinal dystrophies may result from the programmed death of other retinal cell types. Physical damage to retinal cells may also occur through retinal detachment which leads to retinal degeneration and blindness.
The therapeutic Strategies for treating loss of vision caused by retinal cell damage vary, but they are all directed to controlling the illness causing the damage, rather than reversing the damage caused by an illness by restoring or regenerating retinal cells. AS one example, the treatments of uveitis are drawn from the knowledge of changes in the retinal environment when inflammation occurs. Corticosteroids, Such as prednisone, are the preferred drug of treatment. However, these drugs are immuno-suppressants with numerous Side effects. AS well, the Systemic immuno-suppression may have significant negative effects on the development of children as well as on adults in poor health Such as the elderly and patients with chronic disease. These patients must try alternate drugs Such as alkylating agents or antimetabolites which also have side effects. Clearly, patients with eye diseases remain Vulnerable to Sustaining permanent damage to the retinal cells, even if drug treatments are available. There are no known Successful treatments for RP and other retinal dystrophies. There are also no treatments which regenerate new cells endogenously or which transplant healthy tissue to the retina. Even if it were possible to develop Some form of transplantation, it would be Subject to the same problems that accompany transplants in other organ Systems. These include: in many cases, implants provide only temporary relief as the Symptoms associated with the disease often return after a number of years, rejection by the patient of foreign tissue, adverse reactions associated with immunosuppression (immunosuppression is needed to try to help the patient accept the foreign tissue), the inability of a sufficient number of cells in the tissue being implanted to Survive during and after implantation, transmitting other diseases or disorders may be transmit ted to the patient via the implant, and the results may not justify the costs and efforts of a complex procedure. Thus, there is currently no way to reverse permanent damage to the retina and restore vision.
Drug treatments focus on treating the illness and its Symptoms to prevent further damage to the retina. There is a need to reverse damage to the retina and restore vision by endogenously generating new retinal cells or transplanting retinal cells. In tissues other than the eye, Stem cells are used as a Source for alternative treatments of disease or injury to tissues. Stem cells are undifferentiated cells that exist in many tissues of embryos and adult mammals. In embryos, blastocyst stem cells are the source of cells which differentiate to form the specialized tissues and organs of the developing fetus. In adults, specialized Stem cells in individual tissues are the source of new cells which replace cells lost through cell death due to natural attrition, disease or injury. No Stem cell is common to all tissues in adults. Rather, the term “stem cell” in adults describes different groups of cells in different tissues and organs with common characteristics. Stem cells are capable of producing either new stem cells or cells called progenitor cells that differentiate to produce the specialized cells found in mammalian organs. Symmetric division occurs where one stem cell divides into two daughter Stem cells. Asymmetric division occurs where one stem cell forms one new stem cell and one progenitor cell.
A progenitor cell differentiates to produce the mature Specialized cells of mammalian organs. In contrast, Stem cells never terminally differentiate (i.e. they never differentiate into a specialized tissue cells). Progenitor cells and Stem cells are referred to collectively as "precursor cells'. This term is used when it is unclear whether a researcher is dealing with Stem cells or progenitor cells or both. Progenitor cells may differentiate in a manner which is unipotential or multipotential. A unipotential progenitor cell is one which can form only one particular type of cell when it is terminally differentiated. A multipotential progenitor cell has the potential to differentiate to form more than one type of tissue cell. Which type of cell it ultimately becomes depends on conditions in the local environment as Such as the presence or absence of particular peptide growth factors, cell-cell communication, amino acids and Steroids. For example, it has been determined that the hematopoietic Stem cells of the bone marrow produce all of the mature lymphocytes and erythrocytes present in fetuses and adult mammals. There are Several well-Studied progenitor cells pro duced by these Stem cells, including three unipotenltial and one multipotential tissue cell. The multipotential progenitor cell may divide to form one of several types of differentiated cells depending on which hormones act upon it.
Weiss et al, Review, 1-13 (1996) summarizes the five defining characteristics of Stem cells as the ability to:
· Proliferate: Stem cells are capable of dividing to produce daughter cells.
· Exhibit self-maintenance or renewal over the lifetime of the organism: Stem cells are capable of reproducing by dividing Symmetrically or asymmetrically. Symmetric division is a Source of renewal of Stem cells. Symmetric division leads to increases in the number of Stem cells. Asymmetric division maintains a consistent level of Stem cells in an embryo or adult mammal.
· Generate large number of progeny: Stem cells may produce a large number of progeny through the transient amplification of a population of progenitor cells.
· Retain their multilineage potential over time: Stem cells are the ultimate Source of differentiated tissue cells, So it is a characteristic that they retain their ability to produce multiple types of progenitor cells, which will in turn develop into specialized tissue cells.
· Generate new cells in response to injury or disease: This is essential in tissues which have a high turnover rate or which are more likely to be Subject to injury or disease, Such as the epithelium or blood cells.
Thus, the key features of Stem cells are that they are multipotential cells which are capable of long-term Self renewal over the lifetime of a mammal. There is great potential for the use of Stem cells as Substrates for producing healthy tissue where pathological conditions have destroyed or damaged normal tissue. For example, Stem cells may be used as a target for in vivo Stimulation with growth factors or they may be used as a Source of cells for transplantation. There has been much effort to isolate stem cells and determine which peptide growth factors, hormones and other metabolites influence Stem cell renewal and production of progenitor cells, which conditions control and influence the differentiation of progenitor cells into Specialized tissue cells, and which conditions cause a multipotent progenitor cell to develop into a particular type of cell.
In Several tissues, Stem cells have been isolated and characterized to develop new therapies to repair or replace damaged tissues. Recent advances made my Royal College of surgeons indicate that RPE cells exhibiting the characteristics of normal natural RPE can be produced from undifferentiated embryonic stem cells. Batches of RPE cells have been derived by this method to be used in animal model of retinal disease. This might be the trailblazer in the initiation of concept to use such fetal stem cells to treat the human retinal diseases in the near future. The fetal stem cells would be taken out when in second trimester.
Not only that, the novel concept also digs deep to find out that the RPE located in the periphery of adult retina also resembles the characteristics of stem cells. One may readily surmise that this could be a great victory for human kind because if so is true we can relocate the RPE from the margin to the center of retina who has central macular disease like macular degeneration. The rejection, mutation and survival issues for the transplant is thus minimized.
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