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Stem cells are generic cells which has the ability to make exact copies of itself indefinitely. Thus, these cells are undifferentiated cells which differentiate to produce specialised tissues and organs. From these definitions, two important properties of stem cells emerge. First of all, it must have a self renewal ability, allowing numerous cell division and at the same time maintaining the undifferentiated state. Secondly, stem cell must be potent, having the potential to differentiate into different cell types Hans R. Scholer 2007. On this second property of the stem cells lie some characteristics.
These include Totipotency or omnipotency which has the ability to differentiate into embryonic and extraembryonic cell types and can result into a complete viable organism Hans R. Scholer 2007. An example here is a fertilised egg. The other characteristic is pluripotency which represents the dependants of the Totipotency and are derived from three germ layers. Stem cells can be multipotent cells with endogenous trophic support and preside at the top of the linage hierarchy and when induced, differentiate from progenitor cells (transit-amplifying cells and post-mitotic cells) ultimately into more mature morphocytes ( terminally differentiated cells) Baker PS et al 2009.
Stem cell therapies are designed to target specific disease and conditions. In the eye, two areas that have been of immense benefit to stem cell research include the cornea and retina. Diseases resulting from retinal degeneration includes proliferative diabetic retinopathy, age related macular degeneration, Glaucoma (end stage), retinitis pigmentosa, proliferative vitreoretinopathy. In animal models, retinal function has been re-instated using undifferentiated photoreceptors. In Humans, microelectronic implants have been employed as artificial implants to interface with the biological visual pathway Baker PS et al 2009. This has encountered its own difficulty. It is important to note that cell replacement therapies have the ability to improve vision where diagnosis has been considered not treatable.
With all these promising outcomes, it is worth mentioning that generic tumor cell has the capability to develop neoplastic lesion such as Retinoblastoma and conjunctival melanomas. Thus according to cancer stem cells hypothesis undifferentiated stem cells has the ability to self renew and differentiate into benign or malignant cells.
Sources of stem cells
There are various sources of stem cells available. The most common one is the embryonic stem cells. These are pluripotent cell type and are obtained during the embryonic or foetal stage of development. Another one is the Adult stem cells. As explained earlier, these are multipotential cell types that are obtained from mature organisms. Other sources of stem cells are the ocular tissues and central nervous systems.
In the ocular tissues, numerous retinal stem cells have been harvested from the pigmented ciliary margin of the human eyes. This can be obtained from the fetus, adult and also from the eye bank and for retinal disorders like retinitis pigmentosa, grown photoreceptor cultures has been implanted into the diseased eye. These stem cells are also able to produce different retinal cell types and also they have the unique ability of growing rapidly when cultured.
In the anterior segment, there are areas where stem cells are located, which if harvested, cultured and transplanted, will provide therapy for anterior segment disorders. For the cornea epithelium, they are located in limbus. For unilateral diseases, stem cells are transplanted as autografts and for bilateral ocular disease, they are transplanted as allografts. According to Ramaesh et al, a small biopsy specimen from a healthy limbus can be expanded ex vivo and the grafted to an eye with stem cell deficiency.
Conjunctival stem cells can be harnessed from the superior fornix. Using amniotic membrane as a ex vivo tissues culture, they can be transplanted. One good example of this therapy is the post-op trabeculectomy surgery for Glaucoma. Conjunctival stem cell treatment can be used in the treatment of a leaking conjunctival bleb to repair the leak.
Stem cells can also be found in the corneal endothelium. This can be seen in corneal endothelial cells adjacent to the schwalbe line, as evidenced by increased endothelial cell density when compared with the central corneal endothelial density Schimmelpfennig BH 1984.
Stem cells can be harvested from trabecular meshwork and transplanted into the angel of the chamber. It could be derived from adult or foetal stem cells. Here, foetal/embryonic stem cells can proliferate, but not able to differentiate and this increases the risk of outflow of aqueous fluid.
Other sources include the Hematopoietic stem cells. These are multipotent stem cells that produce non-self renewing progenitors. Their unique characteristics include poor linage markers, poor staining with dyes, very small size and various antigenic markers on their surface. They can be found in the bone marrow, embryonic human retina. Embryonic human retina has a pool of precursors [CXCR4+ and c-kit+] that enlarges centrifugally during foetal development; c-kit expression declines with apparent migration and CXCR4 declines canalization of new vessels Hasegawa T et al 2008.
Differentiation of Stem Cells
There are many ways one can direct stem cells to differentiate into a specific outcome. These ways include modification of the microenvironment and/ or altering the intracellular signalling cascades in the engrafted cells that will be needed for the particular tissue injury.
Progenitor cells needed for stem cell therapy for ocular diseases can be obtained from various sources. These sources can be neural sources or non neural sources. Although the sources might look different, they both posses the ability to adapt to the specific target sites that are meant for them. An example of neural source is the retinal stem cells. Under specific conditions, they can develop processes and appears to function like retinal ganglion cells. An example of non neural sources is the stem cells from Limbal epithelium which can differentiate under specific conditions as mentioned above to neuronal and glial cells.
An important factor worth mentioning is that stem cells that are transplanted generally follow the structural organisation of the host eye irrespective of the age of the host recipient. An evidence to support this was shown in a study carried out in a pouchless marsupial called opossum. Opossum, which means white dog, possesses an unspecialised biology that enables them to survive in diverse location and conditions. Their young are born at a very early stage. In this study, which was carried out in Brazil, brain stem cells with a fluorescent marker from mice were transplanted through intraocular injection into developing and also mature opossum eyes. These stem cells differentiated into different layers of the retina, taking up structural characteristics of the amacrine cells, bipolar cells and horizontal cells Van Hoffelen et al 2003.
The knowledge of the transition process from multipotent stem cells to differentiated cells can further enhance if we can determine the genes involved. This can be achieved through gene expression analysis which helps to study the molecular mechanism of the stem cells during these transition processes.
Stem cells in Injured Eyes
It is worth mentioning that, unlike the diseased eye conditions, tissue injury to the eye releases factors that influence a successful outcome of the transplanted stem cells. These can be easily seen in injury situations involving mature (post mitotic) retina. In another condition, involving injury during the developmental stages, stem cells can develop into cells similar to their host recipient. Thus, local microenvironmental factors the phenotypic expression of differentiated stem cells. In 14 month old mice with mild depletion of their retinal ganglion cells, cells that are transplanted to the retina, express their processes and neurofilaments and send these processes into the plexiform layer. Further progression was seen as these fibres reached the optic nerve head at 4 month transplantation.
Stem cells in lower animals
The importance of studying lower animals cannot go unnoticed. Their study has provided us with lots of information that can be applied in Humans. Several characteristics and properties of the stem cells in lower animals have been studied in details both at molecular and cellular levels. These studies has also shed more light on proliferation of undifferentiated and differentiated cells and also has helped to find out which gene is involved at any stage of transition process from undifferentiated to differentiated cells.
The most common model used is the Drosophlia. Retinal growth in lower animals like the fish results from the production of neurons. Thus injuries to the fish retina leads to regenerative process called neurogenesis. Stem cells are located in the Fish retina .This is in contrast to the human retina, which can only be repaired through stem cell therapy. There are ongoing studies aimed at locating the genes expressed by the retinal stem cells and also to establish the molecules that regulate their neurogenic activity, both during normal growth and after injury. Boucher SE et al 1998.
Stem cells and Glaucoma
Glaucoma is a disease resulting from optic nerve damage, which is composed of retinal ganglion cells and support cells. The ultimate feature of glaucoma is visual field loss due to optic nerve damage. Current clinical treatment includes medical therapy (e.g. drugs) or surgical, both aiming to lower the Intraocular pressure. This will in turn reduce optic nerve damage.
As mentioned earlier, nerve damage in Human retina is irreversible. Thus stem cells create an opportunity towards replacing the damaged nerve, which will in turn restore vision. There are three main regions that stem cells targets in Glaucoma. These are retinal ganglion cells, trabecular meshwork and optic nerve head. Bearing in mind that the unit of optic nerve head is the retinal ganglion cells, replacement of the retinal ganglion cells has been the goal of many work done so far. It is important to note that current treatment (medical and surgical) only reduces the rate of damage of the optic nerve head. This deficiency has resulted in the initiation of other possible treatments for glaucoma like the use of vaccine that can initiate protective autoimmunity; increasing blood supply to the optic nerve. Despite the hopeful optional treatment, there are many concerns that need to resolve in order to achieve a successful result. These include sustaining the microenvironment; stem cell differentiation and prognosis; migration of transplanted cell axons; making functional contact with lateral geniculate nucleus and various areas of the cortex.
Even when one factor is resolved, other factors will be pending, thus exposing the complex nature of stem cell therapy. Despite this, there is a great hope that even a small amount of progress will be highly appreciated, if one bears in mind that loss of vision becomes clinically significant when a significant amount of retinal ganglion cell damage has occurred.
Improving trabecular meshwork through stem cell therapy theoretically looks great, but one has to bear in mind the risk of rejection and thus might not result to full restoration of its functional capacity. It is also important to consider the surgical benefit (trabeculectomy) which could outweigh stem cell therapy aimed towards the trabecular meshwork.
As mentioned earlier, stem cell therapy is directed towards optic nerve head. A major drive towards many works and studies done so far is based on the unknown pathophysiology of the low tension glaucoma. In this condition, there is a progressive loss of the optic nerve head, with substantial remodelling and biochemical change, despite a well controlled intraocular pressure. Complications arising from this optic nerve damage include nitric oxide secretion, cell loss, blood flow problems and many more. Thus, supplying stem cell bound astrocytes and fibroblasts might provide an alternative solution. Sources of stem cell for glaucoma include neuronal cells from the conjunctiva, brain, corneal endothelium, retina limbus as well as foetal stem cells.
A promising solution towards stem cell sustainability and survival is modifying the genetic composition of the stem cells. To ensure a successful outcome, much work needs to be done here to determine what changes that can be made in the genes of the stem cells.
Challenges in Using Stem Cells For Eye Disease
One of the Main challenges facing stem cell therapy is Safety. To achieve a therapeutic goal, certain condition must be met. These include growing cells without serum and cell feeder layers; large production of cells at any stage of transition process; complete differentiation; termination of the production process post transplantation( to avoid the risk of neoplasm) and functional adaptation to its new destined target.
Another challenge is the Recipient environment. It is worth mentioning that the transplanted cell came from a different productive background and that the recipient's environment might harsh to these cells during their transformation process. Unless something is done, this limits the survival rate of these transplanted cells.
Ways to alleviate this problem include neuroprotection of these cells until they are able to make successful contact with their recipient. Inflammatory response following injury to the target site can be alleviated using anti-inflammatory drugs. Also the use of growth factors such as neurotrophins in these recipient hosts following assault can help the transplanted cell survival.
Another important issue is the Underlying pathophysiology of the disease. There is a high probability that the newly transplanted cells can be influenced by this problem, thus resulting in poor sustainability. One way of approaching this problem is to remove the underlying pathophysiology before transplantation, to ensure a successful outcome.
Optic nerve tracing is another issue of concern. The complex pathway of optic nerve from the retina to the lateral geniculate nucleus and cortex limits the successful outcomes of the transplanted cells. A possible option will be to manipulate cells that guide this optic nerve pathway. These cells include Muller cells, astrocytes and retinal glial cells.
Remyelination is another challenge. Even when the transplanted cells make a successful connection, the functional integrity of both the transplanted and injured recipient axon is questionable, due to the absence of myelin. Remyelination in the human brain system occurs in the acute and not the chronic phase and there is no relative increase to meet the demands of regeneration. Inability to produce myelin could be due to stem cell exhaustion, trophic signals deficiency, failure of response by the injured axon and many more.
Rejection is another issue of concern. Although the eye a relative immune privilege, there is still a probability of rejection, especially for the allogenic stem cells. Autogenic stem cells can solve this problem, but there is still a risk of transporting pre-existing disease to a new site in the same patient.
Most ophthalmic diseases are neurological degenerative disease. Thus, there is a great need for research in the field of stem cells. Successful outcome has been seen when human brain cells are transplanted to the ventral horn of the spinal cord of animal model suffering from amyotrophic lateral sclerosis.
Major areas of great research needs include enhanced detail of each progenitor cell type. This includes modifying the genetic composition as well as manipulating the production of factors involved in the transformation process.
Another field of research need is sources for stem cell therapy. These include both the neuronal and non neuronal sources.
More work need to be done on the recipient's environment. Improved receptive environment will ensure a successful outcome of transplanted stem cells.
The process of neurogenesis, seen in lower animals like fish, needs to be worked on. It offers lots of opportunities in discovering factors or condition that brings about non regeneration in Humans.
The encouraging results received from current and previous studies, has resulted in an increased need for more research in stem cell therapy. Despite the complex nature of a successful treatment, more light has been shed on possible solution which has been lacking many years back. These includes improving the progenitor cell (through genetic modification), Improving the recipient environment, establishing a functional axon (through remyelination). Great progress has been made so far, with a great expectation of solution to these outstanding problems.
References for stem cells
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Curr Opin Ophthalmol. 2010 May;21(3):213-7. Treatment viability of stem cells in ophthalmology. Jeganathan VS, Palanisamy M. Tun Hussein Onn National Eye Hospital, Petaling Jaya, Selangor Darul Ehsan, Malaysia. [email protected]
Pellegrini G, De Luca M, Arsenijevic Y. Towards therapeutic application of ocular stem cells. Semin Cell Dev Biol 2007; 18:805-818. ExternalResolverBasic Bibliographic Links [Context Link]
Hans R. Schöler (2007). "The Potential of Stem Cells: An Inventory". in Nikolaus Knoepffler, Dagmar Schipanski, and Stefan Lorenz Sorgner. Humanbiotechnology as Social Challenge. Ashgate Publishing, Ltd. p.Â 28. ISBNÂ 0754657558.
Ramaesh K, Dhillon B. Ex vivo expansion of corneal limbal epithelial/stem cells for corneal surface reconstruction. Eur J Ophthalmol. 2003;13:515-524. WEB OF SCIENCE | PUBMED
Schimmelpfennig BH. Direct and indirect determination of nonuniform cell density distribution in human corneal endothelium. Invest Ophthalmol Vis Sci. 1984;25:223-229. FREEHYPERLINK "http://archopht.ama-assn.org/cgi/ijlink?linkType=ABST&journalCode=iovs&resid=25/2/223" FULL TEXT
Hasegawa T, McLeod DS, Prow T, et al. Vascular precursors in developing human retina. Invest Ophthalmol Vis Sci 2008; 49:2178-2192. ExternalResolverBasic Bibliographic Links [Context Link]
Van Hoffelen SJ, Young MJ, Shatos MA, Sakaguchi DS. Incorporation of murine brain progenitor cells into the developing mammalian retina. Invest Ophthalmol Vis Sci. 2003;44:426-434.
Boucher SE, Hitchcock PF. Insulin-related growth factors stimulate proliferation of retinal progenitors in the goldfish. J Comp Neurol. 1998;394:386-394