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Stem Cell Therapy for Retinal Regeneration using iPS Cells

 Masayo Takahashi
 Team Leader  
 Laboratory for Retinal Regeneration
 RIKEN Center for Developmental Biology

 Address: 2-2-3 Minatojima-Minamimachi, Chuo-ku, Kobe 650-0047, Japan 

Adult mammalian retina were thought incapable of regeneration after injury, but in recent years it has been shown that, at least in rats, retina have the ability to generate retinal neural cells at times of damage. This suggests that it may be possible to reconstruct the adult retina and related neural networks. This potential capability, coupled with the transplantation of cells derived from the retina, or alternatively from external sources, may make it possible to achieve the regeneration of retinal function lost from disease. Examining these possibilities is at the core of the research conducted by the Laboratory for Retinal Regeneration.

Stem Cell Therapy using ES and iPS Cells
Human embryonic stem (ES) cell research and induced pluripotent (iPS) stem cell research are both critical research areas in the field of regenerative medicine. ES cells are generated either from the fertilized egg or the blastocyst, an early-stage embryo. The use of ES cells is problematic, both from an ethical perspective and rejection issues. By contrast, iPS cells are generated by inserting DNA into somatic cells, and do not have the same ethical problems associated with ES cells nor similar problems of immune rejection. There is a risk, however, that the transplanted cells may have a carcinogenic effect on the host body. We need to clarify further the properties and potential benefits of both ES and iPS cells, and this will be achieved through continued comparative research.

The application of ES and iPS cells in regenerative medicine requires that stem cells be differentiated into more specific cells. Pluripotent cells are so called because they have the unlimited capacity for proliferation. However, we have yet to establish a method that will allow us to mass-produce these cells to a quality that would enable us to use them in clinical applications. For this reason, the most likely candidates for the early development of clinical applications are the hormone secreting tissue and central nervous tissue, for which only a small number of stem cells is required for treatment.

Having said that, successful transplantation of actual nerve cells requires the extremely difficult task of implanting the transplanted cells into complex neural network and enabling them to function correctly there. In truth, there is still much ground to be covered before effective treatments are established. In the case of retinas, we need first to generate, from stem cells, retinal pigment epithelial cells to support photoreceptor cells, which are a type of nerve cell. These supporting cells are the transplanted to assist the function of the photoreceptor cells and prevent any worsening, or, if the problem being treated is one of functional deterioration rather than degeneration, to regenerate nerve cells. This is the closest we have come to a potential clinical application.

Retinal Pigment Epithelial Cell Transplantation
The research team at the Laboratory for Retinal Regeneration has succeeded in developing a method for the induction of differentiation of autologous retinal pigment epithelial (RPE) cells from iPS cells as well as the fabrication of RPE cell sheets from morphologically and functionally mature human iPS cells, the result of our goal to develop methods of transplantation of functioning cells that are sufficient in volume and cause no immune rejection.

The human retina comprises ten layers, from outside inwards: pigment epithelial layer, photoreceptor cell layer, external limiting membrane, external granular layer, external plexiform layer, inner granular layer, inner plexiform layer, ganglion cell layer, nerve fiber layer, and the inner limiting membrane. Of these, there are a large number of diseases that damage to the RPE causing eyesight deterioration; most visual impairments can be attributed to this cause. The most typical example of such a disease is age-related macular degeneration. Normally, RPE cells are not replaced over a lifetime, meaning the cells cannot repair themselves from the effects of age and significant damage. This means that regenerative medicine must employ cell transplantation methods, and cell sheets fabricated from autologous cells are considered most effective for RPE transplantation. Using RPE cell sheets fabricated from autologous iPS cells makes it possible to replace or regenerate the damaged RPE with new RPE created from patient-induced own iPS cells, once the neovascular membrane has been surgically removed.

At present, our group is working further on the technique that allows us to differentiate RPE cells from iPS cells, making it better suited for clinical applications. We have formulated quality assessment criteria and established a cell processing center. Armed with cell sheets, made from morphologically and functionally mature, highly stable, refined terminally differentiated cells fabricated from human iPS cells, clinical-use culture techniques, and appropriate facilities, we will be able to complete our safety evaluations of this treatment and move into the clinical research phase. (Final confirmations are still to be made for the most stringent of safety tests, namely the transplantation of the end product of RPE, induced from iPS cells generated from the equivalent method to be used in clinical research, together with tumor growth factor into an immunodeficient mouse model).

Although, however, this clinical research can be carried out under the Medical Practitioners’ Act using research funding, the cost of clinical trials is immense, reaching into many billions of yen (several tens of million US dollars). In order to turn this incredible research into a commonly available treatment, we must take appropriate steps to develop it into a profitable treatment method, such as launching it as a business venture.

Toward the Regeneration of Retinal Function
If the proposed clinical applications of RPE transplantation can be developed, those experiences can doubtless be put to good use in achieving true regeneration of central nervous tissue, in other words the transplantation of photoreceptor cells. Our team at the Laboratory for Retinal Regeneration is working toward the goal of retinal regeneration, taking a dual approach from both basic and clinical research.

Fig. 1 Retinal pigment epithelial (RPE) cells induced from iPS cells. RPE cells contain pigment and differentiate by forming colonies, so they can be picked out and refined with the aid of a microscope.

Fig. 2 Transplantation of retinal cells. A cell sheet is inserted underneath the retina, where retinal pigment epithelial cells and photoreceptor cells are present (in between the retina and the pigment epithelial cells).