Seeing is believing: stem cells and retinal regeneration

Seeing is believing: stem cells and retinal regeneration

Tags: , , , , , , , , , , , , ,

By: Brian G. Ballios, MD/PhD Candidate

The eyes are the gateway to our impressions and our most striking memories of the world. The process of visualizing our world is as amazing as it is complex. Light entering the eye is projected onto a light sensing tissue, the retina, at the back of the eye.  The retina is actually an outgrowth of the brain that develops early in the formation of the human central nervous system. And like other parts of the brain and spinal cord, it is exquisitely sensitive to injury. Once damaged, the adult human retina shows no ability to regenerate itself: vision loss is permanent.

Vision loss is devastating for both patients and their families. Polls conducted by the Gallup Organization reveal that blindness is the second most feared disease by Americans after cancer. As arguably one of the most important sensory modalities, loss of vision can take a significant toll on quality of life and the psychosocial well being of patients. In our society, the primary causes of degenerative vision loss span the age spectrum. Age-related macular degeneration (AMD) is the most common cause of irreversible blindness affecting seniors over 651. The macula is the part of the central retina responsible for high acuity vision. With our aging baby-boomer population, rates of newly diagnosed AMD are expected to rise in the coming decade2. Retinitis pigmentosa (RP) affects primarily children and young adults, and is the leading cause of inherited retinal degeneration3.

What most forms of retinal degeneration have in common is the irreversible loss of photoreceptors—the light sensitive cells in our retina that convert light into electrical signals. We are born with only a finite number, and they are literally irreplaceable. Current drug therapies for these conditions can slow the progression of disease, but are not curative.

Cell transplantation is an alternative strategy that holds promise for restoring lost vision to patients. The goal is to replace the lost photoreceptors with new donor photoreceptors. But in approaching the design of this therapy, there are two critical questions that need to be asked. (1) What are the best cell types to transplant to replace lost retinal cells? (2) What is the optimum way to deliver these cells to ensure they distribute, survive, and integrate after transplant into the damaged retina to restore function?

Stem Cells for Transplantation
Early cell transplantation studies in humans involved the transplantation of immature (progenitor) retinal cells taken from fetal tissue. While these studies showed some subjective improvement in function, the measurable increase in retinal function was less convincing4. Many scientists agree that a population of immature retinal cells represents the most promising approach for successful transplantation. As a source of immature cells, stem cells show great promise. Human embryonic stem (hES) cells represent a potential source of therapeutic cell populations for retinal repair. These cells replicate indefinitely in culture, and can be coaxed to mature (differentiate) into multiple retinal cell types5.

The first report of hES-derived cell transplants into human patients represents a significant step forward in taking stem cell research from bench-to-bedside. In this study, retinal pigmented epithelium (RPE) cells derived from hES cells were transplanted into patients with forms of macular degeneration6. The RPE are the support cells of the retina, trapping light within the eye and providing metabolic support for the photoreceptors. Replacement of RPE damaged by retinal disease may help to rescue dying photoreceptors in the retina. Early results suggest that these transplanted cells are well tolerated by the patients’ eyes, and modest visual improvement was reported in one patient. Additional detailed studies will be required to evaluate the long-term benefits of this therapy.

However, even replacement of the RPE cannot restore the vision lost by the absence of retinal photoreceptors. While numerous studies in mouse disease models have shown the potential of hES-derived retinal progenitors to integrate and differentiate into photoreceptors in host retina and restore some visual function7, the inability to purify photoreceptors from these cultures means that a mixed population of cells is transplanted, including some non-retinal cell types. Furthermore, the isolation of hES raises significant ethical issues.

Adult stem cells represent another stem cell type with potential for therapeutic translation—these cells can be isolated from adult tissue and demonstrate the ability to differentiate into multiple tissue-specific cell types. Van der Kooy and colleagues reported the isolation of adult retinal stem cells (RSCs) in the adult mouse8 and human9 eye. These cells can differentiate into all retinal cell types, including photoreceptors. They do not differentiate into non-retinal cells, and their ability to be isolated from adult donor tissue negates the controversy around the use of fetal tissue for cell therapy. To apply these cells for retinal cell therapy, it is necessary to have control over their differentiation toward particular types of photoreceptors, and in particular, the rod photoreceptor. Rod photoreceptors are the predominant type of photoreceptor in the adult eye, and the ability to replace these cells is of critical importance as a step toward retinal cell therapy.

Recently, we demonstrated that by optimizing cell culture conditions, the adult RSC could be differentiated into rod photoreceptors with unprecedented efficiency (>90% pure cultures)10. In addition, with the ability of the RSC to renew indefinitely in culture—a cardinal property of stem cells—the RSC represents a potentially unlimited source of donor photoreceptors. Research suggests that cells committed to maturing into rods are an optimum population for rod-replacement11, and thus, adult RSC-derived rods are an ideal cell source for future therapy.

Improving Stem Cell Transplantation
Three major barriers exist to the application of stem cell therapy for retinal regeneration. These include proper distribution, survival and integration of cells after transplantation. To overcome these barriers, an interdisciplinary approach combining an understanding of basic RSC biology and bio-engineered strategies for cell delivery are essential. Most commonly, these have included the delivery of stem cells on solid biomaterial scaffolds12. While this represents an important advance, these solid scaffolds are not flexible and may cause damage to the sensitive retinal tissue during implantation13.

In collaboration with the laboratory of Dr. Molly Shoichet (U of T, IMS), we have developed a minimally invasive, injectable and biodegradable gel for cell delivery to the retina14 called HAMC. This represents the first report of an injectable bio-engineered delivery vehicle for cell delivery to the retina. A blend of biopolymers normally found in nature, HAMC supports transplanted RSC survival and distribution across the retina, and is completely degraded within a week of injection. This delivery system may be useful in the treatment of advanced retinal disease, where large areas of retina are destroyed. The development of injectable devices represents a new dimension to therapy for retinal regeneration. Translation to the clinic will depend on improved visual function, resulting from greater cell survival and integration into host tissue.

Stem cells hold great promise for future retinal therapy. This is an exciting time for stem cell research in the eye, as advances in the laboratory are beginning to see application in clinical therapy. Innovation in stem cell therapy for retinal regeneration will depend on multidisciplinary collaboration to advance our understanding of the biology of retinal stem cells, and how they may be delivered to the diseased retina.


1. Kaufman, S. R. Developments in age-related macular degeneration: Diagnosis and treatment. Geriatrics 64, 16-19 (2009).

2. Congdon, N. G., Friedman, D. S. & Lietman, T. Important Causes of Visual Impairment in the World Today. Journal of the American Medical Association 290, 2057-2060 (2003).

3. Shintani, K., Shechtman, D. L. & Gurwood, A. S. Review and update: Current treatment trends for patients with retinitis pigmentosa. Optometry 80, 384-401 (2009).

4. Radtke, N. D., Aramant, R. B., Seiler, M. & Petry, H. M. Preliminary report: Indications of improved visual function after retinal sheet transplantation in retinitis pigmentosa patients. American Journal of Ophthalmology 128, 384-387 (1999).

5. Lamba, D. A., Karl, M. O., Ware, C. B. & Reh, T. A. Efficient generation of retinal progenitor cells from human embryonic stem cells. Proc. Natl. Acad. Sci. U S A 103, 12769-12774 (2006).

6. Schwartz, S. D. et al. Embryonic stem cell trials for macular degeneration: a preliminary report. Lancet 379, 713-720 (2012).

7. Lamba, D. A., Gust, J. & Reh, T. A. Transplantation of human embryonic stem cell-derived photoreceptors restores some visual function in Crx-deficient mice. Cell Stem Cell 4, 73-79 (2009).

8. Tropepe, V. et al. Retinal stem cells in the adult mammalian eye. Science 287, 2032-2036 (2000).

9. Coles, B. L. K. et al. Facile isolation and the characterization of human retinal stem cells. Proc. Natl. Acad. Sci. U S A 101, 15772-15777 (2004).

10. Ballios, B. G., Clarke, L., Shoichet, M. S. & van der Kooy, D. The adult retinal stem cell is a rare cell in the ciliary epithelium whose progeny can differentiate into photoreceptors. Biol. Open 1, doi: 10.1242/bio.2012027 (2012).

11. MacLaren, R. E. et al. Retinal repair by transplantation of photoreceptor precursors. Nature 444, 203-207 (2006).

12. Yao, J. et al. Robust cell integration from co-transplantation of biodegradable MMP2-PLGA microspheres with retinal progenitor cells. Biomaterials 32, 1041-1050 (2011).

13. Tomita, M. et al. Biodegradable polymer composite grafts promote the survival and differentiation of retinal progenitor cells. Stem Cells 23, 1579-1588 (2005).

14. Ballios, B. G., Cooke, M. J., van der Kooy, D. & Shoichet, M. S. A hydrogel-based stem cell delivery system to treat retinal degenerative diseases. Biomaterials 31, 2555-2564 (2010).