Physician offers glimpse at future of limbal stem cell transplantation

One of the diagnostic challenges with deficiency of limbal stem cells, which are adult stem cells that further differentiate into the corneal epithelium, is that there is no gold standard.

Reviewed by Stephanie Watson, PhD

More investigations of limbal stem cell transplantation are needed before the practice becomes more widespread, according to Stephanie Watson, PhD. Watson is head of the Corneal Research Group and faculty of medicine and health at The University of Sydney in Australia, head of the Corneal Unit at Sydney Eye Hospital, and chairperson of Australian Vision Research and of the Association for Research in Vision and Ophthalmology’s Advocacy and Outreach Committee.

Delivering the Walter Wright lecture at the 61st Annual Ophthalmology Update Walter Wright Symposium in Toronto, Ontario, Canada, titled “Limbal Stem Cell Transplantation: Where are We Now and Where We Will Be in 10 Years,” Watson called for more long-term analyses to support greater uptake of limbal stem cell transplantation. “We need further research that’s going to help us understand limbal stem cell behavior,” Watson said, noting that the research needs to understand cell dynamics and interaction. “We need to focus on patient-reported outcomes to make sure we’re delivering treatments that patients want. And we need the patients and the community to understand what safe and effective stem cell treatments are.”

One of the diagnostic challenges with deficiency of limbal stem cells, which are adult stem cells that further differentiate into the corneal epithelium, is that there is no gold standard, Watson added, noting that the diagnosis has been largely made through medical history and clinical signs. “Traditionally, limbal stem cell deficiency has been diagnosed clinically, and that’s by looking for classic signs on slit lamp examination, including poor epithelialization with either epithelial defects or recurrent erosions, chronic stromal inflammation with keratitis and scarring, and corneal vascularization ending up with conjunctivochalasis at the end stage,” Watson said.

With the growth in artificial intelligence (AI) in ophthalmology and other areas of medicine, AI is a tool that is gradually being introduced to aid in the detection of limbal stem cell deficiency, Watson explained. “There is now a trend to look toward AI to help optimize what you find with examination and imaging to assist the diagnosis of stem cell deficiency,” she said.

As AI can be a very sophisticated tool, it may offer a more refined diagnosis and enable grading of limbal stem cell deficiency from images, Watson noted, adding that optical coherence tomography angiography is an innovation that can serve to promote the identification of limbal stem cell deficiency. Still, another tool that can support the detection of limbal stem cell deficiency is confocal microscopy, Watson added. “You can also
use confocal imaging to grade the degree of limbal stem cell failure,” she said.

In terms of using limbal stem cell transplantation to manage limbal stem cell deficiency, various grafts have been used, including keratolimbal lamellar grafts, conjunctival-limbal autografts, and oversized grafts, Watson explained.

Using large-tissue techniques has given way to newer approaches that involve taking small pieces of donor limbal tissue from the superior limbus, Watson said. In this approach, referred to as simple limbal epithelial transplantation (SLET), the tissue is transplanted directly onto the affected cornea over a human amniotic graft, Watson explained, adding that it is a suitable approach for unilateral disease. One of the considerations in allo-SLET is that immunosuppression will be required, according to Watson.

Another innovation is cultivated stem cell transplantation (either autograft or allograft), which allows for a small biopsy, measuring approximately 1 to 2 mm², to be taken from a fellow eye, Watson explained. “The concept is that the tissue is taken, divided up into small pieces, then grown in the lab before being transplanted back to the patient,” she said, noting that the biopsy has been taken from limbal tissue, conjunctival tissue, and even the buccal mucous membrane. “Cultivated stem cell transplantation has been developed to overcome some of the limitations of tissue transplantation.”

Some of the limitations include the lack of specific markers and standardized ways to identify limbal stem cells, as well as the fact that donor cells from allogeneic limbal cells are not detected at 9 months post transplantation, as transplanted cells may remodel the damaged niche.

A systematic review that included 30 studies covering 1306 eyes concluded there was success with cultivated limbal stem cell transplantation, equal to a 2-line improvement in visual acuity, with no significant differences in success rates or visual improvement between autograft and allograft surgical techniques.¹ The challenge with expanding cultivated limbal stem cell transplantation is that it will require clean room facilities, complying with Good Manufacturing Practices, Watson noted.

Some of the future directions should include looking at restoration of the limbal niche, using alternative cell sources and substitutes such as hair, skin, and teeth, as well as the use of mesenchymal stem cells, which can modulate wound repair, scarring, and angiogenesis, Watson noted.

“Limbal mesenchymal stem cells have different properties [than] central corneal mesenchymal stem cells,” she said. “We have found that they can have an effect on wound repair, scarring, and angiogenesis. [Inves- tigators] are now looking to cotransplant mesenchymal stem cells with limbal epithelial stem cells.”

Moreover, Watson and colleagues also have observed that the mesenchymal
stem cells conditioned media inhibited the wound healing activities of corneal stromal fibroblasts in vitro.²

Clinical studies of limbal stem cell transplantation have not always documented adverse events, despite the fact that adverse events, such as inflammation, infection, corneal epithelial defects, and blood under the fibrin matrix, may have occurred, Watson said.

As patients are in contact with optometrists much more often than with ophthalmologists, it behooves the research community in ophthalmology to ensure optometrists are well informed on the topic of stem cell therapies, their benefits, their risks, and their financial cost, so they can relay this information to their patients, Watson concluded.

--

Stephanie Watson, PhD

Stephanie Watson, PhD
E: Stephanie.watson@sydney.edu.au
Watson has no financial disclosures related to the content of this article.

Editor’s note: Reader feedback is the most powerful tool in our arsenal as we prepare content. We want to hear from you. Help shape the content by telling us what you would like to know about this topic in a follow-up article. Send us an email and let us know.

References

1. Mishan MA, Yaseri M, Baradaran-Rafii A, Kanavi MR. Systematic review and meta-analysis in- vestigating autograft versus allograft cultivated limbal epithelial transplantation in limbal stem cell deficiency. Int Ophthalmol. 2019;39(11):2685-2696. doi:10.1007/s10792-019-01092-x

2. Watson SL, Marcal H, Sarris M, Di Girolamo N, Coroneo MT, Wakefield D. The effect of mesenchy- mal stem cell conditioned media on corneal stromal fibroblast wound healing activities. Br J Ophthalmol. 2010;94(8):1067-1073. doi:10.1136.bjo.2009.165837