October 2020


Skill Focus
Stem cell transplantation for corneal scarring

by Ellen Stodola Editorial Co-Director

Injuries to the cornea can induce the production of inflammatory cytokines (A). Application of MSCs to the cornea inside a
fibrin gel can modulate inflammation through the secretion
of immunomodulatory factors (B).
Source: Ali Djalilian, MD

Stem cell transplantation for corneal scarring is currently in development, with limited experience so far in human patients. Sayan Basu, MBBS, and Ali Djalilian, MD, discussed this treatment and how it works.
Before getting into treatment options and choosing a treatment, Dr. Basu discussed some of the key terms, including allogeneic grafts, embryonic stem cells, induced pluripotent stem cells, and limbal stem cell transplantation.
He noted that the term allogeneic means from another person. The converse, he said, is autologous, meaning from the same person. “These are terms used to refer to the source of tissue/grafts or organs for transplantation,” he explained.
Embryonic stem cells (ESCs) are those that are found in the early (embryo) stage of the formation of the fetus. Typically, Dr. Basu said, in the case of human ESCs, these are created in the lab or obtained from fertility clinics as unused embryos. They have the potential to create any tissue in the body. ESCs have the greatest potential and are pluripotent, however, they are allogeneic.
Induced pluripotent stem cells (iPSCs), he said, are adult cells that have been programmed to function similar to ESCs by introducing certain genes, known as the Yamanaka factors or some variations thereof. “Usually these are derived from skin fibroblasts,” Dr. Basu said. “Once iPSCs are formed, they can, like ESCs, produce any tissue of the body. The advantage over natural ESCs is that iPSCs are autologous.”
Limbal stem cells are adult stem cells that are present throughout life and are responsible for producing the corneal epithelial cells. Like the cornea, all epithelial surfaces in the body (like the skin, gastric mucosa, or endometrium) have their own adult stem cells in different locations. Dr. Basu said that this is because epithelial surfaces have a high turnover (cells die and fall off and need to be replaced by new cells), and stem cells keep these surfaces epithelialized. However, adult stem cells, unlike iPSCs or ESCs, can only produce cells of one/limited type(s); they can’t make all cells and tissues of the body.
According to Dr. Basu, the corneal epithelial stem cells were discovered at the limbus in the late 1980s, and since then, it has been possible to reverse corneal stem cell damage by transplanting healthy limbal tissue from either the other eye of the same patient (autologous) or another person (allogeneic: living or cadaveric). “There are many techniques of limbal stem cell transplantation; the most recent and popular of them is simple limbal epithelial transplantation (SLET),” he said.

Treatment options now and on the horizon

Currently no therapy exists that can reverse a formed scar, Dr. Basu said. Scarring can be mitigated to an extent by treating the cause early and adequately, he added. “If the scar is significantly opaque and interferes with visual function, it has to be removed surgically.” This can be done with laser, if the scar is superficial, or by performing a corneal transplantation, if the scar is deep.
Surgical therapies include phototherapeutic keratectomy using excimer laser for superficial scars and non-penetrating (DALK) or penetrating (PK) corneal transplantation for deeper scars, Dr. Basu said.
The limbus is also the source of mesenchymal stem/stromal cells (MSC), Dr. Basu said. MSCs are of interest for modulating scarless wound healing. He added that there are a large number of trials using MSCs for various kinds of injuries and degenerations. They also have immunomodulatory properties and are less immunogenic. Therefore, allogeneic therapy is less of a problem with MSCs. They are also known as stromal stem cells, he said. Mesenchymal is a morphological description, while stromal is an anatomical description (based on the location within the tissue).
Dr. Basu said there is a lot of interest in using MSCs, either from the limbus or from the bone marrow to treat corneal stromal pathologies and opacities. At LV Prasad Eye Institute, they are conducting the first human trials using these cells for treating visual impairment and blindness due to stromal pathologies.
Dr. Djalilian said that treatment with MSCs is still highly experimental, and there is very limited data and experience from patients. Completed studies are mostly in animal models, and human patients are just beginning to be tested. India is the only place that has gotten as far as testing in human patients; U.S. testing in humans may start later this year, he said.
The basic idea is that this could be used for corneal scars that are more superficial, Dr. Djalilian said. It may be possible to get the tissue in that area to remodel so that it then gets replaced by a clearer corneal stroma, without removing any tissue.
Another way it could be applied, he said, is when there is a deeper scar in the cornea; remove the tissue and replace it with these cells. Instead of having to transplant corneal tissue, you use a combination of cell and matrix to replace the cornea, Dr. Djalilian said. He added that this has not yet been tested in humans and may be something that could be used in the future.

Conditions causing corneal scarring that would require stem cell transplantation

Dr. Djalilian said that this treatment could be used for any type of condition that has scarring in the cornea, but primarily scarring that’s more anterior. Deep extensive scarring or scarring on the whole cornea cannot be treated adequately with current treatment options, he said.
The other conditions where it might be useful, he said, are conditions where there’s active inflammation.
Corneal scarring or fibrosis is caused by inflammation or trauma involving the corneal stroma, Dr. Basu said. “Corneal scarring is the leading cause of visual impairment or blindness due to corneal diseases,” he said. He added that in developed countries, post-refractive surgery haze, herpetic infections, and contact lens-related infections are the major cause of corneal scarring. Meanwhile, in most of the developing world, trauma or corneal injury followed by bacterial and fungal infections are the most common causes. In children, nutritional deficiency is a cause in the developing world, he said.


Any scar that affects vision can and should be treated, Dr. Basu said. “The problem is that the burden of blindness due to corneal scarring is highest in the developing world, where both lasers and donor corneal tissue are scarce,” he said. “Plus, these treatments need skilled corneal surgeons, and there are not enough around to treat or follow up with the patients. Patients with transplants need lifelong follow-up, and sometimes corneal grafts fail because of poor postoperative care.”
Dr. Djalilian added that there may be a contraindication for patients who already have a perforation in the eye, particularly in the cornea. “You don’t want the cells going inside the eye,” he said. “You want them to stay on the cornea.”
Dr. Djalilian again stressed the experimental nature of this treatment. “In the U.S. any treatment with MSCs is done only under strict monitoring and regulation by the FDA until its safety/efficacy has been established in well-designed clinical trials,” he said.
Dr. Djalilian also noted that some “stem cell clinics” in the U.S. are offering variations of MSCs (a mixed cell population isolated from a patient’s own fat or bone marrow), which they are injecting to different parts of the body. “These clinics are quite often in violation of FDA regulations and unfortunately have led to some devastating complications,” he said. “Specifically, there are published reports of patients who went blind from injecting cells into the vitreous for conditions such as macular degeneration.”

About the doctors

Sayan Basu, MBBS

Director and D Balasubramanian Chair of Eye Research
LV Prasad Eye Institute
Hyderabad, India

Ali Djalilian, MD
Professor of Ophthalmology
University of Illinois College of Medicine
Chicago, Illinois

Relevant disclosures

: None
Djalilian: None


: sayanbasu@lvpei.org
Djalilian: adjalili@uic.edu

Stem cell transplantation for corneal scarring Stem cell transplantation for corneal scarring
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