Limbal stem cell

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Limbal stem cell
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Limbal stem cells, also known as corneal epithelial stem cells, are unipotent stem cells located in the basal epithelial layer of the corneal limbus. They form the border between the cornea and the sclera. Characteristics of limbal stem cells include a slow turnover rate, high proliferative potential, clonogenicity, expression of stem cell markers, as well as the ability to regenerate the entire corneal epithelium. Limbal stem cell proliferation has the role of maintaining the cornea; for example, by replacing cells that are lost via tears. Additionally, these cells also prevent the conjunctival epithelial cells from migrating onto the surface of the cornea. [2]

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Medical conditions and treatments

Damage to the limbus can lead to limbal stem cell deficiency (LSCD); this may be primary - related to an insufficient stromal microenvironment to support stem cell functions, such as aniridia, and other congenital conditions, or secondary – caused by external factors that destroy the limbal stem cells, such as chemical or thermal burns, radiation, surgery, infection, use of contact lenses, or certain drugs. [3]

Signs and symptoms include: conjunctivalisation, corneal vascularisation, ocular discomfort or pain, visual impairment, photophobia, and blindness, which are likely associated with failure in the process of regenerating the corneal epithelium. [4]

Immediate management aims to limit traumatic or chemical damage to the limbus, control inflammation, and help achieve a healthy corneal epithelium. Initial treatment after trauma/injury includes preservative-free artificial tears, topical steroids, ‘bandage’ contact lenses, and autologous eye drops (eye drops manufactured from the patient's own blood serum and plasma). Once the corneal surface has stabilized, surgery is the main approach to treatment. [5]

Types of surgeries:

  1. In the case of a partial LSCD:, a sequential sector conjunctival epitheliectomy (SSCE) can be performed to remove any tissue (pannus) that has grown over the cornea. This procedure is sometimes used as a temporary measure until further surgical interventions are possible.
  2. Transplantation of amniotic membrane from a placenta may also help. Although amniotic membrane does not have stem cells of its own, it supports regeneration of limbal stem cells. However, further surgical intervention may be needed if these approaches are unsuccessful, or when disease is more severe.
  3. Conjunctival limbal autograft (CLAU) involves transplantation of limbal tissue from a patient's healthy eye. As the procedure is achieved by transplanting autologous limbal stem cells from the patient's healthy eye, there is no risk of immune rejection, and hence no need for systemic immunosuppression. However, this procedure represents a risk for the donor eye, as the patient already has one eye damaged.
  4. In the case of bilateral LSCD, where both eyes are affected, it may be possible to transplant limbal tissue from a living donor (usually a relative). This is known as a conjunctival limbal allograft (CLAL). CLAL can be performed with both partial or total LSCD, the donor tissue is usually from a sibling or parent. As with CLAU, only a part of the donor limbus can be transplanted, as a live donor is being used. Being an allogenic transplant, immunosuppression is required, due to the risk of rejection.
  5. Kerato-limbal allograft (KLAL) involves transplantation from someone who has died and donated their organs. KLAL can be used for cases of bilateral LSCD when a living related donor is not available, or for patients with unilateral LSCD, who don't want to jeopardise their healthy eye. However, most of these types of transplant fail within five years. KLAL has a number of limitations: the graft is usually up to 24 hours old before retrieval and a further period of time is often required to screen the cadaver's blood before the tissue can be used; often the limbus is found to be damaged as the tissue is not immunocompatible, there is a high risk of rejection between the recipient and the donor cadaver and studies report only a temporary success in term of transplant effectiveness, with most failing after 5 years.
  6. A recent procedure, less invasive than CLAU, which so far has been tested only in unilateral cases, is simple limbal epithelial transplantation (SLET). In this procedure, healthy limbal tissue from the patient's good eye is cut into a number of pieces and transferred directly to human amniotic membrane covering the cornea in the damaged eye. Studies published so far have only investigated the procedure in unilaterally affected patients, and the long-term effectiveness of the technique is yet to be proven.
  7. Another recent innovation is cultivated limbal epithelial transplant (CLET), either autologous (where donor and recipient are the same patient) or allogenic (where donor and recipient are different patients). This approach can be used when either one or both eyes are affected, providing there is sufficient limbal tissue available (1–2 mm2). A small sample of limbal cells is taken from a healthy part of the eye, and grown in a sterile laboratory to produce a sheet of cells sufficient for transplantation. Once transplanted, they multiply and regrow the corneal epithelium. The manufacturing process is designed to ensure implantation of the right number, size and quality of cells. CLET avoids some of the issues faced by other limbal transplantation procedures and does not pose a threat to the integrity of the donor eye. It also offers the possibility of re-grafting in case of failure of the first graft or need for a further graft. Autologous CLET has been developed to specifically treat LSCD in a recent phase I clinical trial. [6]


Types

There are three types of clonogenic keratinocytes involved in the generation of the corneal epithelium: holoclones, meroclones and paraclones. 1- Holoclones: as true stem cells, have the greatest growth potential, and give rise to 2-meroclones, which have a much lower proliferative capacity, but frequently divide. 3- Paraclones have even lower proliferative capacity. Both meroclones and paraclones are known as transient amplifying cells and their purpose is to form a stratified squamous epithelium. All three types of keratinocytes are present in the basal layer of the limbus, with holoclones in the least abundance (10%–15%). The basal layer of the cornea is populated by meroclones and paraclones at the periphery, and only paraclones in the central cornea, reflecting the above process of cell division and differentiation. Holoclones are identified by high expression of the marker p63 and are also known as p63 bright cells.

Society and culture

In February 2015, the European Commission approved autologous CLET using the stem cell therapy Holoclar for people with severe LSCD due to corneal burns. [1] This is the first time that a stem cell therapy (other than the use of umbilical cord stem cells) has been approved by any regulatory agency in the world. It was created by Graziella Pellegrini and Michele de Luca. [7] [8] Holoclar is a tissue-engineered product that comprises ex vivo expanded autologous human corneal epithelial cells including stem cells, which replace limbal stem cells in patients where the limbus has been destroyed by ocular burns. The use of p63 transcription factor as a biomarker of potency ensures specified amount of stem cells needed for clinical success. Clinically relevant long-term beneficial results have been documented in the treatment of patients with LSCD due to physical or chemical ocular burns.

See also

Figures

The localization of limbal epithelial stem cells and the anatomy of the cornea. LESC: limbal epithelial stem cell.From a review by Ruan et al., 2021. The localization of limbal epithelial stem cells and the anatomy of the cornea.jpg
The localization of limbal epithelial stem cells and the anatomy of the cornea. LESC: limbal epithelial stem cell.From a review by Ruan et al., 2021.

Related Research Articles

<span class="mw-page-title-main">Cornea</span> Transparent front layer of the eye

The cornea is the transparent front part of the eye that covers the iris, pupil, and anterior chamber. Along with the anterior chamber and lens, the cornea refracts light, accounting for approximately two-thirds of the eye's total optical power. In humans, the refractive power of the cornea is approximately 43 dioptres. The cornea can be reshaped by surgical procedures such as LASIK.

<span class="mw-page-title-main">Pterygium (eye)</span> Pinkish, triangular tissue growth on the cornea of the eye

A pterygium of the eye is a pinkish, roughly triangular tissue growth of the conjunctiva onto the cornea of the eye. It typically starts on the cornea near the nose. It may slowly grow but rarely grows so large that it covers the pupil and impairs vision. Often both eyes are involved.

<span class="mw-page-title-main">Corneal endothelium</span>

The corneal endothelium is a single layer of endothelial cells on the inner surface of the cornea. It faces the chamber formed between the cornea and the iris.

<span class="mw-page-title-main">Corneal transplantation</span> Surgical procedure of repairing corneal tissue to treat corneal blindness

Corneal transplantation, also known as corneal grafting, is a surgical procedure where a damaged or diseased cornea is replaced by donated corneal tissue. When the entire cornea is replaced it is known as penetrating keratoplasty and when only part of the cornea is replaced it is known as lamellar keratoplasty. Keratoplasty simply means surgery to the cornea. The graft is taken from a recently deceased individual with no known diseases or other factors that may affect the chance of survival of the donated tissue or the health of the recipient.

<span class="mw-page-title-main">Corneal dystrophy</span> Medical condition

Corneal dystrophy is a group of rare hereditary disorders characterised by bilateral abnormal deposition of substances in the transparent front part of the eye called the cornea.

<span class="mw-page-title-main">Vernal keratoconjunctivitis</span> Medical condition

Vernal keratoconjunctivitis is a recurrent, bilateral, and self-limiting type of conjunctivitis having a periodic seasonal incidence.

An amniotic epithelial cell is a form of stem cell extracted from the lining of the inner membrane of the placenta. Amniotic epithelial cells start to develop around 8 days post fertilization. These cells are known to have some of the same markers as embryonic stem cells, more specifically, Oct-4 and nanog. These transcription factors are the basis of the pluripotency of stem cells. Amniotic epithelial cells have the ability to develop into any of the three germ layers: endoderm, mesoderm, and ectoderm. They can develop into several organ tissues specific to these germ layers including heart, brain, and liver. The pluripotency of the human amniotic epithelial cells makes them useful in treating and fighting diseases and disorders of the nervous system as well as other tissues of the human body. Artificial heart valves and working tracheas, as well as muscle, fat, bone, heart, neural and liver cells have all been engineered using amniotic stem cells. Tissues obtained from amniotic cell lines show promise for patients with congenital diseases or malformations of the heart, liver, lungs, kidneys, and cerebral tissue.

<span class="mw-page-title-main">Corneal ulcer</span> Medical condition of the eye

Corneal ulcer, also called keratitis, is an inflammatory or, more seriously, infective condition of the cornea involving disruption of its epithelial layer with involvement of the corneal stroma. It is a common condition in humans particularly in the tropics and in farming. In developing countries, children afflicted by vitamin A deficiency are at high risk for corneal ulcer and may become blind in both eyes persisting throughout life. In ophthalmology, a corneal ulcer usually refers to having an infection, while the term corneal abrasion refers more to a scratch injury.

<span class="mw-page-title-main">Corneal limbus</span> Border between the cornea and the sclera of the eye

The corneal limbus is the border between the cornea and the sclera. It contains limbal stem cells in its palisades of Vogt. It may be affected by cancer or aniridia, among other issues. The limbal ring is a visible dark ring around the iris of the eye composed of darkened areas of the corneal limbus.

<span class="mw-page-title-main">Pterygium</span>

Pterygium refers to any wing-like triangular membrane occurring in the neck, eyes, knees, elbows, ankles or digits.

Transplantable organs and tissues may refer to both organs and tissues that are relatively often transplanted, as well as organs and tissues which are relatively seldom transplanted. In addition to this it may also refer to possible-transplants which are still in the experimental stage.

<span class="mw-page-title-main">Limbal ring</span> Dark ring around the iris of the eye

A limbal ring is a dark ring around the iris of the eye, where the sclera meets the cornea. It is a dark-colored manifestation of the corneal limbus resulting from optical properties of the region. The appearance and visibility of the limbal ring can be negatively affected by a variety of medical conditions concerning the peripheral cornea. It has been suggested that limbal ring thickness may correlate with health or youthfulness and may contribute to facial attractiveness. The thickness of the limbal ring varies by pupil dilation - when the pupil is larger, the limbal ring narrows. Some contact lenses are colored to simulate limbal rings.

<span class="mw-page-title-main">Herpes simplex keratitis</span> Medical condition

Herpetic simplex keratitis is a form of keratitis caused by recurrent herpes simplex virus (HSV) infection in the cornea.

Cord lining, cord tissue, or umbilical cord lining membrane, is the outermost layer of the umbilical cord. As the umbilical cord itself is an extension of the placenta, the umbilical cord lining membrane is an extension of the amniotic membrane covering the placenta. The umbilical cord lining membrane comprises two layers: the amniotic layer and the sub-amniotic layer. The umbilical cord lining membrane is a rich source of two strains of stem cells (CLSCs): epithelial stem cells (CLECs) and mesenchymal stem cells (CLMCs). Discovered by Singapore-based CellResearch Corporation in 2004, this is the best known source for harvesting human stem cells.

Mooren's ulcer is a rare idiopathic ocular disorder that may lead to blindness due to progressive destruction of the peripheral cornea. Although the etiology of Mooren's ulcer is poorly understood, recent evidence suggests that the pathogenesis of this disease appears to be the result of an autoimmune process directed against molecules expressed in the corneal stroma.

Pre Descemet's endothelial keratoplasty (PDEK) is a kind of endothelial keratoplasty, where the pre descemet's layer (PDL) along with descemet's membrane (DM) and endothelium is transplanted. Conventionally in a corneal transplantation, doctors use a whole cornea or parts of the five layers of the cornea to perform correction surgeries. In May 2013, Dr Harminder Dua discovered a sixth layer between the stroma and the descemet membrane which was named after him as the Dua's layer. In the PDEK technique, doctors take the innermost two layers of the cornea, along with the Dua's layer and graft it in the patient's eye.

Neurotrophic keratitis (NK) is a degenerative disease of the cornea caused by damage of the trigeminal nerve, which results in impairment of corneal sensitivity, spontaneous corneal epithelium breakdown, poor corneal healing and development of corneal ulceration, melting and perforation. This is because, in addition to the primary sensory role, the nerve also plays a role maintaining the integrity of the cornea by supplying it with trophic factors and regulating tissue metabolism.

<span class="mw-page-title-main">V. S. Sangwan</span> Indian ophthalmologist

Virender Singh Sangwan is an Indian ophthalmologist and the Dr. Paul Dubord Chair professor and director of the L. V. Prasad Eye Institute, Hyderabad. Known for his research on limbal stem cells, Sangwan is the founder secretary and an adviser of the Uveitis Society of India. The Council of Scientific and Industrial Research, the apex agency of the Government of India for scientific research, awarded him the Shanti Swarup Bhatnagar Prize for Science and Technology, one of the highest Indian science awards for his contributions to Medical Sciences in 2006.

<span class="mw-page-title-main">Graziella Pellegrini</span> Italian Professor of Cell Biology

Graziella Pellegrini is an Italian Professor of Cell Biology and the Cell Therapy Program Coordinator at the University of Modena and Reggio Emilia. She has developed and championed cell therapy protocols in hospitals across Italy.

<span class="mw-page-title-main">Stem cell therapy for macular degeneration</span> Use of stem cells to treat macular degeneration

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References

  1. 1 2 "Holoclar EPAR". European Medicines Agency (EMA). 17 September 2018. Retrieved 25 August 2020.
  2. ↑ Schlötzer-Schrehardt, Ursula; Kruse, Friedrich E. (2005-09-01). "Identification and characterization of limbal stem cells". Experimental Eye Research. 81 (3): 247–264. doi:10.1016/j.exer.2005.02.016. ISSN   0014-4835. PMID   16051216.
  3. ↑ Dua, H. S.; Saini, J. S.; Azuara-Blanco, A.; Gupta, P. (2000-06-01). "Limbal stem cell deficiency : Concept, aetiology, clinical presentation, diagnosis and management". Indian Journal of Ophthalmology. 48 (2): 83–92. ISSN   0301-4738. PMID   11116520.
  4. ↑ Deng, SophieX; Sejpal, Kunjal; Bakhtiari, Pejman (2013). "Presentation, diagnosis and management of limbal stem cell deficiency". Middle East African Journal of Ophthalmology. 20 (1): 5–10. doi: 10.4103/0974-9233.106381 . ISSN   0974-9233. PMC   3617528 . PMID   23580847.
  5. ↑ Dang, Deanna H.; Riaz, Kamran M.; Karamichos, Dimitrios (2022-02-01). "Treatment of Non-Infectious Corneal Injury: Review of Diagnostic Agents, Therapeutic Medications, and Future Targets". Drugs. 82 (2): 145–167. doi:10.1007/s40265-021-01660-5. ISSN   1179-1950. PMC   8843898 . PMID   35025078.
  6. ↑ Jurkunas, Ula V.; Yin, Jia; Johns, Lynette K.; Li, Sanming; Negre, Helene; Shaw, Kit L.; Samarakoon, Lassana; Ayala, Allison R.; Kheirkhah, Ahmad; Katikireddy, Kishore; Gauthier, Alex; Ong Tone, Stephan; Kaufman, Aaron R.; Ellender, Stacey; Hernandez Rodriguez, Diego E. (2023-08-18). "Cultivated autologous limbal epithelial cell (CALEC) transplantation: Development of manufacturing process and clinical evaluation of feasibility and safety". Science Advances. 9 (33): eadg6470. doi:10.1126/sciadv.adg6470. ISSN   2375-2548. PMC   10438443 . PMID   37595035.
  7. ↑ Pellegrini, Graziella; Lambiase, Alessandro; Macaluso, Claudio; Pocobelli, Augusto; Deng, Sophie; Cavallini, Gian Maria; Esteki, Roza; Rama, Paolo (2016-04-19). "From discovery to approval of an advanced therapy medicinal product-containing stem cells, in the EU". Regenerative Medicine. 11 (4): 407–420. doi:10.2217/rme-2015-0051. ISSN   1746-0751. PMC   5561870 . PMID   27091398.
  8. ↑ "Europe approves Holoclar, the first stem cell-based medicinal product". EuroStemCell. 24 November 2016. Retrieved 25 August 2020.
  9. ↑ Ruan Y, Jiang S, Musayeva A, Pfeiffer N, Gericke A (September 2021). "Corneal Epithelial Stem Cells-Physiology, Pathophysiology and Therapeutic Options". Cells. 10 (9): 2302. doi: 10.3390/cells10092302 . PMC   8465583 . PMID   34571952.


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