Stem cell biology and regenerative medicine in ophthalmology pdf

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stem cell biology and regenerative medicine in ophthalmology pdf

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Alarfaj, Murugan A. Sustenance of visual function is the ultimate focus of ophthalmologists.

Ocular stem cells: a status update!

Metrics details. Stem cells are unspecialized cells that have been a major focus of the field of regenerative medicine, opening new frontiers and regarded as the future of medicine. The ophthalmology branch of the medical sciences was the first to directly benefit from stem cells for regenerative treatment.

The success stories of regenerative medicine in ophthalmology can be attributed to its accessibility, ease of follow-up and the eye being an immune-privileged organ. Cell-based therapies using stem cells from the ciliary body, iris and sclera are still in animal experimental stages but show potential for replacing degenerated photoreceptors.

Limbal, corneal and conjunctival stem cells are still limited for use only for surface reconstruction, although they might have potential beyond this. Iris pigment epithelial, ciliary body epithelial and choroidal epithelial stem cells in laboratory studies have shown some promise for retinal or neural tissue replacement.

Trabecular meshwork, orbital and sclera stem cells have properties identical to cells of mesenchymal origin but their potential has yet to be experimentally determined and validated. Retinal and retinal pigment epithelium stem cells remain the most sought out stem cells for curing retinal degenerative disorders, although treatments using them have resulted in variable outcomes.

The functional aspects of the therapeutic application of lenticular stem cells are not known and need further attention. Recently, embryonic stem cell-derived retinal pigment epithelium has been used for treating patients with Stargardts disease and age-related macular degeneration.

Overall, the different stem cells residing in different components of the eye have shown some success in clinical and animal studies in the field of regenerative medicine. Pluripotency, the capacity to differentiate into multiple lineages, and proliferation are two characteristic attributes of stem cells.

These cells are capable of replacing damaged or diseased cells under certain circumstances. The ease of access for the therapeutic procedure as well as follow-up together with its immune-privileged status makes the eye an ideal organ for studying regenerative medicine. Such therapy involves various procedures where stem cells are injected into both the cellular and extracellular matrix microenvironments [ 1 ].

Corneal epithelial cell transplantation has been the most widely used stem cell-based therapy following bone marrow transplantation. Stem cell-based treatment in ophthalmology follows either a cell replacement therapy strategy or a strategy involving trophic factor-based guidance cues. Throughout treatment, outcomes depend on our in-depth knowledge of the disease, the source of stem cells, the mode of treatment and the plausible mechanism driving the therapeutic outcome [ 2 ].

In this review we discuss region-specific stem cell populations and their respective functions in cell-based therapy. We also address possible hurdles to therapy and means to overcome these in our pursuit of regenerative medicine applications in the field of ophthalmology.

The cornea is at the outermost surface of the eye and safeguards transparency, which is crucial for vision. The corneal stem cell population is located in the periphery of the cornea, in the limbus; these cells are termed limbal epithelial stem cells LESCs [ 3 — 6 ].

Stem cells in the corneal epithelium are located in the basal layer of the limbal region at the corneal periphery, called the palisades of Vogt [ 3 ]. These are visualized in small clusters and are closely associated with the stromal matrix and the basement membrane, thereby assisting in cell-cell, cell-extracellular matrix and paracrine signaling communication.

The corneal epithelial basal layer is composed mostly of transient amplifying cells at various stages of maturity. LESCs are identified by their elevated expression of an isoform of the transcription factor p63 along with a high nuclear to cytoplasmic ratio [ 7 , 8 ]. ABCG2 ATP binding cassette sub family G member 2 positivity has been detected in LESCs as well as several other cells residing in the suprabasal limbus and these markers have the potential to identify the LESC population based on their staining ability in clusters of progenitor-like cells in the limbus [ 9 , 10 ].

Corneal stem cells also express enolase, cytokeratin CK 19, and vimentin but do not express CK3, CK12, or Connexin 43, which are present in corneal epithelial cells [ 11 , 12 ]. Stromal multipotent clonal cells have been identified and expanded to neurospheres in cultures [ 13 , 14 ]. Corneal stromal stem cells are located in the anterior stroma sub-adjacent to the basal side of the palisades of Vogt [ 15 ].

Stem cells in the stroma were identified as a side population using the DNA-binding dye Hoechst LESC deficiency is pathological, either partially or completely, and is caused by either mechanical injury or chemical and thermal burns or acquired by diseases such as aniridia and Stevens Johnson syndrome.

Treatment of such conditions involves LESC transplantation therapy. Alternative, experimental sources for LESCs for cell-based therapy include buccal mucosal epithelial cells, hair follicle stem cells, and human embryonic stem cells ESCs [ 17 , 18 ]. Among non-limbal cell types, cultured oral mucosal cells and conjunctival epithelial cells have been transplanted to treat limbal stem cell deficiency in humans [ 19 , 20 ]. Recent research shows that the peripheral cornea contains a higher density of keratocyte precursors with high proliferative capacity.

A three-dimensional construction using corneal keratocyte precursors and gelatin hydrogels provided cues for attracting keratocytes and extracellular matrix in scarred stroma [ 21 ]. Du and colleagues [ 22 ] demonstrated restoration of corneal transparency, stromal thickness and collagen fibril defects after injecting corneal stromal stem cells in mice. If successful, such therapy would eliminate the shortage of donor corneas needed for transplantations.

Although stem cell transplantation is performed worldwide, variability in clinical outcomes implies that standardized protocols need to be established. Further validation and quality assessment studies on these cell types could provide therapeutic solutions for ocular surface reconstruction, and may also provide insights into the feasibility of their use for reconstruction of tissues beyond the ocular surface.

The conjunctiva, apart from being a barrier to pathogenic entry, is a highly vascularized connective tissue that provides channels for proper flow of nutrients and fluids. Conjunctival cells undergo renewal similar to the corneal epithelium, but the source of the stem cells for this remains elusive [ 23 ]. Conjunctival stem cells can differentiate into either mucin-producing goblet cells or an epithelial cell.

The dividing basal cells migrate from the bulbar conjunctiva to the corneal surface and differentiate. The stem cells residing in the fornical niche can differentiate into epithelial cells as well as goblet cells, as shown in clonal culture assays. This provides strong evidence that the stem cell population for conjunctiva renewal is in the fornix region [ 24 , 25 ].

Ocular processes that affect the cornea also affect the conjunctiva. Conjunctival scarring, cicatricial pemphigoid, thickening, dry eye or mucin deficiency are some of the conditions affecting the conjunctiva. Conjunctival autografts, oral mucous membrane grafts, nasal turbinate mucosa grafts and amniotic membrane are often used to treat conjunctival stem cell deficiency and scarring [ 18 ].

Conjunctival cells cultured on amniotic membrane have been used for cell transplantation in patients with limbal stem cell deficiency. Recent patient follow-up reports have shown that transplantation of autologous conjunctival epithelial cells improved the clinical parameters of total limbal stem cell deficiency with respect to vision acuity, impression cytology and in vivo confocal analysis [ 18 , 26 ].

Ultrathin polymembrane epsilon-caprolactone substrate has also been shown to support conjunctival epithelial cell proliferation [ 27 ]. The iris divides the space between the cornea and lens into anterior and posterior halves. The stroma and the vasculature of the iris are developed from the anterior region of the optic cup [ 28 ].

Studies from mouse iris have revealed that these cells can also be differentiated to neuronal as well as glial lineages and express markers such as Chx10, Rho, Otx2 and Olig2 [ 29 ]. Though the iris pigment epithelial cells have potential to be used in cell-based therapy, not much work on validation and quality assessment has been done.

These cells can be transdifferentiated into retinal neuronal cells expressing retinal-specific markers [ 30 ]. Further studies are needed before iris pigment epithelial cells can be used clinically. The ciliary body produces the aqueous humor and is involved in regulating the aqueous flow, blood flow, intra-ocular pressure and maintenance of the immune-privileged status of the anterior chamber [ 31 ].

Ciliary body stem cells are derived from ciliary epithelium and undergo lineage-specific differentiation to retinal tissues. Ciliary epithelial cells can be cultured in vitro , forming neurospheres expressing transcription factors Sox 2 and Pax 6 and retinal markers Lhx2, Dach1, Six 3 [ 32 ].

During homeostasis ciliary epithelium maintains a balance between epithelial and neuronal cell types, whereas during disease ciliary epithelium cells can act as donor cells for retinal repair. Studies so far have revealed that ciliary epithelium cells differentiate well into the retinal lineage cells that express retinal markers but do not integrate with existing retinal architecture.

Recently, Gualdoni and colleagues [ 33 ] and Yanagi and colleagues [ 34 ] reported that ciliary epithelium cells lack the potential to differentiate into photoreceptors, suggesting that the cells need to be reprogrammed to be useful as a source of new photoreceptors.

Further studies are warranted so we might realize the potential of these cells in clinics. Cicero and colleagues [ 35 ] reported that, although ciliary epithelium stem cells expressed retinal markers, each cell contained pigments and had membrane interdigitations and epithelial junctions.

Ballios and colleagues [ 36 ] showed that clonally derived retinal stem cell progeny from ciliary epithelium can differentiate into mature rhodopsin-positive cells using a combination of exogenous culture additives fibroblast growth factor, heparin, retionic acid, taurine.

Inoue and colleagues [ 37 ] demonstrated that modulation of the retinal transcriptional factors OTX2, CRX and CHX10 increases the potential of retinal stem cell progeny derived from the cilliary margin of adult human eye. The trabecular meshwork TM is a tissue between the cornea and iris in the anterior region that is responsible for drainage of aqueous fluid.

The balance between aqueous secretion and outflow determines intraocular pressure, which is a risk factor for the development of glaucoma. TM cells help to remove debris in the circulating aqueous humor [ 38 ]. TM cells express vimentin, non-muscle actin, aquaporin-1, acetylated and acetoacetylated alpha-2 adrenergic receptor, matrix GLA protein and chitinaselike-1 [ 39 — 41 ].

Recently, the isolation and characterization of TM cells have been widely studied. These studies suggest that TM cells have stem cell-like properties, expressing mesenchymal cell-associated markers such as CD73, CD90, and CD, and the ability to differentiate into adipocytes, osteocytes, and chondrocytes [ 38 , 42 ]. Lowering the intra-ocular pressure is an aim of treatments for glaucoma. The idea for this came primarily from the observation that TM cell division increased after argon laser trabeculoplasty [ 43 ].

Topical and oral medications, argon laser trabeculoplasty and some surgical approaches for example, implant blebs are current first-line treatments.

A very recent study reported that stem cells isolated from human TM and expanded in vitro showed evidence of the ability to home to mouse TM and differentiate into TM cells in vivo [ 44 ].

These TM cells were multipotent and had phagocytic properties [ 38 , 45 ]. Some groups are working on transplanting TM cells or TM progenitor cells combined with argon laser trabeculoplasty as a novel cell-based therapy for glaucoma [ 38 , 43 — 45 ]. The lens is composed of the lens capsule, epithelium and fibers and, like the cornea, is transparent. Lens stem cells are hypothesized to reside in the lens capsule, although they have not yet been identified. It is plausible that they come from the ciliary body, which is anatomically close to the lens [ 46 ].

Lens capsule regeneration has been shown to occur in lower vertebrates from cells residing in the ciliary body. The lens stem cells might thus reside in the lens capsule [ 47 , 48 ]. Lens stem cells have not yet been identified. Lens stem cells are presumed to have a role in maintaining the lens transparency and might be important in cataractogenesis or other lens abnormalities. The retina represents the connecting link between visual input and image processing in the brain.

Retinal diseases mostly result in irreversible damage to the visual pathway. Several studies in animal models have achieved some amount of success using transplantation of photoreceptors, endothelial cells and retinal pigment epithelium RPE [ 17 , 48 ]. Most therapeutic application studies have been conducted on murine retinal disease models.

Diseases in the inner retina include retinopathy ischemic conditions and optic neuropathy, which cause damage in the retinal ganglion cells and amacrine cells [ 49 ]. Transplantation of bone marrow-derived mesenchymal stem cells into the vitreous of a retinal ischemia mouse model demonstrated ganglion cell neuroprotection [ 50 ]. Cell transplantation in a retinal degeneration model has shown promising visual outcomes but the extent of the curative effect remained unclear [ 51 — 55 ].

The injected stem cells integrated into the retinal and subretinal microenvironment modulated differentiation of different cell types [ 51 , 52 ]. These transplanted cells integrate in a temporal-dependent manner that occurs only during rod genesis. Clinical trials using fetal retinal cells have been conducted in patients with retinitis pigmentosa and age-related macular degeneration.

Regenerative Medicine In Ophthalmology

The chapter examines the use of stem cells in ophthalmological pathologies affecting both the anterior and posterior segments. The authors review the clinical trials that have most contributed to defining the role and potential of stem cell regenerative therapy in corneal and retinal pathology. The results described in the scientific literature are analyzed and commented, without neglecting the possible side effects related to the use of this therapy. Within the anterior segment, the greatest efforts were made to study the possible uses of limbal epithelial stem cells LESCs. They were the first stem cells to be discovered at the level of the anterior segment and currently the only ones involved in clinical practice with satisfactory results.

Metrics details. Stem cells are unspecialized cells that have been a major focus of the field of regenerative medicine, opening new frontiers and regarded as the future of medicine. The ophthalmology branch of the medical sciences was the first to directly benefit from stem cells for regenerative treatment. The success stories of regenerative medicine in ophthalmology can be attributed to its accessibility, ease of follow-up and the eye being an immune-privileged organ. Cell-based therapies using stem cells from the ciliary body, iris and sclera are still in animal experimental stages but show potential for replacing degenerated photoreceptors. Limbal, corneal and conjunctival stem cells are still limited for use only for surface reconstruction, although they might have potential beyond this.

Ocular stem cells: a status update!

The promising role of cellular therapies in the preservation and restoration of visual function has prompted intensive efforts to characterize embryonic, adult, and induced pluripotent stem cells for regenerative purposes. Three main approaches to the use of stem cells have been described: sustained drug delivery, immunomodulation, and differentiation into various ocular structures. Studies of the differentiation capacity of all three types of stem cells into epithelial, neural, glial and vascular phenotypes have reached proof-of-concept in culture, but the correction of vision is still in the early developmental stages, and the requirements for effective in vivo implementation are still unclear.

It seems that you're in Germany. We have a dedicated site for Germany. Patient specific and disease specific stem cell lines have already introduced groundbreaking advances into the research and practice of ophthalmology. This volume provides a comprehensive and engaging overview of the latest innovations in the field.

Biomaterials and Regenerative Medicine in Ophthalmology

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Stem Cell Therapy for Treatment of Ocular Disorders

Purchase this article with an account. Jump To Iqbal Ahmad. Author Affiliations.

Boyer, MD, who is in practice in Los Angeles. Several companies are working on gene therapies for retinal diseases, trying to follow in the footsteps of Spark Therapeutics and its therapy Luxturna. Luxturna is the first FDA-approved gene therapy for a genetic disease. It is a one-time prescription gene therapy product that can be used for patients with an inherited retinal disease caused by mutations in both copies of the RPE65 gene and who have enough remaining cells in the retina. It was approved by the FDA in for the treatment of patients with confirmed biallelic RPE65 mutation-associated retinal dystrophy that leads to vision loss. They reported that all six patients in cohort 1 were rescue-injection-free after a year.

Biomaterials and Regenerative Medicine in Ophthalmology, Second Edition, focuses on an aging population and the increasing instances of eye diseases. Consequently, biomaterials and regenerative medicine are becoming increasingly important to the advances of ophthalmology and optometry. This book provides readers with an updated and expanded look at the present status and future direction of biomaterials and regenerative medicine in this important field. Ophthalmic biomaterials, devices and regenerative medicine researchers in both academia and industry. Chemists and clinicians working in the ophthalmic field. Professor Chirila has over thirty years experience in polymer science and biomaterials and is highly respected for his ongoing contribution to the field of ophthalmology.

Stem Cells International

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