Genetics of Stem Cells: Part A: 111 (Progress in Molecular Biology and Translational Science)

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Agri and Aquaculture Journals Dr. Journal of Molecular and Genetic Medicine. Electronic Journal of Biology. European Journal of Experimental Biology. Journal of Biomedical Sciences. Advancements in Genetic Engineering. Current Synthetic and Systems Biology. Journal of Next Generation Sequencing and Applications.

Journal of Regenerative Medicine. Cellular and Molecular Biology. Journal of Aging Science. Molecular Enzymology and Drug Targets. International Journal of Biomedical Data Mining. The three cellular layers must function together to maintain transparency and, therefore, vision.

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Currently, the most common form of treatment for damage to any of these layers involves transplanting tissue, a procedure limited by the availability of donor tissue and complicated by the risk of immune-mediated rejection. In an attempt improve treatment options for corneal disorders and damage, research is being directed at bioprosthetics and stem cell biology. Adult stem cells are characterized as slow-dividing cells with the ability to self-renew and give rise to differentiated progeny via mitosis. These adult stem cells are often found in specialized locations, or niches, in tissues throughout the body.

When tissue is damaged e. Due to the devastating effects of corneal wounds and infections, and the limited options currently available to treat them, the identification and isolation of stem cells in the cornea has received much attention. The identification of stem cells in the cornea has the potential for autologous, cell-based approach to the treatment of damaged corneal tissue.

The corneal epithelium is a nonkeratinized, stratified squamous epithelium approximately 5—6 cells thick that covers the front of the cornea. The outermost layer of cells is continuously sloughed off and replaced by the proliferation of wing and basal cells. As such, there must be a self-renewing source of corneal epithelial cells from which replacement cells can be drawn. It was suggested in that renewal of the corneal epithelium was maintained by the migration of epithelial cells in the basal layer of the epithelium.

A steady movement of epithelial cells in both human and mouse corneas from the limbal region toward the central cornea has been documented in a number of studies. Cells here are protected from UV rays both by the upper and lower eyelids and by the presence of melanocytes. To support the hypothesis that this niche harbors LESC, the niche cells have been analyzed in a multitude of in vitro and in vivo studies for stem cell characteristics.

The cornea is composed of three cellular layers: The vascular limbal region is located at the peripheral cornea and is bordered by the conjunctiva—this region is the proposed niche for stem cell populations in each layer.

Basal limbal cells also show differences in protein expression when compared to basal cells of the central epithelium. Additionally, basal limbal cells grow clonally as holoclones, whereas clones from epithelial cells isolated from the central cornea are rare and do not proliferate extensively. Orange, limbal epithelial stem cell LESC markers, expression generally compared to central epithelial cells; green, human corneal stromal stem cell markers; and purple, proposed markers and characteristics corneal endothelial progenitor cells.

In self-renewing epithelia, stem cells are essential for normal tissue maintenance; a second important characteristic is the ability of stem cells to regenerate tissue that has been damaged or lost. When the limbal cells were in place, however, wounds healed without vascularization and cells from the limbal region migrated into the central cornea to reform the epithelium.

The idea is supported by a study of destrin knockout mice, which show limited or no migration of epithelial cells.

A more recent study reconfirmed limbal stem cell-driven migration using lineage-tracing expression of fluorescent proteins driven by a K14 promoter. This gene is limited to stem and progenitor cells in the limbus, thus all fluorescent cells after induction will represent descendants of those progenitors. The current state of our understanding leaves open the question as to whether stem cells in the central cornea can and do contribute to epithelial homeostasis on a long-term basis and whether the centripetal movement of progenitor-derived cells is a requirement for maintenance of healthy and stable corneal epithelium.

In spite of these unresolved questions, there remains no doubt in the clinical importance of LESC.

This is manifest in the condition known as limbal stem cell deficiency LSCD. In this relatively rare condition, loss of limbal cells, typically as a result of genetic disease or chemical burns, results in conjunctivalization of the cornea, inflammation, neovascularization, pain, and corneal opacity. The corneal stroma is a tough, collagenous tissue derived from the embryonic neural crest.

Corneal collagen is arranged in sheets of fibrils called lamellae that are arranged orthogonally throughout the stroma. The precise spacing and arrangement of the fibrils and lamellae are essential to stromal transparency. Loss of visual acuity due to stromal opacity affects more than 23 million individuals worldwide and 4. Although comprehensive data are limited, stromal opacity is the source of most corneal blindness, greatly exceeding the numbers of individuals affected by LSCD.

Translational research

Upon wounding, the normally quiescent keratocytes adjacent to the affected area become mitotically active fibroblasts, migrate to the wounded area, and subsequently differentiate to myofibroblasts. These cells are responsible for the production of fibrotic extracellular matrix components that contribute to light scatter by stromal scarring. Over the past 15—20 years, a large number of reports have identified and characterized stem cells from various mesenchymal tissues.

These stem cell populations are identified by self-renewal ability, differentiation into multiple cell types, and their ability to grow clonally.

François Jacob set to work on eukaryotes

In an initial study, a small population of cells exhibiting clonal growth from bovine corneal stroma was found to express genes associated with mesenchymal stem cells. To achieve this, the well-documented adult stem cell marker ABCG2 was used. When cultured in serum-free medium supplemented with ascorbic acid and insulin, the human corneal SP cells upregulated keratocyte-specific markers, including the corneal stroma-specific proteoglycan keratocan. Several studies have shown limbal mesenchymal cells with stem cell properties to be closely associated in vivo with limbal epithelial cells.

Both LESC and the limbal mesenchymal stem cell express N-cadherin, suggesting this cell—cell junction protein provides interaction between these cell populations. Limited access to donated cadaveric tissue reduces the number of individuals with corneal blindness who benefit from corneal grafts. This shortage has led to widespread interest in development of alternative to penetrating keratoplasty.

Alternatives include fully synthetic corneal prostheses as well as acellular polymeric replacements for scarred regions of the stroma. When cultured on parallel, aligned nanofibers, CSSC secrete layers of organized collagen nearly identical in fibril diameter and spacing to that of the corneal stroma.

Stem Cells in the Cornea

This tissue construct also contains the unique corneal proteoglycans which are known to be required for corneal transparency. In addition to their ability to generate corneal tissues in vitro, CSSC like many mesenchymal stem cells exhibit a potential to mediate immune response. In the lumican knockout mouse model of corneal haze, CSSC were shown to restore transparency after being injected directly into the stroma. This points to both the immune-privilege and immunomodulatory characteristics of CSSC. The corneal endothelium is a simple, squamous epithelial sheet on the posterior side of the cornea.

The corneal endothelium serves as a leaky barrier between the corneal stroma anterior and anterior chamber posterior. Water passively moves from the ac into the stroma, while protein and other nutrients such as glucose are actively transported by corneal endothelial cells. To pump water from the stroma into the anterior chamber, bicarbonate is actively pumped out of the endothelial cells along with other ions and water follows.

The corneal endothelium is notable for its lack of mitotic activity after birth and inability to regenerate after damage.

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If enough cells are lost, the pump function is compromised and the cornea becomes edematous and cloudy. Currently, the only treatment option to restore vision requires transplantation of donor tissue. While this is largely successful, it does not avoid the problems often encountered with transplant operations, namely immune rejection and the declining availability of donor tissue.

Many laboratories are searching for corneal endothelial stem cells for their potential in regenerative medicine. It has been shown that cells with clonogenic potential exist in the normal adult corneal endothelium by sphere formation. Recently, a progenitor cell population in human corneal endothelium was identified using the established stem cell marker LGR5. Corneal wounding and disease often have the devastating consequence of visual impairment or blindness.

While there are treatment options available when this occurs, tissue rejection and graft availability limit the ability to treat the numerous patients in need. Stem cells isolated from the cornea may offer an alternative to the current treatment options in that they can be used in an autologous fashion. This is already being used for trauma and corneal epithelial disorders such as LSCD and is widely successful.

The corneal endothelium appears to have a progenitor population that may provide a source of cells for regeneration, though more studies need to be completed to demonstrate this. Taken together, the progress made thus far in the isolation and use of corneal stem cells for use in the clinic is promising. Though much work still needs to be done, an alternative, cell-based treatment for corneal pathologies is achievable. National Center for Biotechnology Information , U. Prog Mol Biol Transl Sci. Author manuscript; available in PMC Feb Hertsenberg and James L. Author information Copyright and License information Disclaimer.

See other articles in PMC that cite the published article. Abstract The cornea is the tough, transparent tissue through which light first enters the eye and functions as a barrier to debris and infection as well as two-thirds of the refractive power of the eye.

Open in a separate window. The molecular basis of corneal transparency. Thoft RA, Friend J. The X, Y, Z hypothesis of corneal epithelial maintenance. Invest Ophthalmol Vis Sci. Davanger M, Evensen A. Role of the pericorneal papillary structure in renewal of corneal epithelium. Nagasaki T, Zhao J. Centripetal movement of corneal epithelial cells in the normal adult mouse. Clonal analysis of patterns of growth, stem cell activity, and cell movement during the development and maintenance of the murine corneal epithelium.

Measurement of centripetal migration of normal corneal epithelial cells in the mouse. Identification and characterization of limbal stem cells. Existence of slow-cycling limbal epithelial basal cells that can be preferentially stimulated to proliferate: Differentiation-related expression of a major 64K corneal keratin in vivo and in culture suggests limbal location of corneal epithelial stem cells. Suprabasal expression of a kilodalton keratin no.

Corneal epithelial stem cells at the limbus: Characterization of putative stem cell phenotype in human limbal epithelia. ABCG2 transporter identifies a population of clonogenic human limbal epithelial cells. ABCB5 is a limbal stem cell gene required for corneal development and repair. Identification of Notch-1 expression in the limbal basal epithelium. Adult intestinal stem cells: Nat Rev Mol Cell Biol.

Stem cells find their niche. Tadeu AM, Horsley V. Epithelial stem cells in adult skin. Curr Top Dev Biol. Corneal epithelial wound healing in partial limbal deficiency. Corneal epithelial wound healing in the absence of limbal epithelium.

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