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Journal ArticleDOI: 10.1016/J.PRETEYERES.2021.100956

Human limbal epithelial stem cell regulation, bioengineering and function.

04 Mar 2021-Progress in Retinal and Eye Research (Pergamon)-Vol. 85, pp 100956-100956
Abstract: The corneal epithelium is continuously renewed by limbal stem/progenitor cells (LSCs), a cell population harbored in a highly regulated niche located at the limbus. Dysfunction and/or loss of LSCs and their niche cause limbal stem cell deficiency (LSCD), a disease that is marked by invasion of conjunctival epithelium into the cornea and results in failure of epithelial wound healing. Corneal opacity, pain, loss of vision, and blindness are the consequences of LSCD. Successful treatment of LSCD depends on accurate diagnosis and staging of the disease and requires restoration of functional LSCs and their niche. This review highlights the major advances in the identification of potential LSC biomarkers and components of the LSC niche, understanding of LSC regulation, methods and regulatory standards in bioengineering of LSCs, and diagnosis and staging of LSCD. Overall, this review presents key points for researchers and clinicians alike to consider in deepening the understanding of LSC biology and improving LSCD therapies.

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Topics: Limbal stem cell (62%), Population (51%)
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10 results found



Open accessJournal ArticleDOI: 10.1016/J.JTOS.2021.08.006
Naresh Polisetti1, Andreas Gießl2, Matthias Zenkel2, Lukas Heger2  +6 moreInstitutions (2)
20 Aug 2021-Ocular Surface
Abstract: Purpose Limbal melanocytes (LMel) represent essential components of the corneal epithelial stem cell niche and are known to protect limbal epithelial stem/progenitor cells (LEPCs) from UV damage by transfer of melanosomes. Here, we explored additional functional roles for LMel in niche homeostasis, immune regulation and angiostasis. Methods Human corneoscleral tissues were morphologically analyzed in normal, inflammatory and wound healing conditions. The effects of LMel on LEPCs were analyzed in direct and indirect co-culture models using electron microscopy, immunocytochemistry, qRT-PCR, Western blotting and functional assays; limbal mesenchymal stromal cells and murine embryonic 3T3 fibroblasts served as controls. The immunophenotype of LMel was assessed by flow cytometry before and after interferon-γ stimulation, and their immunomodulatory properties were analyzed by mixed lymphocytes reaction, monocyte adhesion assays and cytometric bead arrays. Their angiostatic effects on human umbilical cord endothelial cells (HUVECs) were evaluated by proliferation, migration, and tube formation assays. Results LMel and LEPCs formed structural units in the human limbal stem cell niche in situ, which could be functionally replicated, including melanosome transfer, by co-cultivation in vitro. LMel supported LEPCs during clonal expansion and during epithelial wound healing by stimulating proliferation and migration, and suppressed their differentiation through direct contact and paracrine effects. Under inflammatory conditions, LMel were increased in numbers and upregulated expression of ICAM-1 and MHC II molecules (HLA-DR), but lacked expression of HLA-G, -DP, -DQ and costimulatory molecules CD80 and CD86. They were also found to be potent suppressors of alloreactive T- cell proliferation and cytokine secretion, which largely depended on direct cell-cell interaction. Moreover, the LMel secretome exerted angiostatic activity by inhibiting vascular endothelial cell proliferation and capillary network formation. Conclusion These findings suggest that LMel are not only professional melanin-producing cells, but exert various non-canonical functions in limbal niche homeostasis by regulating LEPC maintenance, immune responses, and angiostasis. Their potent regulatory, immunomodulatory and anti-angiogenic properties may have important implications for future regenerative cell therapies.

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Topics: Limbal stem cell (61%), Stem cell (57%), Vascular endothelial cell proliferation (56%) ... show more

2 Citations


Open accessJournal ArticleDOI: 10.1039/D1CB00063B
05 Aug 2021-
Abstract: Wnt proteins are secreted morphogens that play critical roles in embryonic development, stem cell proliferation, self-renewal, tissue regeneration and remodeling in adults. While aberrant Wnt signaling contributes to diseases such as cancer, activation of Wnt/β-catenin signaling is a target of interest in stem cell therapy and regenerative medicine. Recent high throughput screenings from chemical and biological libraries, combined with improved gene expression reporter assays of Wnt/β-catenin activation together with rational drug design, led to the development of a myriad of Wnt activators, with different mechanisms of actions. Among them, Wnt mimics, antibodies targeting Wnt inhibitors, glycogen-synthase-3β inhibitors, and indirubins and other natural product derivatives are emerging modalities to treat bone, neurodegenerative, eye, and metabolic disorders, as well as prevent ageing. Nevertheless, the creation of Wnt-based therapies has been hampered by challenges in developing potent and selective Wnt activators without off-target effects, such as oncogenesis. On the other hand, to avoid these risks, their use to promote ex vivo expansion during tissue engineering is a promising application.

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Topics: Wnt signaling pathway (65%), Stem cell (52%), Stem-cell therapy (51%)

2 Citations


Open accessPosted ContentDOI: 10.1038/S41598-021-00273-Y
Clemence Bonnet1, Clemence Bonnet2, Denise Oh1, Hua Mei3  +6 moreInstitutions (3)
22 Oct 2021-Scientific Reports
Abstract: The corneal epithelium is consistently regenerated by limbal stem/progenitor cells (LSCs), a very small population of adult stem cells residing in the limbus. Several Wnt ligands, including Wnt6, are preferentially expressed in the limbus. To investigate the role of Wnt6 in regulating proliferation and maintenance of human LSCs in an in vitro LSC expansion setting, we generated NIH-3T3 feeder cells to overexpress different levels of Wnt6. Characterization of LSCs cultured on Wnt6 expressing 3T3 cells showed that high level of Wnt6 increased proliferation of LSCs. Medium and high levels of Wnt6 also increased the percentage of small cells (diameter ≤ 12 µm), a feature of the stem cell population. Additionally, the percentage of cells expressing the differentiation marker K12 was significantly reduced in the presence of medium and high Wnt6 levels. Although Wnt6 is mostly known as a canonical Wnt ligand, our data showed that canonical and non-canonical Wnt signaling pathways were activated in the Wnt6-supplemented LSC cultures, a finding suggesting that interrelationships between both pathways are required for LSC regulation.

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Topics: Adult stem cell (60%), Progenitor cell (58%), Wnt signaling pathway (56%) ... show more

1 Citations


Journal ArticleDOI: 10.1016/J.PRETEYERES.2021.101011
Abstract: The cornea is the outmost layer of the eye, unique in its transparency and strength. The cornea not only transmits the light essential for vision, also refracts light, giving focus to images. Each of the three layers of the cornea has properties essential for the function of vision. Although the epithelium can often recover from injury quickly by cell division, loss of limbal stem cells can cause severe corneal surface abnormalities leading to corneal blindness. Disruption of the stromal extracellular matrix and loss of cells determining this structure, the keratocytes, leads to corneal opacity. Corneal endothelium is the inner part of the cornea without self-renewal capacity. It is very important to maintain corneal dehydration and transparency. Permanent damage to the corneal stroma or endothelium can be effectively treated by corneal transplantation; however, there are drawbacks to this procedure, including a shortage of donors, the need for continuing treatment to prevent rejection, and limits to the survival of the graft, averaging 10-20 years. There exists a need for new strategies to promote regeneration of the stromal structure and restore vision. This review highlights critical contributions in regenerative medicine with the aim of corneal reconstruction after injury or disease. These approaches include corneal stromal stem cells, corneal limbal stem cells, embryonic stem cells, and other adult stem cells, as well as induced pluripotent stem cells. Stem cell-derived trophic factors in the forms of secretomes or exosomes for corneal regeneration are also discussed. Corneal sensory nerve regeneration promoting corneal transparency is discussed. This article provides description of the up-to-date options for corneal regeneration and presents exciting possible avenues for future studies toward clinical applications for corneal regeneration.

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Topics: Corneal endothelium (69%), Corneal transplantation (62%), Cornea (60%) ... show more

References
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236 results found


Open accessJournal ArticleDOI: 10.1016/0092-8674(93)90529-Y
03 Dec 1993-Cell
Abstract: Summary h-4 is essential for the normal temporal control of diverse postembryonic developmental events in C. elegans. /in-4 acts by negatively regulating the level of LIN-14 protein, creating a temporal decrease in LIN-14 protein starting in the first larval stage (Ll). We have cloned the C. elegans lin-4 locus by chromosomal walking and transformation rescue. We used the C. elegans clone to isolate the gene from three other Caenorhabditis species; all four Caenorhabditis clones functionally rescue the h-4 null allele of C. elegans. Comparison of the /in-4 genomic sequence from these four species and site-directed mutagenesis of potential open reading frames indicated that /in-d does not encode a protein. Two small /in-4 transcripts of approximately 22 and 61 nt were identified in C. elegans and found to contain sequences complementary to a repeated sequence element in the 3’untranslated region (UTR) of lin-74 mRNA, suggesting that /in-4 regulates h-74 translation via an antisense RNA-RNA interaction.

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Topics: Caenorhabditis elegans (58%), Caenorhabditis (58%), Lin-4 microRNA precursor (57%) ... show more

10,957 Citations


Journal ArticleDOI: 10.1038/NG1536
Azra Krek1, Dominic Grün1, Matthew N. Poy2, Rachel Wolf1  +7 moreInstitutions (2)
03 Apr 2005-Nature Genetics
Abstract: MicroRNAs are small noncoding RNAs that recognize and bind to partially complementary sites in the 3' untranslated regions of target genes in animals and, by unknown mechanisms, regulate protein production of the target transcript. Different combinations of microRNAs are expressed in different cell types and may coordinately regulate cell-specific target genes. Here, we present PicTar, a computational method for identifying common targets of microRNAs. Statistical tests using genome-wide alignments of eight vertebrate genomes, PicTar's ability to specifically recover published microRNA targets, and experimental validation of seven predicted targets suggest that PicTar has an excellent success rate in predicting targets for single microRNAs and for combinations of microRNAs. We find that vertebrate microRNAs target, on average, roughly 200 transcripts each. Furthermore, our results suggest widespread coordinate control executed by microRNAs. In particular, we experimentally validate common regulation of Mtpn by miR-375, miR-124 and let-7b and thus provide evidence for coordinate microRNA control in mammals.

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Topics: MicroRNA Gene (54%), Lin-4 microRNA precursor (53%)

4,483 Citations


Open accessJournal ArticleDOI: 10.1016/J.CELL.2009.03.045
Raphael Kopan1, Maria Xenia G Ilagan1Institutions (1)
17 Apr 2009-Cell
Abstract: Notch signaling regulates many aspects of metazoan development and tissue renewal. Accordingly, the misregulation or loss of Notch signaling underlies a wide range of human disorders, from developmental syndromes to adult-onset diseases and cancer. Notch signaling is remarkably robust in most tissues even though each Notch molecule is irreversibly activated by proteolysis and signals only once without amplification by secondary messenger cascades. In this Review, we highlight recent studies in Notch signaling that reveal new molecular details about the regulation of ligand-mediated receptor activation, receptor proteolysis, and target selection.

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Topics: Notch signaling pathway (71%), Notch 1 (71%), Notch proteins (70%) ... show more

2,743 Citations


Open accessJournal ArticleDOI: 10.1126/SCIENCE.1094291
W. James Nelson1, Roel Nusse1Institutions (1)
05 Mar 2004-Science
Abstract: The specification and proper arrangements of new cell types during tissue differentiation require the coordinated regulation of gene expression and precise interactions between neighboring cells. Of the many growth factors involved in these events, Wnts are particularly interesting regulators, because a key component of their signaling pathway, β-catenin, also functions as a component of the cadherin complex, which controls cell-cell adhesion and influences cell migration. Here, we assemble evidence of possible interrelations between Wnt and other growth factor signaling, β-catenin functions, and cadherin-mediated adhesion.

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Topics: Catenin (60%), Cadherin (60%), Wnt signaling pathway (59%) ... show more

2,315 Citations


Open accessJournal ArticleDOI: 10.1016/S1097-2765(00)80275-0
Annie Yang1, Mourad Kaghad, Yunmei Wang1, Emily Gillett1  +8 moreInstitutions (3)
01 Sep 1998-Molecular Cell
Abstract: We describe the cloning of p63, a gene at chromosome 3q27-29 that bears strong homology to the tumor suppressor p53 and to the related gene, p73. p63 was detected in a variety of human and mouse tissues, including proliferating basal cells of epithelial layers in the epidermis, cervix, urothelium, and prostate. Unlike p53, the p63 gene encodes multiple isotypes with remarkably divergent abilities to transactivate p53 reporter genes and induce apoptosis. Importantly, the predominant p63 isotypes in many epithelial tissues lack an acidic N terminus corresponding to the transactivation domain of p53. We demonstrate that these truncated p63 variants can act as dominant-negative agents toward transactivation by p53 and p63, and we suggest the possibility of physiological interactions among members of the p53 family.

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Topics: Transactivation (60%), Reporter gene (54%), Gene (51%) ... show more

2,031 Citations


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