Ciliary Neurotrophic Factor Promotes the Migration of Corneal Epithelial Stem/progenitor Cells by Up-regulation of MMPs through the Phosphorylation of Akt

Chen, Jialin; Chen, Peng; Backman, Ludvig J.; Zhou, Qingjun; Danielson, Patrik

doi:10.1038/srep25870

Cited by 36 publications

(36 citation statements)

References 39 publications

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“…The mice corneal epithelial stem/progenitor cells used in this study have high expression levels of limbal progenitor cells markers ΔNp63 and importin 13 and have low expression levels of differentiated markers ck3/12 and involucrin, implying that these cells still retain stem cell properties. The TKE2 cells were cultured in keratinocyte serum‐free low‐Ca 2+ medium to maintain the undifferentiated state, and this cell line has already been characterized and used for the study of CESC and corneal wound healing in other reports . In addition, in order to validate our results from the TKE2 cells, we used primary cultured rabbit corneal epithelial cells for key experiments such as cell cycle and apoptosis detection.…”

Section: Discussionmentioning

confidence: 99%

“…that these cells still retain stem cell properties. The TKE2 cells were cultured in keratinocyte serum-free low-Ca 2+ medium to maintain the undifferentiated state, and this cell line has already been characterized and used for the study of CESC and corneal wound healing in other reports [40][41][42][43]. In addition, in order to validate our results from the TKE2 cells, we used primary cultured rabbit corneal epithelial cells for key experiments such as cell cycle and apoptosis detection.…”

Section: Discussionmentioning

confidence: 99%

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Different Effects of Pro-Inflammatory Factors and Hyperosmotic Stress on Corneal Epithelial Stem/Progenitor Cells and Wound Healing in Mice

Yang

Zhang

Dong

et al. 2018

Stem Cells Translational Medicine

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Chronic inflammation and severe dry eye are two important adverse factors for the successful transplant of cultured limbal stem cells. The aim of this study was to investigate the effects of inflammation and hyperosmotic stress (a key pathological factor in dry eye) on corneal epithelial stem cells (CESCs) and corneal epithelial wound healing. We observed that the CESCs exhibited significant morphological changes when treated with interleukin‐1 beta (IL‐1β), tumor necrosis factor alpha (TNF‐α), or hyperosmotic stress. Colony‐forming efficiency or colony‐forming size was decreased with the increasing concentrations of IL‐1β, TNF‐α, or hyperosmotic stress, which was exacerbated when treated simultaneously with pro‐inflammatory factors and hyperosmotic stress. However, the colony‐forming capacity of CESCs recovered more easily from pro‐inflammatory factor treatment than from hyperosmotic stress treatment. Moreover, when compared with pro‐inflammatory factors treatment, hyperosmotic stress treatment caused a more significant increase of apoptotic and necrotic cell numbers and cell cycle arrest in the G2/M phase. Furthermore, the normal ability of corneal epithelial wound healing in the mice model was suppressed by both pro‐inflammatory factors and hyperosmotic stress treatment, and especially severely by hyperosmotic stress treatment. In addition, inflammation combined with hyperosmotic stress treatment induced more serious epithelial repair delays and apoptosis in corneal epithelium. Elevated levels of inflammatory factors were found in hyperosmotic stress‐treated cells and mice corneas, which persisted even during the recovery period. The results suggested that pro‐inflammatory factors cause transient inhibition, while hyperosmotic stress causes severe apoptosis and necrosis, persistent cell cycle arrest of CESCs, and severe corneal wound healing delay. Stem Cells Translational Medicine 2019;8:46–57

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Different Effects of Pro-Inflammatory Factors and Hyperosmotic Stress on Corneal Epithelial Stem/Progenitor Cells and Wound Healing in Mice

Yang

Zhang

Dong

et al. 2018

Stem Cells Translational Medicine

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“…MTS Cell Proliferation Assay : 1.2 × 10 4 cells were seeded on each 14 mm silk fibroin film and cultured for the defined time periods ( n = 4 per group). Cell proliferation was measured using the CellTiter 96 AQueous One Solution Cell Proliferation Assay (Promega, Fitchburg, WI) according to the previous study . The absorbance of the culture medium was measured at 490 nm using a Synergy HT plate reader (BioTek, Winooski, VT).…”

Section: Methodsmentioning

confidence: 99%

Surface Topography and Mechanical Strain Promote Keratocyte Phenotype and Extracellular Matrix Formation in a Biomimetic 3D Corneal Model

Zhang

Chen

Backman

et al. 2016

Adv Healthcare Materials

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The optimal functionality of the native corneal stroma is mainly dependent on the well-ordered arrangement of extracellular matrix (ECM) and the pressurized structure. In order to develop an in vitro corneal model, it is crucial to mimic the in vivo microenvironment of the cornea. In this study, the influence of surface topography and mechanical strain on keratocyte phenotype and ECM formation within a biomimetic 3D corneal model is studied. By modifying the surface topography of materials, it is found that patterned silk fibroin film with 600 grooves mm -1 optimally supports cell alignment and ECM arrangement. Furthermore, treatment with 3% dome-shaped mechanical strain, which resembles the shape and mechanics of native cornea, significantly enhances the expression of keratocyte markers as compared to flat-shaped strain. Accordingly, a biomimetic 3D corneal model, in the form of a collagen-modified, silk fibroin-patterned construct subjected to 3% domeshaped strain, is created. Compared to traditional 2D cultures, it supports a significantly higher expression of keratocyte and ECM markers, and in conclusion better maintains keratocyte phenotype, alignment, and fusiform cell shape. Therefore, the novel biomimetic 3D corneal model developed in this study serves as a useful in vitro 3D culture model to improve current 2D cultures for corneal studies.The outermost epithelium, Bowman's layer, the stroma, Descemet's membrane, and the innermost endothelium. [2] The stroma, which constitutes up to 90% of the corneal thickness, is composed of well-organized collagen fibrils and quiescent stromal cells called keratocytes. [3,4] The structure of the stroma is important for the transparency and consequently the vision. The properties of the stroma are based on the combination of the orthogonal lamellar arrangement of aligned collagen fibrils (mainly collagen I and V) [5][6][7][8] and the spacing of these fibrils and the regulation of collagen diameter achieved by proteoglycans (such as lumican and keratocan). [9][10][11][12] It has been shown that keratocytes during in vitro cell culture conditions easily differentiate, as shown by reduced expression of the typical keratocyte markers, including keratocan, CD34, and ALDH3A1. [13,14] However, most of the in vitro corneal studies are conducted on 2D monolayers. [15][16][17] To overcome the limitations of 2D monolayer cell cultures, several 3D corneal in vitro models have been developed using tissue-engineered strategies and a number of biomaterials, such as colla gen, silk, chitosan, and other synthetic polymers. [14,18] Among the various materials, collagen is the most commonly used, as it is the main constituent of native cornea, and collagen-based corneal 3D models have shown promising results as substrates for the culture of corneal cells. [19][20][21] However, few of the 3D corneal in vitro models can replicate the in vivo microenvironment of the native cornea, due to the complexity of the corneal structure and the uniqueness of the mechanical environment created by the ...

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“…Keratinocyte growth factor (KGF) secreted by limbal fibroblasts increases the mitotic activity of LSC, that express KGF receptor, leading to acceleration of corneal epithelial wound healing . Ciliary neurotrophic factor promotes migration of corneal epithelial stem/progenitor cells through activation of Akt signaling mediated by matrix metalloproteinases . In the setting of corneal injury, LSC proliferation can also be stimulated by EGF and fibroblast growth factor‐β (FGF‐β) produced by the damaged corneal epithelium, whereas LSC differentiation is driven by insulin‐like growth factor‐I (IGF‐I), which induces expression of IGF receptor on LSC .…”

Section: Lsc In Corneal Homeostasis and Wound Healing—therapeutic Potmentioning

confidence: 99%

Limbal stem cells: identity, developmental origin, and therapeutic potential

González

Sasamoto

Ksander

et al. 2017

WIREs Developmental Biology

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The cornea is our window to the world and our vision is critically dependent on corneal clarity and integrity. Its epithelium represents one of the most rapidly regenerating mammalian tissues, undergoing full-turnover over the course of approximately 1-2 weeks. This robust and efficient regenerative capacity is dependent on the function of stem cells residing in the limbus, a structure marking the border between the cornea and the conjunctiva. Limbal stem cells (LSC) represent a quiescent cell population with proliferative capacity residing in the basal epithelial layer of the limbus within a cellular niche. In addition to LSC, this niche consists of various cell populations such as limbal stromal fibroblasts, melanocytes and immune cells as well as a basement membrane, all of which are essential for LSC maintenance and LSC-driven regeneration. The LSC niche's components are of diverse developmental origin, a fact that had, until recently, prevented precise identification of molecularly defined LSC. The recent success in prospective LSC isolation based on ABCB5 expression and the capacity of this LSC population for long-term corneal restoration following transplantation in preclinical in vivo models of LSC deficiency underline the considerable potential of pure LSC formulations for clinical therapy. Additional studies, including genetic lineage tracing of the developmental origin of LSC will further improve our understanding of this critical cell population and its niche, with important implications for regenerative medicine. WIREs Dev Biol 2018, 7:e303. doi: 10.1002/wdev.303 This article is categorized under: Adult Stem Cells, Tissue Renewal, and Regeneration > Stem Cells and Disease Adult Stem Cells, Tissue Renewal, and Regeneration > Tissue Stem Cells and Niches Adult Stem Cells, Tissue Renewal, and Regeneration > Regeneration.

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Ciliary Neurotrophic Factor Promotes the Migration of Corneal Epithelial Stem/progenitor Cells by Up-regulation of MMPs through the Phosphorylation of Akt

Cited by 36 publications

References 39 publications

Different Effects of Pro-Inflammatory Factors and Hyperosmotic Stress on Corneal Epithelial Stem/Progenitor Cells and Wound Healing in Mice

Different Effects of Pro-Inflammatory Factors and Hyperosmotic Stress on Corneal Epithelial Stem/Progenitor Cells and Wound Healing in Mice

Surface Topography and Mechanical Strain Promote Keratocyte Phenotype and Extracellular Matrix Formation in a Biomimetic 3D Corneal Model

Limbal stem cells: identity, developmental origin, and therapeutic potential

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