Human Corneal Fibroblast Pattern Evolution and Matrix Synthesis on Mechanically Biased Substrates

Zareian, Ramin; Susilo, Monica E.; Paten, Jeffrey A.; McLean, James; Hollmann, Joseph L.; Karamichos, Dimitrios; Messer, Conor S; Tambe, Dhananjay; Saeidi, Nima; Zieske, James D.; Ruberti, Jeffrey W.

doi:10.1089/ten.tea.2016.0164

Cited by 16 publications

(17 citation statements)

References 71 publications

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“…Since IOP only influences eye patterning and not cell differentiation as noted by Coulombre [43], the factors controlling stromal organization are likely due to keratocyte differentiation. This notion is supported by seminal studies by Ruberti and colleagues who demonstrated that human keratocytes can produce an orthogonal, three-dimensional matrix that resembles the corneal stromal architecture [67–69]. This further advocates that the directionality of the mechanical stimuli, which are likely very weak in an expanding cornea, cannot override the patterning behaviour of the corneal stromal cells.…”

Section: Discussionmentioning

confidence: 87%

Cell regulation of collagen fibril macrostructure during corneal morphogenesis

et al. 2018

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This work by using an ex ovo model system, begins to investigate the potential mechanisms controlling collagen fibril macrostructure. In particular, this work highlights a convergent role for the corneal keratocytes in organizing the complex collagen macrostructure, necessary to support high visual acuity. Our data supports that the intraocular pressure does not influence collagen fibril macrostructure and suggest that the avian cornea represents an excellent experimental model for elucidating key regulatory steps and mechanisms controlling the collagen fiber organization that is critical to determining tissue form and function. Clearly understanding the cellular and molecular mechanisms that underlie collagen fibril macrostructure will be highly beneficial for future tissue engineering and regenerative medicine applications.

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Section: Discussionmentioning

confidence: 87%

Cell regulation of collagen fibril macrostructure during corneal morphogenesis

et al. 2018

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“…The effect of mechanical strain on tenocytes, ligament fibroblasts, and myocytes has been extensively studied . For corneal cells, only some work has so far been done to investigate the mechanical effects with flat, uniaxial load, which cannot totally reflect the in vivo mechanical environment . In the present study, we created a novel static equibiaxial dome‐shaped strain which highly replicated the cornea shape and strain.…”

Section: Resultsmentioning

confidence: 97%

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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“…Furthermore, it is not yet known how the topography of the wound may impact the underlying cellular and biological activity and final healing outcome. Although biophysical and topographical cues have been increasingly recognized as key players modulating the biochemical signaling patterns associated with cell differentiation, secretion, and organization of ECM may also be involved 94 – 96 .…”

Section: Discussionmentioning

confidence: 99%

Recapitulation of normal collagen architecture in embryonic wounded corneas

Koudouna

Spurlin

Babushkina

et al. 2020

Sci Rep

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Wound healing is characterized by cell and extracellular matrix changes mediating cell migration, fibrosis, remodeling and regeneration. We previously demonstrated that chick fetal wound healing shows a regenerative phenotype regarding the cellular and molecular organization of the cornea. However, the chick corneal stromal structure is remarkably complex in the collagen fiber/lamellar organization, involving branching and anastomosing of collagen bundles. It is unknown whether the chick fetal wound healing is capable of recapitulating this developmentally regulated organization pattern. The purpose of this study was to examine the three-dimensional collagen architecture of wounded embryonic corneas, whilst identifying temporal and spatial changes in collagen organization during wound healing. Linear corneal wounds that traversed the epithelial layer, Bowman´s layer, and anterior stroma were generated in chick corneas on embryonic day 7. Irregular thin collagen fibers are present in the wounded cornea during the early phases of wound healing. As wound healing progresses, the collagen organization dramatically changes, acquiring an orthogonal arrangement. Fourier transform analysis affirmed this observation and revealed that adjacent collagen lamellae display an angular displacement progressing from the epithelium layer towards the endothelium. these data indicate that the collagen organization of the wounded embryonic cornea recapitulate the native macrostructure. Open wounds or excessive scarring arise from genetic disorders or as a result of traumatic burns or injury. Such aberrations in tissue represent a devastating source of morbidity to patients and a tremendous financial burden to the healthcare system 1-3. Over 10 million people worldwide suffer from corneal blindness as a result of ocular trauma and infection 4,5 , whereas the total annual cost for anti-scarring treatments is estimated at $12 billion 6. While today's treatments including revision surgeries, generally restore structural integrity, they still struggle to overcome the natural barriers of basic wound repair process and are unable to support scarless wound healing. The promise of regenerative medicine, founded on its potential and ability to regenerate and replace tissue defects, trauma and diseases, is limited by lack of knowledge on the mechanistic basis and control between regeneration and repair. The reasons for this knowledge gap are multi-faceted, yet originating by the lack of a reliable and reproducible regenerative model, particularly for tissues with low regenerative capacities like cornea. Tissue regeneration is a dynamic process by which damaged tissue architecture and function is restored to its normal state via cellular proliferation, differentiation, and synthesis of extracellular matrix (ECM) that matches unaffected tissue. Repair refers to a fibroproliferative response that heals damaged tissue by excessive deposition and accumulation of interstitial matrix proteins, which leads to scar formation, pathological fibrosis and lo...

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Human Corneal Fibroblast Pattern Evolution and Matrix Synthesis on Mechanically Biased Substrates

Cited by 16 publications

References 71 publications

Cell regulation of collagen fibril macrostructure during corneal morphogenesis

Cell regulation of collagen fibril macrostructure during corneal morphogenesis

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

Recapitulation of normal collagen architecture in embryonic wounded corneas

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