Human corneal fibroblast migration and extracellular matrix synthesis during stromal repair: Role played by platelet‐derived growth factor‐BB, basic fibroblast growth factor, and transforming growth factor‐β1

Gallego‐Muñoz, Patricia; Ibares‐Frías, Lucía; Garrote, José Antonio; Valsero-Blanco, M.Cruz; Cantalapiedra-Rodríguez, Roberto; Merayo‐Lloves, Jesús; Martínez-García, María Carmen

doi:10.1002/term.2360

Cited by 22 publications

(20 citation statements)

References 38 publications

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“…We observed a significant up-regulation of collagen type I and III mRNA expression levels in the wound area. This was consistent with previous in vitro studies that also found an up-regulation of collagens type I and III by cultured human myofibroblasts and cultured bovine myofibroblasts (Funderburgh et al, 2001;Gallego-Munoz et al, 2018). The presence of both collagen types has been described during corneal scarring by Massoudi et al (2016), indicating the presence of a disorganized ECM that was related to the loss of transparency, as we found here.…”

Section: Discussionsupporting

confidence: 93%

“…During wound healing, the quiescent keratocytes present in the stroma are activated and transitioned into the repair phenotypes fibroblasts and myofibroblasts that synthesize and release ECM components in the wound area. Myofibroblasts proliferate and migrate towards the site of the injury to close the wound by depositing excessive amounts of ECM proteins, including collagens type I, III, IV, and V to facilitate tissue repair (Chaurasia et al, 2015;Gallego-Munoz et al, 2018;Tandon et al, 2010). During this process, the collagen type I/type III ratio can be disrupted, and this fact has been described as one of the main reasons for corneal opacity after corneal injury (Chen et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

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Dynamic changes of the extracellular matrix during corneal wound healing

Lorenzo-Martín

Gallego‐Muñoz

Mar

et al. 2019

Experimental Eye Research

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The extracellular matrix (ECM) confers transparency to the cornea because of the precise organization of collagen fibrils and a wide variety of proteoglycans. We monitored the corneal wound healing process after alkali burns in rabbits. We analyzed the location and expression of collagens and proteoglycans, the clinical impact, and the recovery of optical transparency. After the animals received both general and ocular topical anesthesia, the central cornea of the left eye was burned by placing an 8-mm diameter filter paper soaked in 0.5 N NaOH for 60 s. The eyes were evaluated under a surgical microscope at 1, 3, and 6 months after burning. At each time point, the clinical conditions of the burned and control corneas were observed. The arrangement of collagen fibers in the corneal stroma was visualized by Picrosirius-red staining, Gomori's silver impregnation and transmission electronic microscopy. Corneal light transmittance was also measured. Myofibroblasts presence was analyzed by immunohistochemistry. mRNA expression levels of collagen types I and III, lumican, decorin, keratocan and alpha-smooth muscle actin were determined by quantitative real-time polymerase chain reaction. One month after alkali burn, the ECM was disorganized and filled with lacunae containing different types of cells and collagen type III fibers in the wound area. Corneal opacities were present with attendant loss of light transmittance. Collagen and proteoglycan mRNA expression levels were up-regulated. After three months, wound healing progress was indicated by reduced corneal opacity, increased light transmittance, reorganization of collagen fibers and only collagen type I expression levels were at control levels. After six months, the wound area ECM morphology was similar to controls, but transmittance values remained low, denoting incomplete restoration of the stromal architecture. This multidisciplinary study of the stromal wound healing process revealed changes in corneal transmittance, collagen organization, myofibroblasts presence and ECM composition at 1, 3, and 6 months after alkali burning. Documenting wound resolution during the six-month period provided reliable information that can be used to test new therapies.

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Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Dynamic changes of the extracellular matrix during corneal wound healing

Lorenzo-Martín

Gallego‐Muñoz

Mar

et al. 2019

Experimental Eye Research

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“…We previously demonstrated that ECM composition can modulate corneal behavior in 3-D culture in response to PDGF BB, which stimulates corneal fibroblast spreading and migration [ 28 , 29 , 30 , 31 , 32 ]. Specifically, whereas corneal fibroblasts generally move independently within 3-D collagen matrices, fibrin induces a switch to an interconnected, collective mode of cell spreading and migration that is independent of differences in ECM stiffness [ 33 , 34 ].…”

Section: Introductionmentioning

confidence: 99%

Coupling of Fibrin Reorganization and Fibronectin Patterning by Corneal Fibroblasts in Response to PDGF BB and TGFβ1

Miron-Mendoza¹,

Vazquez²,

García-Rámila³

et al. 2020

Bioengineering

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We previously reported that corneal fibroblasts within 3D fibrin matrices secrete, bind, and organize fibronectin into tracks that facilitate cell spreading and migration. Other cells use these fibronectin tracks as conduits, which leads to the development of an interconnected cell/fibronectin network. In this study, we investigate how cell-induced reorganization of fibrin correlates with fibronectin track formation in response to two growth factors present during wound healing: PDGF BB, which stimulates cell spreading and migration; and TGFβ1, which stimulates cellular contraction and myofibroblast transformation. Both PDGF BB and TGFβ1 stimulated global fibrin matrix contraction (p < 0.005); however, the cell and matrix patterning were different. We found that, during PDGF BB-induced cell spreading, fibronectin was organized simultaneously with the generation of tractional forces at the leading edge of pseudopodia. Over time this led to the formation of an interconnected network consisting of cells, fibronectin and compacted fibrin tracks. Following culture in TGFβ1, cells were less motile, produced significant local fibrin reorganization, and formed fewer cellular connections as compared to PDGF BB (p < 0.005). Although bands of compacted fibrin tracks developed in between neighboring cells, fibronectin labeling was not generally present along these tracks, and the correlation between fibrin and fibronectin labeling was significantly less than that observed in PDGF BB (p < 0.001). Taken together, our results show that cell-induced extracellular matrix (ECM) reorganization can occur independently from fibronectin patterning. Nonetheless, both events seem to be coordinated, as corneal fibroblasts in PDGF BB secrete and organize fibronectin as they preferentially spread along compacted fibrin tracks between cells, producing an interconnected network in which cells, fibronectin and compacted fibrin tracks are highly correlated. This mechanism of patterning could contribute to the formation of organized cellular networks that have been observed following corneal injury and refractive surgery.

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“…Previous studies showed that PDGF-BB and bFGF are involved in corneal wound healing, but their actions on ECM synthesis were not well understood [52, 53]. After scratch wound injury, PDGF-BB and bFGF-treated HCF wound had a similar healing pattern, and the wounds were completely closed at day 10, while wound in serum-free media had a slower healing rate [54]. In the same study, PDGF-BB-treated cells also had a higher level of collagen III expression, which is a marker of repair matrix synthesis.…”

Section: Resultsmentioning

confidence: 99%

A Systematic Review on Cornea Epithelial-Stromal Homeostasis

Wong¹,

Poon²,

Bu³

et al. 2020

Ophthalmic Res

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Introduction: This review aims to summarise the role of different cells, genes, proteins and lipid in regulating cornea epithelial-stromal homeostasis. Methods: We performed an Entrez PubMed literature search using keywords “human,” “cornea,” “epithelial,” “stromal,” “homeostasis,” “fibrosis response,” and “pathogenesis” on 24th of September 2019, resulting in 35 papers, of which 18 were chosen after filtering for “English language” and “published within 10 years” as well as curation for relevance by the authors. Results: The 18 selected papers showed that corneal epithelial cells, fibroblasts and telocytes, together with genes such as Klf4, Pax6 and Id found in the cells, play important roles in achieving homeostasis to maintain corneal integrity and transparency. Proteins classified as pro-fibrotic ligands and anti-fibrotic ligands are responsible for regulating cornea stromal fibrosis and extracellular matrix deposition, thus regulators of scar formation during wound healing. Anti-inflammatory ligands and wound repairing ligands are critical in eliciting protective inflammation and promoting epithelial healing, respectively. Protein receptors located on cellular membrane play a role in maintaining intercellular connections as well as corneal hydration. Discussion/Conclusion: These studies prompt development of novel therapeutic strategies such as tear drops or ointments that target certain proteins to maintain corneal homeostasis. However, more in vitro and in vivo studies are required to prove the effectiveness of exogenous administration of molecules in improving healing outcome. Hence, future investigations of the molecular pathways highlighted in this review will reveal novel therapeutic tools such as gene or cell therapy to treat corneal diseases.

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Human corneal fibroblast migration and extracellular matrix synthesis during stromal repair: Role played by platelet‐derived growth factor‐BB, basic fibroblast growth factor, and transforming growth factor‐β1

Cited by 22 publications

References 38 publications

Dynamic changes of the extracellular matrix during corneal wound healing

Dynamic changes of the extracellular matrix during corneal wound healing

Coupling of Fibrin Reorganization and Fibronectin Patterning by Corneal Fibroblasts in Response to PDGF BB and TGFβ1

A Systematic Review on Cornea Epithelial-Stromal Homeostasis

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