Rapamycin Inhibits the Production of Myofibroblasts and Reduces Corneal Scarring After Photorefractive Keratectomy

Milani, Behrad Y.; Milani, Farnoud Y.; Park, Dong Wouk; Namavari, Abed; Shah, Jarna; Amirjamshidi, Hossein; Ying, Hongyu; Djalilian, Ali R.

doi:10.1167/iovs.13-12674

Cited by 43 publications

(37 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Increasing myofibroblast accumulation in TSC1 CKO mice in response to CCl 4 treatment is thought to contribute to the noted significant increase in liver fibrosis. This result is also consistent with a previous study in which rapamycin appeared to inhibit proliferation and differentiation of corneal myofibroblasts in vitro 25.…”

Section: Discussionsupporting

confidence: 93%

mTOR Overactivation in Mesenchymal cells Aggravates CCl4− Induced liver Fibrosis

Shan

Ding

et al. 2016

Sci Rep

View full text Add to dashboard Cite

Hepatic stellate cells are of mesenchymal cell type located in the space of Disse. Upon liver injury, HSCs transactivate into myofibroblasts with increase in expression of fibrillar collagen, especially collagen I and III, leading to liver fibrosis. Previous studies have shown mTOR signaling is activated during liver fibrosis. However, there is no direct evidence in vivo. The aim of this study is to examine the effects of conditional deletion of TSC1 in mesenchymal on pathogenesis of liver fibrosis. Crossing mice bearing the floxed TSC1 gene with mice harboring Col1α2-Cre-ER(T) successfully generated progeny with a conditional knockout of TSC1 (TSC1 CKO) in collagen I expressing mesenchymal cells. TSC1 CKO and WT mice were subjected to CCl4, oil or CCl4+ rapamycin treatment for 8 weeks. TSC1 CKO mice developed pronounced liver fibrosis relative to WT mice, as examined by ALT, hydroxyproline, histopathology, and profibrogenic gene. Absence of TSC1 in mesenchymal cells induced proliferation and prevented apoptosis in activated HSCs. However, there were no significant differences in oil-treated TSC1 CKO and WT mice. Rapamycin, restored these phenotypic changes by preventing myofibroblasts proliferation and enhancing their apoptosis. These findings revealed mTOR overactivation in mesenchymal cells aggravates CCl4− induced liver fibrosis and the rapamycin prevent its occurance.

show abstract

Section: Discussionsupporting

confidence: 93%

mTOR Overactivation in Mesenchymal cells Aggravates CCl4− Induced liver Fibrosis

Shan

Ding

et al. 2016

Sci Rep

View full text Add to dashboard Cite

show abstract

“…Cell culture lacks the different inflammatory cells, growth factors, and cytokines that are key players in corneal wound healing, and therefore, ultimately fail to replicate the complicated process of wound healing in vivo . Small laboratory animal species such as rodents and rabbits are commonly used in current corneal fibrosis research (Milani et al 2013, Gu et al 2014). While the in vivo studies overcome the limitations of in vitro experiments by representing native corneal wound healing, the cornea of rats, rabbits and mice differ significantly from those of people in terms of thickness and diameter (Vezina 2013).…”

Section: Introductionmentioning

confidence: 99%

Development of a novel in vivo corneal fibrosis model in the dog

Gronkiewicz

Giuliano

Kuroki

et al. 2016

Experimental Eye Research

View full text Add to dashboard Cite

The aim of this study was to develop a novel in vivo corneal model of fibrosis in dogs utilizing alkali burn and determine the ability of suberanilohydroxamic acid (SAHA) to inhibit corneal fibrosis using this large animal model. To accomplish this, we used seven research Beagle dogs. An axial corneal alkali burn in dogs was created using 1 N NaOH topically. Six dogs were randomly and equally assigned into 2 groups: A) vehicle (DMSO, 2 μL/mL); B) anti-fibrotic treatment (50 μM SAHA). The degree of corneal opacity, ocular health, and anti-fibrotic effects of SAHA were determined utilizing the Fantes grading scale, modified McDonald-Shadduck (mMS) scoring system, optical coherence tomography (OCT), corneal histopathology, immunohistochemistry (IHC), and transmission electron microscopy (TEM). The used alkali burn dose to produce corneal fibrosis was well tolerated as no significant difference in mMS scores between control and treatment groups (p=0.89) were detected. The corneas of alkali burned dogs showed significantly greater levels of α-smooth muscle actin, the fibrotic marker, than the controls (p=0.018). Total corneal thickness of all dogs post-burn was significantly greater than baseline OCT images irrespective of treatment (p=0.004); TEM showed that alkali burned corneas had significantly greater minimum and maximum interfibrillar distances than the controls (p=0.026, p=0.018). The tested topical corneal alkali burn dose generated significant opacity and fibrosis in dog corneas without damaging the limbus as evidenced by histopathology, IHC, TEM, and OCT findings, and represents a viable large animal corneal fibrosis in vivo model. Additional in vivo SAHA dosing studies with larger sample size are warranted.

show abstract

“…However, so far the treatment or prevention of pathological corneal scars is difficult due to limited therapeutic options 8 . Topical treatment with corticosteroids or chemotherapeutic agents, such as Mitomycin C, has shown some antifibrotic effect in the cornea; however their use is limited due to their potentially severe side effects 9 .…”

Section: Introductionmentioning

confidence: 99%

miR-145 Is a Promising Therapeutic Target to Prevent Cornea Scarring

et al. 2015

View full text Add to dashboard Cite

Corneal scarring is an expected outcome of corneal injury or infection and is one of the major causes for visual loss. The formation of light-scattering myofibroblasts is thought to be the underlying cause of corneal haze formation. Recently, microRNA (miRNA) gene therapies have been proposed as novel approach for complex processes such as fibrosis and scarring. In this study, we focused on the role of miR-145 in corneal myofibroblast differentiation and function. Analysis of human corneal scar tissue and transforming growth factor (TGF)-β1-induced corneal myofibroblasts showed a 13- and 4-fold increase of miR-145, respectively, compared with healthy cornea and nonstimulated fibroblasts (p<0.01). Furthermore, myofibroblasts showed an increase in α-smooth muscle actin (α-SMA) expression and a decreased expression of Kruppel-like factor 4 (KLF4). These results indicated that TGF-β1 increases miR-145 expression, which indirectly induces α-SMA expression via downregulation of KLF4, a known negative regulator of α-SMA. Consistently, miR-145 silencing in corneal myofibroblasts using a specific antimiR resulted in increased KLF4 and strongly decreased α-SMA expression. In addition, miR-145 inhibition also significantly decreased myofibroblast contractility, migratory capacity, and TGF-β1 secretion, which are all thought to contribute to corneal scarring. Hence, miR-145 plays an important role in TGF-β1-stimulated corneal myofibroblast differentiation and activation, which can be reversed by miR-145 silencing. Therefore, we suggest miR-145 as a promising therapeutic target for miRNA-based gene therapy to prevent or treat visual loss caused by corneal fibrosis.

show abstract

Rapamycin Inhibits the Production of Myofibroblasts and Reduces Corneal Scarring After Photorefractive Keratectomy

Abstract: Rapamycin appears to inhibit proliferation and differentiation of corneal myofibroblasts and, thus, may provide an effective therapeutic measure for preventing corneal scarring.

Cited by 43 publications

References 34 publications

mTOR Overactivation in Mesenchymal cells Aggravates CCl4− Induced liver Fibrosis

mTOR Overactivation in Mesenchymal cells Aggravates CCl4− Induced liver Fibrosis

Development of a novel in vivo corneal fibrosis model in the dog

miR-145 Is a Promising Therapeutic Target to Prevent Cornea Scarring

Contact Info

Product

Resources

About