Fibrocytes, Wound Healing, and Corneal Fibrosis

Oliveira, Rodrigo Carlos de; Wilson, Steven E.

doi:10.1167/iovs.61.2.28

Cited by 91 publications

(59 citation statements)

References 106 publications

(273 reference statements)

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“…Accordingly, in kidneys, TGF-β1/Smad3-P signaling regulates the transition of BM-derived macrophages into myofibroblasts, leading to inflammation and tissue fibrosis 43 , 44 and CD206-positive M2-macrophages are strongly associated with renal fibrosis, both in humans and in experimental diseases 44 . One may also speculate that the observed pro-fibrotic cells could be, at least in part, fibrocytes, as they have been implicated in the pathogenesis of multiple diseases such as idiopathic pulmonary fibrosis or corneal fibrosis 25 , 45 , and in tissue healing in experimental models of muscle injury and muscular dystrophy 46 . Fibrocytes appear to differentiate from peripheral blood monocytes 47 , bear characteristics of both fibroblasts and monocytes and are able to differentiate in myofibroblast-like cells increasing their expression of TGFβ and endothelin 25 .…”

Section: Discussionmentioning

confidence: 99%

Hypoxia-induced miR-210 modulates the inflammatory response and fibrosis upon acute ischemia

et al. 2021

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Hypoxia-induced miR-210 is a crucial component of the tissue response to ischemia, stimulating angiogenesis and improving tissue regeneration. Previous analysis of miR-210 impact on the transcriptome in a mouse model of hindlimb ischemia showed that miR-210 regulated not only vascular regeneration functions, but also inflammation. To investigate this event, doxycycline-inducible miR-210 transgenic mice (Tg-210) and anti-miR-210 LNA-oligonucleotides were used. It was found that global miR-210 expression decreased inflammatory cells density and macrophages accumulation in the ischemic tissue. To dissect the underpinning cell mechanisms, Tg-210 mice were used in bone marrow (BM) transplantation experiments and chimeric mice underwent hindlimb ischemia. MiR-210 overexpression in the ischemic tissue was sufficient to increase capillary density and tissue repair, and to reduce inflammation in the presence of Wt-BM infiltrating cells. Conversely, when Tg-210-BM cells migrated in a Wt ischemic tissue, dysfunctional angiogenesis, inflammation, and impaired tissue repair, accompanied by fibrosis were observed. The fibrotic regions were positive for α-SMA, Vimentin, and Collagen V fibrotic markers and for phospho-Smad3, highlighting the activation of TGF-β1 pathway. Identification of Tg-210 cells by in situ hybridization showed that BM-derived cells contributed directly to fibrotic areas, where macrophages co-expressing fibrotic markers were observed. Cell cultures of Tg-210 BM-derived macrophages exhibited a pro-fibrotic phenotype and were enriched with myofibroblast-like cells, which expressed canonical fibrosis markers. Interestingly, inhibitors of TGF-β type-1-receptor completely abrogated this pro-fibrotic phenotype. In conclusion, a context-dependent regulation by miR-210 of the inflammatory response was identified. miR-210 expression in infiltrating macrophages is associated to improved angiogenesis and tissue repair when the ischemic recipient tissue also expresses high levels of miR-210. Conversely, when infiltrating an ischemic tissue with mismatched miR-210 levels, macrophages expressing high miR-210 levels display a pro-fibrotic phenotype, leading to impaired tissue repair, fibrosis, and dysfunctional angiogenesis.

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Section: Discussionmentioning

confidence: 99%

Hypoxia-induced miR-210 modulates the inflammatory response and fibrosis upon acute ischemia

et al. 2021

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“…The results from immunofluorescence studies show that hCSCs cultured in fibrin–EdECM hydrogels exhibited significantly higher expression of CD73 and lower of CD90 compared to fibrin controls at the end of the five-day culture period ( Figure 3 F,G and Figure S6 ). In addition, the fibrocytic marker α-SMA, a standard marker used for labeling activated fibrocytes/myofibroblasts that play a major role in tissue fibrosis [ 37 ], was significantly downregulated in cells cultured in the presence of EdECM microparticles compared to fibrin controls ( Figure 3 H and Figure S6 ) at all three time points. This data clearly indicate that EdECM microparticles inhibit the differentiation of hCSCs to a myofibroblast lineage which plays a major role in fibrotic ECM deposition that leads to corneal opacity [ 38 ].…”

Section: Resultsmentioning

confidence: 99%

Human Cadaveric Donor Cornea Derived Extra Cellular Matrix Microparticles for Minimally Invasive Healing/Regeneration of Corneal Wounds

Chandru¹,

Agrawal²,

Ojha³

et al. 2021

Biomolecules

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Biological materials derived from extracellular matrix (ECM) proteins have garnered interest as their composition is very similar to that of native tissue. Herein, we report the use of human cornea derived decellularized ECM (dECM) microparticles dispersed in human fibrin sealant as an accessible therapeutic alternative for corneal anterior stromal reconstruction. dECM microparticles had good particle size distribution (≤10 µm) and retained the majority of corneal ECM components found in native tissue. Fibrin–dECM hydrogels exhibited compressive modulus of 70.83 ± 9.17 kPa matching that of native tissue, maximum burst pressure of 34.3 ± 3.7 kPa, and demonstrated a short crosslinking time of ~17 min. The fibrin–dECM hydrogels were found to be biodegradable, cytocompatible, non-mutagenic, non-sensitive, non-irritant, and supported the growth and maintained the phenotype of encapsulated human corneal stem cells (hCSCs) in vitro. In a rabbit model of anterior lamellar keratectomy, fibrin–dECM bio-adhesives promoted corneal re-epithelialization within 14 days, induced stromal tissue repair, and displayed integration with corneal tissues in vivo. Overall, our results suggest that the incorporation of cornea tissue-derived ECM microparticles in fibrin hydrogels is non-toxic, safe, and shows tremendous promise as a minimally invasive therapeutic approach for the treatment of superficial corneal epithelial wounds and anterior stromal injuries.

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“…In our experiments cells were cultured in physiological conditions before incubating with MMC, this might have resulted in lower mRNA levels of Col 3A1 gene. It has also been shown that Col 3A1 expression increases in the initial stages of wound healing and eventually replaced with Col 1 41 , 42 . Col 4A is primarily present in the corneal basement membrane, Bowman’s membrane and Descemet’s membrane with role in development, maintainence and wound healing process of the cornea 43 , 44 .…”

Section: Discussionmentioning

confidence: 99%

Safety and efficacy of combination of suberoylamilide hydroxyamic acid and mitomycin C in reducing pro-fibrotic changes in human corneal epithelial cells

Shetty

Kumar

Subramani

et al. 2021

Sci Rep

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Corneal haze post refractive surgery is prevented by mitomycin c (MMC) treatment though it can lead to corneal endothelial damage, persistent epithelial defects and necrosis of cells. Suberanilohydroxamic acid (SAHA) however has been proposed to prevent corneal haze without any adverse effects. For clinical application we have investigated the short and long term outcome of cells exposed to SAHA. Human donor cornea, cultured limbal epithelial cells, corneal rims and lenticules were incubated with SAHA and MMC. The cells/tissue was then analyzed by RT-qPCR, immunofluorescence and western blot for markers of apoptosis and fibrosis. The results reveal that short term exposure of SAHA and SAHA + MMC reduced apoptosis levels and increased αSMA expression compared to those treated with MMC. Epithelial cells derived from cultured corneal rim that were incubated with the MMC, SAHA or MMC + SAHA revealed enhanced apoptosis, reduced levels of CK3/CK12, ∆NP63 and COL4A compared to other treatments. In SAHA treated lenticules TGFβ induced fibrosis was reduced. The results imply that MMC treatment for corneal haze has both short term and long term adverse effects on cells and the cellular properties. However, a combinatorial treatment of SAHA + MMC prevents expression of corneal fibrotic markers without causing any adverse effect on cellular properties.

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Fibrocytes, Wound Healing, and Corneal Fibrosis

Cited by 91 publications

References 106 publications

Hypoxia-induced miR-210 modulates the inflammatory response and fibrosis upon acute ischemia

Hypoxia-induced miR-210 modulates the inflammatory response and fibrosis upon acute ischemia

Human Cadaveric Donor Cornea Derived Extra Cellular Matrix Microparticles for Minimally Invasive Healing/Regeneration of Corneal Wounds

Safety and efficacy of combination of suberoylamilide hydroxyamic acid and mitomycin C in reducing pro-fibrotic changes in human corneal epithelial cells

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