Corneal Mesenchymal Stromal Cells Are Directly Antiangiogenic via PEDF and sFLT-1

Eslani, Medi; Putra, Ilham; Shen, Xiang; Hamouie, Judy; Afsharkhamseh, Neda; Besharat, Soroush; Rosenblatt, Mark I.; Dana, Reza; Hematti, Peiman; Djalilian, Ali R.

doi:10.1167/iovs.17-22680

Cited by 52 publications

(54 citation statements)

References 72 publications

(80 reference statements)

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“…MSCs are found in most adult tissues, including cornea/limbus, 7 and play an important role in tissue repair and maintenance. 1 Over the past decade, they have been increasingly investigated for their therapeutic potential in a wide range of human diseases given their anti-inflammatory and regenerative properties.…”

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confidence: 99%

“…It is now widely accepted that the therapeutic effects of MSCs are mediated largely through their secreted factors. 7 – 11 We previously showed that human corneal MSC (cMSC) secretome is able to inhibit corneal neovascularization, 7 and modulate macrophages toward an anti-angiogenic and anti-inflammatory immunophenotype, 12 suggesting that human cMSC secreted factors may be used therapeutically in ocular surface diseases. Secreted factors present considerable advantages over cells regarding manufacturing, storage, handling, product shelf life and their potential as a ready-to-go biologic product.…”

mentioning

confidence: 99%

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Effect of Human Corneal Mesenchymal Stromal Cell-derived Exosomes on Corneal Epithelial Wound Healing

Samaeekia

Rabiee

Putra

et al. 2018

Invest. Ophthalmol. Vis. Sci.

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171

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PurposeMesenchymal stromal cells (MSCs) have been used therapeutically to modulate inflammation and promote repair. Extracellular vesicles, including exosomes, have been identified as one of the important mediators. This study investigated the effect of human corneal MSC-derived exosomes on corneal epithelial wound healing.MethodsCorneal MSCs (cMSCs) were isolated from human cadaver corneas. The secretome was collected after 72 hours and exosomes were isolated using differential ultracentrifugation. Morphology and size of exosomes were examined by electron microscopy and dynamic light scattering. Expression of CD9, CD63, and CD81 by cMSC exosomes was evaluated by western blotting. Cellular uptake of exosomes was studied using calcein-stained exosomes. The effect of exosome on wound healing was measured in vitro using a scratch assay and in vivo after 2-mm epithelial debridement wounds in mice.ResultscMSC exosomes were morphologically round and main population ranged between 40 and 100 nm in diameter. They expressed CD9, CD63, and CD81, and did not express GM130, Calnexin, and Cytochrome-C. Stained cMSC exosomes were successfully taken up by human cMSCs, human corneal epithelial cells (HCECs), and human macrophages in vitro and by corneal epithelium in vivo. In scratch assay, after 16 hours, cMSC exosome treated HCECs had 30.1% ± 14% remaining wound area compared to 72.9% ± 8% in control (P < 0.005). In vivo, after 72 hours, cMSC exosome-treated corneas had 77.5% ± 3% corneal wound healing compared to 41.6% ± 7% in the control group (P < 0.05).ConclusionsHuman cMSC exosomes can accelerate corneal epithelial wound healing, and thus, may provide a therapeutic approach for ocular surface injuries.

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confidence: 99%

mentioning

confidence: 99%

Effect of Human Corneal Mesenchymal Stromal Cell-derived Exosomes on Corneal Epithelial Wound Healing

Samaeekia

Rabiee

Putra

et al. 2018

Invest. Ophthalmol. Vis. Sci.

Self Cite

171

147

View full text Add to dashboard Cite

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“…The therapeutic potential of cMSCs has been demonstrated in both in vitro and in vivo laboratory studies, 19,30 and cMSCs could provide a novel source of MSCs for corneal regenerative treatments. For clinical applications, however, protocols for cMSC isolation and expansion will have to be scalable while maintaining high reproducibility.…”

Section: Discussionmentioning

confidence: 99%

“…These antiangiogenic properties were found to be conferred in part by the secretion of pigment epithelium-derived factor and soluble fms-like tyrosine kinase-1 and low secretion of vascular endothelial growth factor A. 19 cMSCs also induce secretion of antiinflammatory factors by the macrophages and modulate their phenotype to an inflammation-resolving phenotype, 30 in addition to inhibiting T-cell proliferation. 42 Other studies have shown that cMSCs can induce increased cytokeratin 12-positive corneal epithelial cells and decreased neovascularization, conjunctivalization, and K8-positive conjunctival goblet cells.…”

Section: Discussionmentioning

confidence: 99%

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Reproducible Derivation and Expansion of Corneal Mesenchymal Stromal Cells for Therapeutic Applications

Jabbehdari

Yazdanpanah

Kanu

et al. 2020

Trans. Vis. Sci. Tech.

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A reproducible protocol for the production of corneal mesenchymal stem/stromal cells (cMSCs) is necessary for potential clinical applications. We aimed to describe successful generation and expansion of cMSCs using an explant method. Methods: Corneoscleral rims of human cadaveric eyes were divided into four pieces and used as explants to allow outgrowth of cMSCs (passage 0, or P0). The cells were subcultured at a 1:10 ratio until passage 5 (P5). The characteristics as well as therapeutic effects of expanded cMSCs were evaluated both in vitro, using a scratch assay, and in vivo using epithelial debridement and chemical injury mouse models. Results: All explants demonstrated outgrowth of cells by 7 days. Although the initial outgrowth included mixed mesenchymal and epithelial cells, by P1 only cMSCs remained. By subculturing each flask at a ratio of 1:10, the potential yield from each cornea was approximately 12 to 16 × 10 10 P5 cells. P5 cMSCs demonstrated the cell surface markers of MSCs. The secretome of P5 cMSCs induced faster closure of wounds in an in vitro scratch assay. Subconjunctival injection of P5 cMSCs in mouse models of mechanical corneal epithelial debridement or ethanol injury led to significantly faster wound healing and decreased inflammation, relative to control. Conclusions: cMSCs can be reproducibly derived from human cadaveric corneas using an explant method and expanded with preservation of characteristics and corneal wound healing effects. Translational Relevance: The results of our study showed that cMSCs produced using this scheme can be potentially used for clinical applications.

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Pigment epithelium‐derived factor enhances peripheral nerve regeneration through modulating oxidative stress and stem cells

Önger

Altun

Yıldıran

2023

The Anatomical Record

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Peripheral nerve injury is common and negatively affects an individual's quality of life. Drugs used for peripheral nerve regeneration should aim to eliminate symptoms such as neuropathic pain and have therapeutic effects. In recent studies, pigment epithelium‐derived factor (PEDF) has been considered an essential therapeutic agent because of its potential neuroprotective properties. In this study, we aimed to investigate the efficacy of locally applied PEDF for peripheral nerve regeneration. Twenty‐four Wistar albino male rats were used. The study groups included Injury (n = 12) and Injury+PEDF (n = 12). An injury model was created by applying 50 N pressure to the right sciatic nerves in groups, and 10 μg/kg local PEDF was injected into the Injury+PEDF group. After 28 days of recovery, functional tests and stereological, immunohistochemical, and biochemical analyses were performed. A significant difference was found between the Injury and Injury+PEDF groups in amplitude, whereas no difference was found in latency. The number of myelinated axons and the myelinated axon area increased significantly in the Injury+PEDF group, while no statistically significant difference was found in myelin sheath thickness. Superoxide dismutase, catalase, and glutathione peroxidase activities were increased by PEDF, whereas they were suppressed in mesenchymal stem cells. PEDF exerts functional, quantitative, and antioxidative effects on sciatic nerve injury during neuroregeneration. In addition, when oxidative stress parameters were examined, it was seen that PEDF reduced oxidative stress following sciatic nerve injury.

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Corneal Mesenchymal Stromal Cells Are Directly Antiangiogenic via PEDF and sFLT-1

Cited by 52 publications

References 72 publications

Effect of Human Corneal Mesenchymal Stromal Cell-derived Exosomes on Corneal Epithelial Wound Healing

Effect of Human Corneal Mesenchymal Stromal Cell-derived Exosomes on Corneal Epithelial Wound Healing

Reproducible Derivation and Expansion of Corneal Mesenchymal Stromal Cells for Therapeutic Applications

Pigment epithelium‐derived factor enhances peripheral nerve regeneration through modulating oxidative stress and stem cells

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