Mesenchymal Stem Cells Promote Diabetic Corneal Epithelial Wound Healing Through TSG-6–Dependent Stem Cell Activation and Macrophage Switch

Di, Guohu; Du, Xianli; Qi, Xia; Zhao, Xiaowen; Duan, Haoyun; Li, Suxia; Xie, Lixin; Zhou, Qingjun

doi:10.1167/iovs.17-21506

Cited by 96 publications

(84 citation statements)

References 50 publications

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“…Mice were anaesthetized by an intraperitoneal injection of 0.5 mL 0.9% sodium chloride solution containing 40 μL ketamine and 10 μL chlorpromazine hydrochloride, followed by topical application of proparacaine hydrochloride eye drops (Alcon) in the eye; then, an Algerbrush II remover (Alger Co) was used to scrape the central corneal epithelium (2.75 mm diameter) in mice. Fluorescein staining method was used to examine the residual epithelial defects, and the percentage of the original defect area was calculated with ImageJ software (NIH) as described in our previous studies 29‐31 . For DNase I treatment, diabetic mice were topically applied with 1 mg/mL DNase I (5 μL/eye; Roche Diagnostics GmbH) six times a day after the removal of corneal epithelium, whereas age‐matched control mice were topically applied with equal phosphate buffer saline (PBS) as the vehicle control.…”

Section: Methodsmentioning

confidence: 99%

DNase I improves corneal epithelial and nerve regeneration in diabetic mice

Zhang

Dai

Wei

et al. 2020

J Cellular Molecular Medi

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DNase I has been reported to improve diabetic wound healing through the clearance of neutrophils extracellular traps (NETs) caused by neutrophil aggregation. However, the function of DNase I on diabetic corneal wound healing remains unclear. Here, we investigated the effect and mechanism of topical DNase I application on diabetic mouse corneal epithelial and nerve regeneration. Corneal epithelial defects, inflammatory response, regeneration-related signalling pathways, oxidative stress, corneal innervation and sensation were examined and compared between the diabetic and normal mice. The results confirmed firstly the increased NETs production during the delayed corneal epithelial wound healing of diabetic mice, which was significantly improved through either DNase I or Cl-amidine administration. Mechanistically, DNase I improved inflammation resolution, reactivated epithelial regeneration-related signalling pathways and attenuated the accumulation of reactive oxygen species (ROS).Moreover, DNase I application also promoted corneal nerve regeneration and restored the impaired corneal sensitivity in diabetic mice. Therefore, these results indicate that topical DNase I application promotes corneal epithelial wound healing and mechanical sensation restoration in diabetic mice, representing the potential therapeutic approach for diabetic keratopathy. K E Y W O R D Scorneal wound healing, diabetes mellitus, DNase I, inflammation, oxidative stress

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Section: Methodsmentioning

confidence: 99%

DNase I improves corneal epithelial and nerve regeneration in diabetic mice

Zhang

Dai

Wei

et al. 2020

J Cellular Molecular Medi

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“…54 The antiinflammatory protein TNF-alpha-stimulated gene/protein 6 (TSG-6), which is produced from bone marrow-derived MSCs in response to injured-tissue signals, decreased the corneal inflammatory response, promoted corneal epithelial wound healing, and activated corneal epithelial stem/progenitor cells in a mouse corneal allotransplantation model and a diabetic mouse model. 55,56 TSG-6 in conditioned medium from human AM-derived MSCs was also related to the inflammatory response using LPS-stimulated murine bone marrow-derived neutrophils. 57 Human corneal epithelial cell migration increased significantly with the use of 15% and 30% AMconditioned medium.…”

Section: Discussionmentioning

confidence: 93%

Effects of Amniotic Membrane–Derived Fibroblast Supernatant on Corneal Epithelium

Higa

Higuchi

Kimoto

et al. 2019

Invest. Ophthalmol. Vis. Sci.

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Citation: Higa K, Higuchi J, Kimoto R, et al. Effects of amniotic membranederived fibroblast supernatant on corneal epithelium. Invest Ophthalmol Vis Sci. 2019;60:3718-3726. https:// doi.org/10.1167/iovs.19-27041 PURPOSE. To evaluate the effects of human amniotic membrane-derived fibroblast (AMF) cell supernatant (AMF-sup) on corneal epithelium.METHODS. The phenotype of AMF cells was analyzed by flow cytometry using cell-surface markers. AMF cells were also induced to form osteoblasts and neural cells, and cell phenotypes were observed by staining and RT-PCR. Cultivated human corneal limbal epithelial sheets generated using AMF-sup were analyzed using immunohistochemistry and colony-forming efficiency, and the wound healing of epithelial defects was observed using a tissue-punch method. The effects of instillation of each supernatant in a rabbit corneal epithelial wound healing model were compared. RESULTS.Mesenchymal stem cell (CD29, CD44, CD73, and CD90) and neural crest (CD49d and CD56) markers were expressed on the AMF cell surface. Following induction of differentiation, isolated AMF cells showed characteristics of osteoblasts and neural cells. Application of AMF-sup resulted in maintenance of the limbal epithelial phenotype and immature state, and significantly promoted wound healing in cultivated human corneal limbal epithelial sheets (P < 0.05) and rabbit corneal epithelium (P < 0.05) compared with the control.CONCLUSIONS. These data suggest that AMF cells have multi-differentiation potential, and that AMF-sup is effective in maintaining the limbal epithelial phenotype and promoting corneal epithelial wound healing, which may be of value in ocular surface reconstruction.

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“…[ 17 ] In in vitro macrophage culture, TSG‐6 can promote the polarization of recruited macrophages to anti‐inflammatory M2 phenotypes with increased phagocytotic capacity. [ 18 ] Thus, we speculated that heADSCs alleviate fibrosis through tissue‐protective effects by TSG‐6 and regulate pro‐ and anti‐inflammatory cytokines through TSG‐6‐mediated macrophage switching. In our study, we isolated whole cornea for western blot and RT‐qPCR assay, in this case, the difference may be minimized by expression of TSG‐6 in the stromal cells.…”

Section: Discussionmentioning

confidence: 99%

Systemic Transplantation of Eyelid Adipose‐Derived Stem Cells for Antifibrotic Treatment

Fang

Chen

Teng

et al. 2020

Advanced Therapeutics

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Fibrosis is a result of the pathological wound‐healing response initiated by immune cells and leads to permanent scarring, such as corneal scarring, which impairs the vision of millions of people worldwide. However, there is currently no available treatment strategy that specifically targets the pathogenesis of fibrosis and can be translated in a safe and versatile way. Herein, it is illustrated that systemic transplantation of easily accessible human eyelid adipose‐derived stem cells (heADSCs) can successfully and safely exert antifibrotic effects in both corneal and skin scarring cases. Intravenous injection of heADSCs alleviates scar formation after rat corneal lamellar injury with accelerated epithelization, increases tumor necrosis factor‐stimulated gene‐6 (TSG‐6) in the epithelium, and decreases inflammatory factors. Cell tracing shows the presence of detectable signals until the 7th day, while no pulmonary embolism or other discomfort occurs. heADSCs effectively reduce corneal scarring by ameliorating stromal inflammation by increasing endogenous tissue‐protective TSG‐6 in the epithelium and macrophage phenotype switching, which is more effective with systemic transplantation than subconjunctival transplantation. Systemic transplantation of heADSCs shows safe antifibrotic effects in both corneal and skin scarring cases and this result identifies systemic transplantation with autologous adipose‐derived stem cells as a generally versatile and safe therapy for antifibrotic treatment.

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Mesenchymal Stem Cells Promote Diabetic Corneal Epithelial Wound Healing Through TSG-6–Dependent Stem Cell Activation and Macrophage Switch

Abstract: This study provided the first evidence of TSG-6 secreted by MSCs promoting corneal epithelial wound healing in diabetic mice through activating corneal epithelial stem/progenitor cells and accelerating M2 macrophage polarization.

Cited by 96 publications

References 50 publications

DNase I improves corneal epithelial and nerve regeneration in diabetic mice

DNase I improves corneal epithelial and nerve regeneration in diabetic mice

Effects of Amniotic Membrane–Derived Fibroblast Supernatant on Corneal Epithelium

Systemic Transplantation of Eyelid Adipose‐Derived Stem Cells for Antifibrotic Treatment

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