Publications by authors named "Ali R Djalilian"

81 Publications

Gene dosage manipulation alleviates manifestations of hereditary haploinsufficiency in mice.

Sci Transl Med 2020 12;12(573)

Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL 60612, USA.

In autosomal dominant conditions with haploinsufficiency, a single functional allele cannot maintain sufficient dosage for normal function. We hypothesized that pharmacologic induction of the wild-type allele could lead to gene dosage compensation and mitigation of the disease manifestations. The paired box 6 () gene is crucial in tissue development and maintenance particularly in eye, brain, and pancreas. Aniridia is a panocular condition with impaired eye development and limited vision due to haploinsufficiency. To test our hypothesis, we performed a chemical screen and found mitogen-activated protein kinase kinase (MEK) inhibitors to induce expression in normal and mutant corneal cells. Treatment of newborn -deficient mice ( ) with topical or systemic MEK inhibitor PD0325901 led to increased corneal PAX6 expression, improved corneal morphology, reduced corneal opacity, and enhanced ocular function. These results suggest that induction of the wild-type allele by drug repurposing is a potential therapeutic strategy for haploinsufficiencies, which is not limited to specific mutations.
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http://dx.doi.org/10.1126/scitranslmed.aaz4894DOI Listing
December 2020

Proposed Nomenclature for Descemet Stripping Automated Endothelial Keratoplasty Procedures.

Cornea 2020 12;39(12):e29-e30

Department of Ophthalmology, University of Illinois at Chicago Eye and Ear Infirmary, Chicago, IL.

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http://dx.doi.org/10.1097/ICO.0000000000002528DOI Listing
December 2020

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

Transl Vis Sci Technol 2020 02 21;9(3):26. Epub 2020 Feb 21.

Stem Cell Therapy and Corneal Tissue Engineering Laboratory, Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL, USA.

Purpose: 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 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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http://dx.doi.org/10.1167/tvst.9.3.26DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7354855PMC
February 2020

The Effect of Mesenchymal Stem Cell Secretome on Corneal Endothelial Cell Preservation in an Oxidative Injury Model.

Cornea 2020 Nov;39(11):1426-1430

Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL; and.

Purpose: To describe a reproducible oxidative injury model in ex vivo porcine corneas and to investigate the effects of corneal mesenchymal stem cell (Co-MSC) secretome and specific factors on the preservation of corneal endothelium after oxidative injury.

Methods: Porcine corneas underwent vital staining with trypan blue and alizarin red with different concentration and time points. Ex vivo porcine corneas were exposed (endothelial side) to varied concentrations of hydrogen peroxide. After injury, 3 groups of 5 corneas underwent treatment with secretome from either a wild-type (WT) murine Co-MSC, a pigment epithelium derived factor (PEDF) knock out (K/O) murine Co-MSC, or basal media for 4 hours at 37°C. The viability of the endothelium was evaluated using the optimized vital staining protocol.

Results: The optimal vital staining was achieved with 0.4% trypan blue for 60 seconds and 0.5% alizarin red for 90 seconds. The optimal oxidative injury (for consistency and level of damage) was obtained with 1% hydrogen peroxide for 15 seconds. Treatment with both WT Co-MSC and PEDF K/O Co-MSC secretome significantly reduced the endothelial damage compared with control (17.2% ± 10.0%, 33.5% ± 11.6%, and 68% ± 17%, respectively, P < 0.01). The WT Co-MSC secretome was significantly more effective compared with PEDF K/O Co-MSC secretome (P < 0.05).

Conclusions: A reproducible model of vital staining and oxidative injury is described for studying porcine corneal endothelial survival. Our results demonstrate a beneficial role of a corneal MSC secretome in reducing oxidative damage to the corneal endothelium. In addition, it suggests a potential role for PEDF in this process.
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http://dx.doi.org/10.1097/ICO.0000000000002442DOI Listing
November 2020

Bioengineering Approaches for Corneal Regenerative Medicine.

Tissue Eng Regen Med 2020 10 21;17(5):567-593. Epub 2020 Jul 21.

Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, 1200 W Harrison St, Chicago, IL, 60607, USA.

Background: Since the cornea is responsible for transmitting and focusing light into the eye, injury or pathology affecting any layer of the cornea can cause a detrimental effect on visual acuity. Aging is also a reason for corneal degeneration. Depending on the level of the injury, conservative therapies and donor tissue transplantation are the most common treatments for corneal diseases. Not only is there a lack of donor tissue and risk of infection/rejection, but the inherent ability of corneal cells and layers to regenerate has led to research in regenerative approaches and treatments.

Methods: In this review, we first discussed the anatomy of the cornea and the required properties for reconstructing layers of the cornea. Regenerative approaches are divided into two main categories; using direct cell/growth factor delivery or using scaffold-based cell delivery. It is expected delivered cells migrate and integrate into the host tissue and restore its structure and function to restore vision. Growth factor delivery also has shown promising results for corneal surface regeneration. Scaffold-based approaches are categorized based on the type of scaffold, since it has a significant impact on the efficiency of regeneration, into the hydrogel and non-hydrogel based scaffolds. Various types of cells, biomaterials, and techniques are well covered.

Results: The most important characteristics to be considered for biomaterials in corneal regeneration are suitable mechanical properties, biocompatibility, biodegradability, and transparency. Moreover, a curved shape structure and spatial arrangement of the fibrils have been shown to mimic the corneal extracellular matrix for cells and enhance cell differentiation.

Conclusion: Tissue engineering and regenerative medicine approaches showed to have promising outcomes for corneal regeneration. However, besides proper mechanical and optical properties, other factors such as appropriate sterilization method, storage, shelf life and etc. should be taken into account in order to develop an engineered cornea for clinical trials.
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http://dx.doi.org/10.1007/s13770-020-00262-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7373337PMC
October 2020

Reply to Comment on: Management of Congenital Aniridia-Associated Keratopathy: Long-term Outcomes From a Tertiary Referral Center.

Am J Ophthalmol 2020 09 17;217:349-350. Epub 2020 Jul 17.

Chicago, Illinois, USA.

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http://dx.doi.org/10.1016/j.ajo.2020.05.041DOI Listing
September 2020

Update on the pathogenesis and management of ocular rosacea: an interdisciplinary review.

Eur J Ophthalmol 2021 Jan 25;31(1):22-33. Epub 2020 Jun 25.

Department of Ophthalmology, University of Illinois at Chicago, Chicago, IL, USA.

Purpose: Rosacea is one of the most common conditions affecting the ocular surface. The purpose of this review is to provide an update on the pathogenesis and treatment of rosacea based on the dermatology and ophthalmology literatures.

Methods: Literature searches were conducted for rosacea and ocular rosacea. Preference was given to systematic reviews, meta-analysis, case-controlled studies, and documented case reports while excluding poorly documented case studies and commentaries. The data were examined and independently analyzed by more than two of the authors.

Results: Rosacea is a complex inflammatory condition involving the pilosebaceous unit. Its underlying mechanism involves an interplay of the microbiome, innate immunity, adaptive immunity, environmental triggers, and neurovascular sensitivity. The latest classification of rosacea includes three dermatologic subgroups and a fourth subgroup, ocular rosacea. Ocular rosacea clinically displays many features that are analogous to the cutaneous disease, such as lid margin telangiectasia and phlyctenulosis. The role of environmental triggers in the exacerbation of ocular rosacea appears to be understudied. While lid hygiene and systemic treatment with tetracycline drugs remain the mainstay of treatment for ocular rosacea, newer dermatologic targets and therapies may have potential application for the eye disease.

Conclusions: Ocular rosacea appears to embody many of the manifestation of the dermatologic disease. Hence, the basic pathophysiologic mechanisms of the ocular and cutaneous disease are likely to be shared. Better understanding of the ocular surface microbiome and the immunologic mechanisms, may lead to novel approaches in the management of ocular rosacea.
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http://dx.doi.org/10.1177/1120672120937252DOI Listing
January 2021

Therapeutic Effects of Lyophilized Conditioned-Medium Derived from Corneal Mesenchymal Stromal Cells on Corneal Epithelial Wound Healing.

Curr Eye Res 2020 12 14;45(12):1490-1496. Epub 2020 May 14.

Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago , Chicago, Illinois, USA.

: The conditioned-medium derived from corneal mesenchymal stromal cells (cMSCs) has been shown to have wound healing and immunomodulatory effects in corneal injury models. Here, the therapeutic effects of lyophilized cMSC conditioned-medium were compared with fresh conditioned-medium. : The epithelial wound healing effects of fresh and lyophilized cMSC conditioned-medium were compared with conditioned-medium from non-MSC cells (corneal epithelial cells) using scratch assay. To evaluate the anti-inflammatory effects of fresh and lyophilized cMSC conditioned-media, macrophages were stimulated by a Toll-Like Receptor (TLR) ligand followed by treatment with the conditioned-media and measuring the expression of inflammatory genes. wound healing effects of fresh and lyophilized cMSC conditioned-media were assessed in a murine model of cornea epithelial injury. : Both fresh and lyophilized cMSCs-derived conditioned-medium induced significantly faster closure of in vitro epithelial wounds compared to conditioned-medium from non-MSC cells ( < .0001). Treating stimulated macrophages with fresh or lyophilized cMSCs-derived conditioned-media significantly decreased the expression of inflammatory genes compared to control ( < .0001). Murine corneal epithelial wounds were healed by 87.6 ± 2.7% and 86.2 ± 4.6% following treatment with fresh and lyophilized cMSC conditioned-media, respectively, while the control was healed by 64.7 ± 16.8% ( < .05). : Lyophilized cMSC-derived conditioned-medium is as effective as fresh conditioned-medium in promoting wound healing and modulating inflammation. The results of this study support the application of lyophilized cMSCs-derived conditioned-medium, which allows for more extended storage, as a promising non-invasive option in the treatment of corneal wounds.
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http://dx.doi.org/10.1080/02713683.2020.1762227DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7666083PMC
December 2020

Reply to Comment on: Management of Congenital Aniridia-Associated Keratopathy: Long-term Outcomes From a Tertiary Referral Center.

Am J Ophthalmol 2020 06 18;214:197. Epub 2020 Apr 18.

Chicago, Illinois, USA.

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http://dx.doi.org/10.1016/j.ajo.2020.03.001DOI Listing
June 2020

A surgical skills assessment rubric for pterygium surgery.

Ocul Surf 2020 07 25;18(3):494-498. Epub 2020 Feb 25.

Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL, USA.

Purpose: To introduce an assessment tool (rubric) for evaluating ophthalmology residents' competency in pterygium surgery.

Methods: A panel of experienced international surgeons collaborated and developed the rubric. After describing various stages of the procedure, the Dreyfus scale of skill acquisition was used for scoring each stage. After finalizing the rubric, two surgeons independently evaluated 20 masked pterygium surgery videos of 10 residents and scored the videos according to the rubric. The agreement between the scores of them was examined with the intra-class correlation coefficient test.

Results: This rubric divides pterygium surgery into 13 different stages and covers the two most common techniques of pterygium surgery; conjunctival autograft and amniotic membrane transplant. The rubric showed face and content validity. Overall, an intraclass correlation coefficient of 0.90 (95% confidence interval 0.76-0.96, P < 0.001) was achieved between the two surgeons. The residents scored significantly higher on surgeries performed later in their rotation compared to the earlier surgeries (4.32 ± 0.35 vs 3.96 ± 0.31, P = 0.006). Certain stages of pterygium surgery were more strongly correlated with the residents' past pterygium surgical experience.

Conclusion: This study introduces an international rubric for assessing competency in pterygium surgery. In addition to face and content validity, this rubric shows high inter-rater reliability. This may be a useful tool for teaching and measuring competency in pterygium surgery.
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http://dx.doi.org/10.1016/j.jtos.2020.02.004DOI Listing
July 2020

Corrigendum to "A gut connection in mucous membrane pemphigoid: Insights into the role of the microbiome" [Ocul Surf 17 (4) (2019) 615-616].

Ocul Surf 2020 04 13;18(2):349. Epub 2020 Feb 13.

Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL, United States. Electronic address:

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http://dx.doi.org/10.1016/j.jtos.2020.02.002DOI Listing
April 2020

Management of Congenital Aniridia-Associated Keratopathy: Long-Term Outcomes from a Tertiary Referral Center.

Am J Ophthalmol 2020 02 12;210:8-18. Epub 2019 Nov 12.

Department of Ophthalmology and Visual Sciences, Illinois Eye and Ear Infirmary, University of Illinois at Chicago, Chicago, Illinois, USA. Electronic address:

Purpose: To report the outcomes of medical and surgical management for congenital aniridia-associated keratopathy (AAK) over a long-term follow-up period.

Design: Retrospective, comparative case series.

Methods: Medical records of patients diagnosed with congenital aniridia were retrospectively reviewed. Age, sex, ethnicity, follow-up time, AAK stage, noncorneal abnormalities, ocular surgeries, and complications were recorded. The visual acuity equivalent (VAE), approximate Early Treatment Diabetic Retinopathy Study (appETDRS) letter score, was calculated using recorded Snellen visual acuities.

Results: A total of 92 eyes of 47 patients (31 females) with mean age of 48.0 ± 18.0 years and mean follow-up of 78.6 ± 42.2 months were included. At the initial visit, 12 eyes (13%) were classified as Stage I AAK, 33 eyes (35.9%) were Stage II, 25 eyes (27.2%) were Stage III, 17 eyes (18.5%) were Stage IV, and 5 eyes (5.4%) were Stage V. Limbal stem cell transplantation (LSCT) and Boston keratoprosthesis (KPro) were frequently performed in eyes with Stages III-V. These advanced corneal surgeries significantly improved the median (95% confidence interval [CI]) of calculated appETDRS scores from 2 (0-20) to 26 (15-41) (Snellen values, 20/20,000 to 20/300; P = 0.0004). Patients with earlier Stages (I-II) of AAK were managed medically and had stable visual acuity through their final visits (appETDRS score of 26 [20-35] to 35 [26-35]; Snellen, 20/300 to 20/200; P > 0.05). The appETDRS VAE was significantly improved from 20 (0-35) to 30 (20-55), Snellen, 20/400 to 20/250, following LSCT (P = 0.021) and from 2 (0-20) to 2 (0-41) after KPro; Snellen, 20/20,000 VAE but with improved 95% CI after follow-up (P = 0.019).

Conclusions: With proper characterization and staging of AAK, individualized medical and advanced surgical interventions preserves and improves visual acuity.
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http://dx.doi.org/10.1016/j.ajo.2019.11.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6964251PMC
February 2020

Ocular surface involvement in pemphigus vulgaris: An interdisciplinary review.

Ocul Surf 2020 01 12;18(1):40-46. Epub 2019 Oct 12.

Department of Ophthalmology, University of Illinois Health Hospital System, Chicago, IL, USA.

Purpose: A review of the published literature on the history, pathogenesis, and treatment of pemphigus vulgaris (PV) and its ocular involvement.

Methods: Literature searches were conducted in MEDLINE (Ovid), and google scholar for pemphigus vulgaris and ocular PV. Inclusion criteria were given to meta-analysis, case-controlled studies, and documented case reports. The data were examined and independently analyzed by more than two of the authors.

Results: PV is a humoral autoimmune disease with a preponderance of IgG4 anti-desmoglein 3 antibodies. Upon antibody binding, there is an intracellular signaling mechanism that leads to blister formation. Ocular findings are seen in up to 16% of PV patients with conjunctivitis being the most common clinical presentation. New steroid-sparing agents have helped with the control of this deadly disease, and with better understanding of the pathogenesis of PV, other cytokine blockers currently available are promising steroid-sparing agents.

Conclusions: Ocular pemphigus can occasionally present prior to mucocutaneous findings. Recalcitrant conjunctivitis with conjunctival blisters should warrant a workup for systemic PV.
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http://dx.doi.org/10.1016/j.jtos.2019.09.008DOI Listing
January 2020

Facial Nerve Paralysis Due to Spontaneous Intracranial Hypotension.

Ear Nose Throat J 2021 Mar 23;100(3):NP137-NP138. Epub 2019 Sep 23.

Department of Otolaryngology-Head and Neck Surgery, 8788University of California, Irvine, Irvine, CA, USA.

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http://dx.doi.org/10.1177/0145561319864577DOI Listing
March 2021

A gut connection in mucous membrane pemphigoid: Insights into the role of the microbiome.

Ocul Surf 2019 10 18;17(4):615-616. Epub 2019 Sep 18.

Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL, United States. Electronic address:

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http://dx.doi.org/10.1016/j.jtos.2019.09.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6988187PMC
October 2019

Measuring the Impact of our work.

Authors:
Ali R Djalilian

Ocul Surf 2019 07 22;17(3):369. Epub 2019 Jul 22.

University of Illinois at Chicago, United States. Electronic address:

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http://dx.doi.org/10.1016/j.jtos.2019.07.007DOI Listing
July 2019

Amniotic Membrane Transplantation in Acute Severe Ocular Chemical Injury: A Randomized Clinical Trial.

Am J Ophthalmol 2019 09 11;205:203. Epub 2019 Jul 11.

Cincinnati, Ohio.

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http://dx.doi.org/10.1016/j.ajo.2019.05.002DOI Listing
September 2019

Emerging Approaches for Ocular Surface Regeneration.

Curr Ophthalmol Rep 2019 Mar 17;7(1):1-10. Epub 2019 Jan 17.

Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, Illinois, USA.

Purpose Of Review: In this manuscript, the recent advancements and novel approaches for regeneration of the ocular surface are summarized.

Recent Findings: Following severe injuries, persistent inflammation can alter the rehabilitative capability of the ocular surface environment. Limbal stem cell deficiency (LSCD) is one of the most characterized ocular surface disorders mediated by deficiency and/or dysfunction of the limbal epithelial stem cells (LESCs) located in the limbal niche. Currently, the most advanced approach for revitalizing the ocular surface and limbal niche is based on transplantation of limbal tissues harboring LESCs. Emerging approaches have focused on restoring the ocular surface microenvironment using (1) cell-based therapies including cells with capabilities to support the LESCs and modulate the inflammation, e.g., mesenchymal stem cells (MSCs), (2) bio-active extracellular matrices from decellularized tissues, and/or purified/synthetic molecules to regenerate the microenvironment structure, and (3) soluble cytokine/growth factor cocktails to revive the signaling pathways.

Summary: Ocular surface/limbal environment revitalization provide promising approaches for regeneration of the ocular surface.
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http://dx.doi.org/10.1007/s40135-019-00193-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6605053PMC
March 2019

The power of open-mindedness and diversity.

Authors:
Ali R Djalilian

Ocul Surf 2019 04 5;17(2):173. Epub 2019 Apr 5.

University of Illinois at Chicago, United States. Electronic address:

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http://dx.doi.org/10.1016/j.jtos.2019.04.005DOI Listing
April 2019

Staphylococcus aureus alpha-hemolysin impairs corneal epithelial wound healing and promotes intracellular bacterial invasion.

Exp Eye Res 2019 04 27;181:263-270. Epub 2019 Feb 27.

Stem Cell Therapy and Corneal Tissue Engineering Laboratory, Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, 1905 W. Taylor St., L-213, Chicago, IL, 60612, United States. Electronic address:

Colonization by Staphylococcus aureus (S. aureus) has been implicated in many infectious and wound healing disorders. This study was performed to characterize the pathogenic role of S. aureus alpha-hemolysin (alpha-toxin) in corneal epithelial wound healing and infectious keratitis in the setting of a corneal wound. The effect of wild-type and isogenic Hla mutant (α-hemolysin gene deleted) S. aureus bacteria and conditioned media on corneal epithelial wound healing was tested in vitro using a scratch assay and in vivo using a murine epithelial debridement model. The invasiveness of wild-type and Hla mutant S. aureus was evaluated in vitro in human corneal epithelial cells and in vivo in a murine model of infectious keratitis following total epithelial debridement. S. aureus and its conditioned media significantly delayed epithelial wound closure both in vitro (P < 0.05) and in vivo (P < 0.05). The effect of S. aureus on wound healing was significantly diminished with the Hla mutant strain (P < 0.05). Likewise, compared to the wild-type strain, the Hla mutant strain demonstrated significantly reduced ability to invade corneal epithelial cells in vitro (P < 0.05) and infect murine corneas following total epithelial debridement in vivo (P < 0.05). In conclusion, S. aureus alpha-hemolysin plays a major role in the pathologic modulation of corneal epithelial wound healing and the intracellular invasion of the bacteria. Limiting colonization by S. aureus and/or blocking alpha-hemolysin may provide a therapeutic approach for corneal wound healing and infectious disorders.
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http://dx.doi.org/10.1016/j.exer.2019.02.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6447303PMC
April 2019

Corneal Wound Healing Effects of Mesenchymal Stem Cell Secretome Delivered Within a Viscoelastic Gel Carrier.

Stem Cells Transl Med 2019 05 15;8(5):478-489. Epub 2019 Jan 15.

Department of Ophthalmology, Byers Eye Institute at Stanford University School of Medicine, Palo Alto, California, USA.

Severe corneal injuries often result in permanent vision loss and remain a clinical challenge. Human bone marrow-derived mesenchymal stem cells (MSCs) and their secreted factors (secretome) have been studied for their antiscarring, anti-inflammatory, and antiangiogeneic properties. We aimed to deliver lyophilized MSC secretome (MSC-S) within a viscoelastic gel composed of hyaluronic acid (HA) and chondroitin sulfate (CS) as a way to enhance corneal re-epithelialization and reduce complications after mechanical and chemical injuries of the cornea. We hypothesized that delivering MSC-S within HA/CS would have improved wound healing effects compared the with either MSC-S or HA/CS alone. The results showed that a once-daily application of MSC-S in HA/CS enhances epithelial cell proliferation and wound healing after injury to the cornea. It also reduced scar formation, neovascularization, and hemorrhage after alkaline corneal burns. We found that combining MSC-S and HA/CS increased the expression of CD44 receptors colocalized with HA, suggesting that the observed therapeutic effects between the MSC-S and HA/CS are in part mediated by CD44 receptor upregulation and activation by HA. The results from this study demonstrate a reproducible and efficient approach for delivering the MSC-S to the ocular surface for treatment of severe corneal injuries. Stem Cells Translational Medicine 2019;8:478-489.
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http://dx.doi.org/10.1002/sctm.18-0178DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6477005PMC
May 2019

Strategies for reconstructing the limbal stem cell niche.

Ocul Surf 2019 04 8;17(2):230-240. Epub 2019 Jan 8.

Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL, USA. Electronic address:

The epithelial cell layer that covers the surface of the cornea provides a protective barrier while maintaining corneal transparency. The rapid and effective turnover of these epithelial cells depends, in part, on the limbal epithelial stem cells (LESCs) located in a specialized microenvironment known as the limbal niche. Many disorders affecting the regeneration of the corneal epithelium are related to deficiency and/or dysfunction of LESCs and the limbal niche. Current approaches for regenerating the corneal epithelium following significant injuries such as burns and inflammatory attacks are primarily aimed at repopulating the LESCs. This review summarizes and assesses the clinical feasibility and efficacy of current and emerging approaches for reconstruction of the limbal niche. In particular, the application of mesenchymal stem cells along with appropriate biological scaffolds appear to be promising strategies for long-term revitalization of the limbal niche.
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http://dx.doi.org/10.1016/j.jtos.2019.01.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6529262PMC
April 2019

New Year's resolutions for The Ocular Surface journal.

Authors:
Ali R Djalilian

Ocul Surf 2019 01 12;17(1). Epub 2018 Dec 12.

University of Illinois at Chicago, Department of Ophthalmology and Visual Sciences, 1855 W. Taylor Street, EEI, 3164 Chicago, IL 60612, USA. Electronic address:

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http://dx.doi.org/10.1016/j.jtos.2018.12.004DOI Listing
January 2019

Management of advanced ocular surface disease in patients with severe atopic keratoconjunctivitis.

Ocul Surf 2019 04 4;17(2):303-309. Epub 2018 Dec 4.

Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL, USA. Electronic address:

Aim & Objective: Severe ocular surface disease, including limbal stem cell deficiency (LSCD) can occur as a consequence of severe atopic keratoconjunctivitis (AKC) that has been inadequately treated. Our goal was to describe the management and outcomes of severe ocular surface disease in AKC patients.

Methods: We performed a retrospective analysis of a case series of 13 eyes of 8 patients with advanced ocular surface disease associated with severe AKC. The clinical presentation, medical and surgical management, and visual and anatomic outcomes were analyzed.

Results: Five eyes were treated with medical interventions alone, which included topical or systemic immunomodulatory therapy (IMT) for all eyes. These eyes had a decline in mean visual acuity from LogMAR 0.96 to 2.04 between the initial and final visits related to recurrent epithelial defects or corneal ulceration. Eight eyes were treated with surgical approaches in addition to medical treatment. Initial surgical treatments included limbal stem cell transplantation (n = 5), Boston keratoprosthesis (n = 2), and superficial keratectomy (n = 1). Both eyes that underwent primary keratoprosthesis had severe post-operative complications and became no light perception. In the remainder of the surgically treated eyes, there was an improvement visual acuity from LogMAR 1.43 to 0.6 between the pre-operative and final post-operative visit.

Conclusion: Visual rehabilitation in eyes severe ocular surface disease due to prolonged AKC is challenging. While some patients did experience improved vision, most eyes did not improve or experienced severe complications with vision loss. Early intervention with immunomodulatory therapy may prevent progression of the disease to advanced stages.
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http://dx.doi.org/10.1016/j.jtos.2018.12.002DOI Listing
April 2019

New ex vivo model of corneal endothelial phacoemulsification injury and rescue therapy with mesenchymal stromal cell secretome.

J Cataract Refract Surg 2019 03 7;45(3):361-366. Epub 2018 Dec 7.

Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Illinois, USA. Electronic address:

Purpose: To develop a reproducible ex vivo model of corneal endothelial cell injury using phacoemulsification in porcine eyes and to evaluate the effects of mesenchymal stromal cell secretome in this injury model.

Setting: Department of Ophthalmology, University of Illinois at Chicago, Illinois, USA.

Design: Experimental study.

Methods: A corneal endothelial injury model was optimized using different powers and durations of ultrasound energy inside ex vivo porcine eyes. Conditioned media from corneal mesenchymal stem cells was collected under serum-free conditions from passages 4 to 6. Immediately after the phacoemulsification injury, the anterior chamber fluid was replaced with unconditioned media or conditioned media and incubated at 37°C for 4 hours. At the end, endothelial cell viability was evaluated using trypan blue staining and analyzed with ImageJ software.

Results: Using specific parameters (50% power for 30 seconds), phacoemulsification inside fresh porcine eyes led to a consistent level of endothelial cell injury. Incubation with corneal mesenchymal stromal cell-conditioned media after the injury significantly reduced endothelial cells loss compared with unconditioned media (mean 1.29% ± 0.91% [SD] and 5.33% ± 3.24%, respectively, P < .05).

Conclusions: Phacoemulsification inside fresh porcine eyes provided a reproducible model to study endothelial cell injury. Treatment with corneal mesenchymal stromal cell secretome after injury appeared to significantly enhance the survival of corneal endothelial cells. This might provide a new strategy for preventing corneal endothelial cell loss after phacoemulsification or other endothelial injuries. Further in vivo studies are necessary to determine the therapeutic potential.
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http://dx.doi.org/10.1016/j.jcrs.2018.09.030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6409103PMC
March 2019

Amniotic Membrane Transplantation in Acute Severe Ocular Chemical Injury: A Randomized Clinical Trial.

Am J Ophthalmol 2019 03 10;199:209-215. Epub 2018 Nov 10.

Cincinnati Eye Institute, Edgewood, Kentucky, USA; Department of Ophthalmology, University of Cincinnati, Cincinnati, Ohio, USA. Electronic address:

Purpose: To compare the outcomes of conventional medical treatment vs combined medical treatment and amniotic membrane transplantation (AMT) in the management of patients with Roper-Hall grade IV ocular chemical injury.

Design: Randomized, parallel-controlled clinical trial.

Methods: Setting: Single tertiary referral hospital.

Patients: Sixty eyes of 60 patients with Roper-Hall grade IV ocular chemical injury with a minimum follow-up of 12 months were enrolled in the study.

Intervention: Patients were randomly assigned to 2 groups: Group 1 (30 eyes) received topical preservative-free lubricating gel and drops, chloramphenicol, betamethasone, homatropine, oral vitamin C, and doxycycline; Group 2 (30 eyes) received amniotic membrane transplant (AMT) on the entire ocular surface in addition to the medical treatment provided in Group 1.

Outcome Measures: The main outcome measure was time to complete corneal epithelialization. Secondary outcome measures were best-corrected visual acuity (BCVA) and neovascularization in the central 5 mm of the cornea.

Results: Mean follow-up time was 20.3 ± 2.5 months (range 13-24 months). Corneal epithelial defects healed within 72.6 ± 30.4 (21-180) days in Group 1 vs 75.8 ± 29.8 (46-170) days in Group 2 (P = .610). Mean BCVA was 2.06 ± 0.67 (0.4-2.6) logMAR vs 2.06 ± 0.57 (1-2.9) logMAR in Groups 1 and 2, respectively (P = .85). Group 1 developed more central corneal neovascularization (22 eyes; 73.3%) compared to Group 2 (16 eyes; 53.3%); however, it was not statistically significant (P = .108).

Conclusions: In comparison to conventional medical therapy, combined amniotic membrane transplantation and medical therapy does not accelerate corneal epithelialization or affect final visual acuity in severe chemical injuries.
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http://dx.doi.org/10.1016/j.ajo.2018.11.001DOI Listing
March 2019

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

Invest Ophthalmol Vis Sci 2018 10;59(12):5194-5200

Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, Illinois, United States.

Purpose: Mesenchymal 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.

Methods: Corneal 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.

Results: cMSC 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).

Conclusions: Human cMSC exosomes can accelerate corneal epithelial wound healing, and thus, may provide a therapeutic approach for ocular surface injuries.
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http://dx.doi.org/10.1167/iovs.18-24803DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6203220PMC
October 2018

Current and emerging therapies for corneal neovascularization.

Ocul Surf 2018 10 20;16(4):398-414. Epub 2018 Jun 20.

Cincinnati Eye Institute, Edgewood, KY/ University of Cincinnati, Department of Ophthalmology, Cincinnati, OH, USA. Electronic address:

The cornea is unique because of its complete avascularity. Corneal neovascularization (CNV) can result from a variety of etiologies including contact lens wear; corneal infections; and ocular surface diseases due to inflammation, chemical injury, and limbal stem cell deficiency. Management is focused primarily on the etiology and pathophysiology causing the CNV and involves medical and surgical options. Because inflammation is a key factor in the pathophysiology of CNV, corticosteroids and other anti-inflammatory medications remain the mainstay of treatment. Anti-VEGF therapies are gaining popularity to prevent CNV in a number of etiologies. Surgical options including vessel occlusion and ocular surface reconstruction are other options depending on etiology and response to medical therapy. Future therapies should provide more effective treatment options for the management of CNV.
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http://dx.doi.org/10.1016/j.jtos.2018.06.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6461401PMC
October 2018

Cornea-Derived Mesenchymal Stromal Cells Therapeutically Modulate Macrophage Immunophenotype and Angiogenic Function.

Stem Cells 2018 05 27;36(5):775-784. Epub 2018 Jan 27.

Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, Illinois, USA.

Macrophages are crucial drivers of inflammatory corneal neovascularization and thus are potential targets for immunomodulatory therapies. We hypothesized that therapeutic use of cornea-derived mesenchymal stromal cells (cMSCs) may alter the function of macrophages. We found that cMSCs can modulate the phenotype and angiogenic function of macrophages. In vitro, cMSCs induce apoptosis of macrophages while preferentially promoting a distinct CD14 CD16 CD163 CD206 immunophenotype that has significantly reduced angiogenic effects based on in vitro angiogenesis assays. In vivo, application of cMSCs to murine corneas after injury leads to reduced macrophage infiltration and higher expression of CD206 in macrophages. Macrophages cocultured ("educated") by cMSCs express significantly higher levels of anti-angiogenic and anti-inflammatory factors compared with control macrophages. In vivo, injured corneas treated with cMSC-educated macrophages demonstrate significantly less neovascularization compared with corneas treated with control macrophages. Knocking down the expression of pigment epithelial derived factor (PEDF) in cMSCs significantly abrogates its modulating effects on macrophages, as shown by the reduced rate of apoptosis, decreased expression of sFLT-1/PEDF, and increased expression of vascular endothelial growth factor-A in the cocultured macrophages. Similarly, cMSCs isolated from PEDF knockout mice are less effective compared with wild-type cMSCs at inhibiting macrophage infiltration when applied to wild-type corneas after injury. Overall, these results demonstrate that cMSCs therapeutically suppress the angiogenic capacity of macrophages and highlight the role of cMSC secreted PEDF in the modulation of macrophage phenotype and function. Stem Cells 2018;36:775-784.
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http://dx.doi.org/10.1002/stem.2781DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5918156PMC
May 2018

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

Invest Ophthalmol Vis Sci 2017 10;58(12):5507-5517

Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, Illinois, United States.

Purpose: To evaluate the angiogenic properties of corneal derived mesenchymal stromal cells (Co-MSC).

Methods: Co-MSCs were extracted from human cadaver, and wild-type (C57BL/6J) and SERPINF1-/- mice corneas. The MSC secretome was collected in a serum-free medium. Human umbilical vein endothelial cell (HUVEC) tube formation and fibrin gel bead assay (FIBA) sprout formation were used to assess the angiogenic properties of Co-MSC secretome. Complete corneal epithelial debridement was used to induce corneal neovascularization in wild-type mice. Co-MSCs embedded in fibrin gel was applied over the debrided cornea to evaluate the angiogenic effects of Co-MSCs in vivo. Immunoprecipitation was used to remove soluble fms-like tyrosine kinase-1 (sFLT-1) and pigment epithelium-derived factor (PEDF, SERPINF1 gene) from the Co-MSC secretome.

Results: Co-MSC secretome significantly inhibited HUVECs tube and sprout formation. Co-MSCs from different donors consistently contained high levels of antiangiogenic factors including sFLT-1 and PEDF; and low levels of the angiogenic factor VEGF-A. In vivo, application of Co-MSCs to mouse corneas after injury prevented the development of corneal neovascularization. Removing PEDF or sFLT-1 from the secretome significantly diminished the antiangiogenic effects of Co-MSCs. Co-MSCs isolated from SERPINF1-/- mice had significantly reduced antiangiogenic effects compared to SERPINF1+/+ (wild-type) Co-MSCs.

Conclusions: These results illustrate the direct antiangiogenic properties of Co-MSCs, the importance of sFLT-1 and PEDF, and their potential clinical application for preventing pathologic corneal neovascularization.
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http://dx.doi.org/10.1167/iovs.17-22680DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5661382PMC
October 2017