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Faircloth TU, Temple S, Parr R, Soma A, Massoumi H, Jalilian E, Djalilian AR, Hematti P, Rajan D, Chinnadurai R. Human cornea-derived mesenchymal stromal cells inhibit T cells through indoleamine 2,3 dioxygenase. Cytotherapy 2025; 27:597-608. [PMID: 39891632 PMCID: PMC12097958 DOI: 10.1016/j.jcyt.2025.01.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2024] [Revised: 01/15/2025] [Accepted: 01/15/2025] [Indexed: 02/03/2025]
Abstract
Defining the mechanism of immune modulation by mesenchymal stromal cells (MSCs) from distinct anatomical tissues is of great translational interest. The human cornea is an immunologically privileged organ, and the mechanism of immunoregulation of cornea-derived MSCs (cMSCs) is currently unknown. We investigated cMSCs derived from the corneas of 5 independent human donorS for their fitness and mechanism of action in suppressing T cells. cMSCs display the immunophenotype CD45-CD73+CD105+CD90+CD44+ and robust in vitro growth. 30-plex secretome analysis identified that cMSCs innately secrete specific molecules in a dose-dependent manner. cMSCs do not express or upregulate costimulatory but do upregulate coinhibitory molecules upon stimulation with interferon γ (IFNγ). cMSCs inhibit T-cell proliferation in contact-dependent co-cultures, which can be predicted by a unique secretome signature. In addition, co-culturing in a 2-chamber transwell system has demonstrated that cMSCs also inhibit T-cell proliferation in a non-contact-dependent manner. Mechanistic analysis has demonstrated that activated T cells effectively induce indoleamine 2,3-dioxygenase (IDO) but not other enzymes of the tryptophan metabolic pathway in cMSCs. Silencing of IDO in cMSCs reduces their fitness to suppress T cells. These results provide evidence that in cMSCs, one of the principal mechanisms of immunosuppression on T cells is through IDO. These results suggest that MSCs derived from the human cornea display immunoregulatory properties and, thus, may play a role in maintaining the immune-privileged niche of the cornea.
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Affiliation(s)
- Tyler U Faircloth
- Department of Biomedical Sciences, Mercer University School of Medicine, Savannah, Georgia, USA
| | - Sara Temple
- Department of Biomedical Sciences, Mercer University School of Medicine, Savannah, Georgia, USA
| | - Rhett Parr
- Department of Biomedical Sciences, Mercer University School of Medicine, Savannah, Georgia, USA
| | - Alyssa Soma
- Department of Biomedical Sciences, Mercer University School of Medicine, Savannah, Georgia, USA
| | - Hamed Massoumi
- Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Elmira Jalilian
- Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Ali R Djalilian
- Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Peiman Hematti
- Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Devi Rajan
- Department of Biomedical Sciences, Mercer University School of Medicine, Savannah, Georgia, USA
| | - Raghavan Chinnadurai
- Department of Biomedical Sciences, Mercer University School of Medicine, Savannah, Georgia, USA.
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Wang J, Rabiee B, Patel C, Jafri M, Hussain H, Chaudhry A, Chaudhry I, Kamoun L, Chaudhry I, Oh L, Bobat FI, Shukla D, Farooq AV. Herpesvirus Infections of the Corneal Endothelium. Microorganisms 2025; 13:778. [PMID: 40284615 PMCID: PMC12029634 DOI: 10.3390/microorganisms13040778] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2024] [Revised: 02/24/2025] [Accepted: 03/11/2025] [Indexed: 04/29/2025] Open
Abstract
Corneal endotheliitis is an inflammatory process, most commonly of viral etiology, that manifests clinically with features including corneal edema, keratic precipitates, and a mild anterior chamber reaction. Several studies have implicated human herpesviruses from the Herpesviridae family as primary causes of corneal endotheliitis, including cytomegalovirus (CMV), varicella zoster virus (VZV), and herpes simplex viruses 1 and 2 (HSV-1 and HSV-2). This review critically evaluates the present literature surrounding herpesvirus infections of the corneal endothelium.
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Affiliation(s)
- Jessie Wang
- Duke Eye Center, Duke University, Durham, NC 27705, USA;
| | - Behnam Rabiee
- Department of Ophthalmology, Nazareth Hospital, Trinity Health Mid-Atlantic, Philadelphia, PA 19152, USA; (B.R.); (C.P.); (A.C.); (I.C.); (L.K.); (I.C.)
- IC Laser Eye Care, Bensalem, PA 19020, USA; (M.J.); (H.H.)
| | - Chandani Patel
- Department of Ophthalmology, Nazareth Hospital, Trinity Health Mid-Atlantic, Philadelphia, PA 19152, USA; (B.R.); (C.P.); (A.C.); (I.C.); (L.K.); (I.C.)
- IC Laser Eye Care, Bensalem, PA 19020, USA; (M.J.); (H.H.)
- Rowan-Virtua School of Osteopathic Medicine, Rowan University, Stratford, NJ 08084, USA
| | - Mansab Jafri
- IC Laser Eye Care, Bensalem, PA 19020, USA; (M.J.); (H.H.)
| | - Hamad Hussain
- IC Laser Eye Care, Bensalem, PA 19020, USA; (M.J.); (H.H.)
| | - Aaila Chaudhry
- Department of Ophthalmology, Nazareth Hospital, Trinity Health Mid-Atlantic, Philadelphia, PA 19152, USA; (B.R.); (C.P.); (A.C.); (I.C.); (L.K.); (I.C.)
- IC Laser Eye Care, Bensalem, PA 19020, USA; (M.J.); (H.H.)
| | - Imtiaz Chaudhry
- Department of Ophthalmology, Nazareth Hospital, Trinity Health Mid-Atlantic, Philadelphia, PA 19152, USA; (B.R.); (C.P.); (A.C.); (I.C.); (L.K.); (I.C.)
- IC Laser Eye Care, Bensalem, PA 19020, USA; (M.J.); (H.H.)
| | - Layla Kamoun
- Department of Ophthalmology, Nazareth Hospital, Trinity Health Mid-Atlantic, Philadelphia, PA 19152, USA; (B.R.); (C.P.); (A.C.); (I.C.); (L.K.); (I.C.)
- IC Laser Eye Care, Bensalem, PA 19020, USA; (M.J.); (H.H.)
| | - Iftikhar Chaudhry
- Department of Ophthalmology, Nazareth Hospital, Trinity Health Mid-Atlantic, Philadelphia, PA 19152, USA; (B.R.); (C.P.); (A.C.); (I.C.); (L.K.); (I.C.)
- IC Laser Eye Care, Bensalem, PA 19020, USA; (M.J.); (H.H.)
| | - Lewis Oh
- Pritzker School of Medicine, The University of Chicago, Chicago, IL 60637, USA;
| | - Fatima I. Bobat
- Department of Ophthalmology and Visual Sciences, The University of Illinois Chicago, Chicago, IL 60607, USA; (F.I.B.); (D.S.)
| | - Deepak Shukla
- Department of Ophthalmology and Visual Sciences, The University of Illinois Chicago, Chicago, IL 60607, USA; (F.I.B.); (D.S.)
| | - Asim V. Farooq
- Department of Ophthalmology and Visual Science, The University of Chicago, Chicago, IL 60637, USA
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Chen K, Xu WY, Sun SS, Zhou HW. Corneal endothelial cells and acoustic cavitation in phacoemulsification. World J Clin Cases 2023; 11:1712-1718. [PMID: 36969995 PMCID: PMC10037277 DOI: 10.12998/wjcc.v11.i8.1712] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Revised: 01/14/2023] [Accepted: 02/22/2023] [Indexed: 03/07/2023] Open
Abstract
Postoperative complications of phacoemulsification, such as corneal edema caused by human corneal endothelial cell (CEC) injury, are still a matter of concern. Although several factors are known to cause CEC damage, the influence of ultrasound on the formation of free radicals during surgery should be considered. Ultrasound in aqueous humor induces cavitation and promotes the formation of hydroxyl radicals or reactive oxygen species (ROS). ROS-induced apoptosis and autophagy in phacoemulsification have been suggested to significantly promote CEC injury. CEC cannot regenerate after injury, and measures must be taken to prevent the loss of CEC after phacoemulsification or other CEC injuries. Antioxidants can reduce the oxidative stress injury of CEC during phacoemulsification. Evidence from rabbit eye studies shows that ascorbic acid infusion during operation or local application of ascorbic acid during phacoemulsification has a protective effect by scavenging free radicals or reducing oxidative stress. Both in experiments and clinical practice, hydrogen dissolved in the irrigating solution can also prevent CEC damage during phacoemulsification surgery. Astaxanthin (AST) can inhibit oxidative damage, thereby protecting different cells from most pathological conditions, such as myocardial cells, luteinized granulosa cells of the ovary, umbilical vascular endothelial cells, and human retina pigment epithelium cell line (ARPE-19). However, existing research has not focused on the application of AST to prevent oxidative stress during phacoemulsification, and the related mechanisms need to be studied. The Rho related helical coil kinase inhibitor Y-27632 can inhibit CEC apoptosis after phacoemulsification. Rigorous experiments are required to confirm whether its effect is realized through improving the ROS clearance ability of CEC.
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Affiliation(s)
- Kai Chen
- Department of Ophthalmology, Lianshui County People's Hospital, Huai’an 223400, Jiangsu Province, China
| | - Wen-Ya Xu
- Department of Ophthalmology, Lianshui County People's Hospital, Huai’an 223400, Jiangsu Province, China
| | - Si-Si Sun
- Department of Ophthalmology, Lianshui County People's Hospital, Huai’an 223400, Jiangsu Province, China
| | - Hong-Wei Zhou
- Department of Ophthalmology, Huai’an 82 Hospital, Huai'an 223001, Jiangsu Province, China
- Department of Industrial Engineering, Tsinghua University, Beijing 100084, China
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The Effect of Mesenchymal Stem Cell Secretome on Corneal Endothelial Cell Preservation in an Oxidative Injury Model. Cornea 2021; 39:1426-1430. [PMID: 32732699 DOI: 10.1097/ico.0000000000002442] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
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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Harman RM, Marx C, Van de Walle GR. Translational Animal Models Provide Insight Into Mesenchymal Stromal Cell (MSC) Secretome Therapy. Front Cell Dev Biol 2021; 9:654885. [PMID: 33869217 PMCID: PMC8044970 DOI: 10.3389/fcell.2021.654885] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2021] [Accepted: 03/01/2021] [Indexed: 12/13/2022] Open
Abstract
The therapeutic potential of the mesenchymal stromal cell (MSC) secretome, consisting of all molecules secreted by MSCs, is intensively studied. MSCs can be readily isolated, expanded, and manipulated in culture, and few people argue with the ethics of their collection. Despite promising pre-clinical studies, most MSC secretome-based therapies have not been implemented in human medicine, in part because the complexity of bioactive factors secreted by MSCs is not completely understood. In addition, the MSC secretome is variable, influenced by individual donor, tissue source of origin, culture conditions, and passage. An increased understanding of the factors that make up the secretome and the ability to manipulate MSCs to consistently secrete factors of biologic importance will improve MSC therapy. To aid in this goal, we can draw from the wealth of information available on secreted factors from MSC isolated from veterinary species. These translational animal models will inspire efforts to move human MSC secretome therapy from bench to bedside.
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Affiliation(s)
| | | | - Gerlinde R. Van de Walle
- Baker Institute for Animal Health, College of Veterinary Medicine, Cornell University, Ithaca, NY, United States
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Guo Q, He J, Zhang H, Yao L, Li H. Oleanolic acid alleviates oxidative stress in Alzheimer's disease by regulating stanniocalcin-1 and uncoupling protein-2 signalling. Clin Exp Pharmacol Physiol 2020; 47:1263-1271. [PMID: 32100892 DOI: 10.1111/1440-1681.13292] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2019] [Revised: 02/21/2020] [Accepted: 02/22/2020] [Indexed: 12/12/2022]
Abstract
Oxidative stress is thought to play an important role in the occurrence and development of Alzheimer's disease (AD) and antioxidants may delay or even treat AD. Oleanolic acid (OA) exhibits antioxidant properties against many diseases. However, its effects on oxidative stress in AD remain unclear. Here, we explored the role and mechanism of action of OA in N2a/APP695swe cells exposed to oxidative stress. The cells were incubated with different concentrations of OA (0, 5, 8, 10, 15, and 25 μmol/L) for 24 hours. Higher concentrations of OA (10, 15, and 25 μmol/L) significantly suppressed the apoptosis, caspase-3 activity, reactive oxygen species level, and β amyloid (Aβ) content and increased the viability of these cells. OA (10 μmol/L) also increased the expression of stanniocalcin-1 (STC-1) and uncoupling protein-2 (UCP2) in N2a/APP695swe cells. STC-1 interference markedly reversed the effect of OA on UCP2, indicating that OA may regulate UCP2 expression in N2a/APP695swe cells via STC-1. Moreover, UCP2 inhibition significantly reversed the OA-mediated effects on cell viability, caspase-3 activity, reactive oxygen species, and Aβ level. Thus, OA regulates UCP2 expression via STC-1 to alleviate oxidative stress and Aβ level in N2a/APP695swe cells.
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Affiliation(s)
- Qiang Guo
- Department of Neurology, Xidian Group Hospital, Xi'an, China
| | - Jianbo He
- Department of Neurology, Xidian Group Hospital, Xi'an, China
| | - Heng Zhang
- Department of Neurology, Xidian Group Hospital, Xi'an, China
| | - Li Yao
- Department of Neurology, Xidian Group Hospital, Xi'an, China
| | - Huiqi Li
- Department of Neurology, Xidian Group Hospital, Xi'an, China
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7
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Hsueh YJ, Meir YJJ, Lai JY, Chen HC, Ma DHK, Huang CC, Lu TT, Cheng CM, Wu WC. Lysophosphatidic acid improves corneal endothelial density in tissue culture by stimulating stromal secretion of interleukin-1β. J Cell Mol Med 2020; 24:6596-6608. [PMID: 32333497 PMCID: PMC7299697 DOI: 10.1111/jcmm.15307] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2019] [Revised: 02/10/2020] [Accepted: 04/05/2020] [Indexed: 12/13/2022] Open
Abstract
The short supply of donor corneas is exacerbated by the unsuitability of donors with insufficient endothelial cell density. Few studies have investigated promoting corneal endothelial cell proliferation to increase the endothelial cell density. We hypothesize that pre‐transplantation treatment of proliferative tissue‐cultivated corneas may increase corneal endothelial cell density. We observed that the airlift cultures were superior to immersion cultures with respect to both transparency and thickness. In this tissue culture system, we observed that lysophosphatidic acid increased the rabbit corneal endothelial cell density, number of BrdU‐positive cells and improve wound healing. We also observed an indirect effect of lysophosphatidic acid on corneal endothelial cell proliferation mediated by the stimulation of interleukin‐1β secretion from stromal cells. Human corneal tissues treated with lysophosphatidic acid or interleukin‐1β contained significantly more Ki‐67‐positive cells than untreated group. The lysophosphatidic acid‐ or interleukin‐1β‐treated cultured tissue remained hexagon‐shaped, with ZO‐1 expression and no evidence of the endothelial‐mesenchymal transition. Our novel protocol of tissue culture may be applicable for eye banks to optimize corneal grafting.
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Affiliation(s)
- Yi-Jen Hsueh
- Department of Ophthalmology, Chang Gung Memorial Hospital, Linkou, Taiwan.,Center for Tissue Engineering, Chang Gung Memorial Hospital, Linkou, Taiwan
| | - Yaa-Jyuhn James Meir
- Center for Tissue Engineering, Chang Gung Memorial Hospital, Linkou, Taiwan.,Department of Biomedical Sciences, Chang Gung University, Taoyuan, Taiwan
| | - Jui-Yang Lai
- Institute of Biochemical and Biomedical Engineering, Chang Gung University, Taoyuan, Taiwan.,Department of Materials Engineering, Ming Chi University of Technology, New Taipei City, Taiwan
| | - Hung-Chi Chen
- Department of Ophthalmology, Chang Gung Memorial Hospital, Linkou, Taiwan.,Center for Tissue Engineering, Chang Gung Memorial Hospital, Linkou, Taiwan.,Department of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - David Hui-Kang Ma
- Department of Ophthalmology, Chang Gung Memorial Hospital, Linkou, Taiwan.,Center for Tissue Engineering, Chang Gung Memorial Hospital, Linkou, Taiwan.,Department of Chinese Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Chieh-Cheng Huang
- Center for Tissue Engineering, Chang Gung Memorial Hospital, Linkou, Taiwan.,Institute of Biomedical Engineering, National Tsing Hua University, Hsinchu, Taiwan
| | - Tsai-Te Lu
- Center for Tissue Engineering, Chang Gung Memorial Hospital, Linkou, Taiwan.,Institute of Biomedical Engineering, National Tsing Hua University, Hsinchu, Taiwan
| | - Chao-Min Cheng
- Center for Tissue Engineering, Chang Gung Memorial Hospital, Linkou, Taiwan.,Institute of Biomedical Engineering, National Tsing Hua University, Hsinchu, Taiwan
| | - Wei-Chi Wu
- Department of Ophthalmology, Chang Gung Memorial Hospital, Linkou, Taiwan.,Department of Medicine, Chang Gung University, Taoyuan, Taiwan
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Kunzmann BC, Wenzel DA, Bartz‐Schmidt KU, Spitzer MS, Schultheiss M. Effects of ultrasound energy on the porcine corneal endothelium - Establishment of a phacoemulsification damage model. Acta Ophthalmol 2020; 98:e155-e160. [PMID: 31469490 DOI: 10.1111/aos.14235] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2019] [Accepted: 08/07/2019] [Indexed: 11/26/2022]
Abstract
PURPOSE The purpose of this study was to establish a standardized in vitro phacoemulsification damage model for future investigations of the effects of phacoemulsification, surgical devices, protective ophthalmic viscoelastic devices (OVDs), irrigation solutions and other aspects related to cataract phacoemulsification surgery on the corneal endothelium using porcine eyes. METHODS Thirty-four porcine eyes were randomly assigned to three groups (phacoemulsification (n = 13), irrigation (n = 9), control (n = 12)). A total of 5 min of ultrasound energy with intermittent irrigation/aspiration was applied in the eyes of the phacoemulsification group. The eyes of the irrigation group received the identical treatment, but without the application of ultrasound energy. The control group was left untreated. All eyes were then prepared to split corneal buttons followed by 15 days of cultivation. Endothelial cell density (ECD) was assessed blinded on day 15. RESULTS Endothelial cell density declined significantly more until day 15 in the phacoemulsification group (2567 ± 317/267 cells/mm² (median ± 25%/75%-quartiles), -32.5 ± 7.0/6.4%) compared to the irrigation (3450 ± 350/383 cells/mm², -11.8 ± 5.3/2.6%; p < 0.001) and the control group (3650 ± 288/258 cells/mm², -10.2 ± 3.2/4.6%; p < 0.001). CONCLUSION The phacoemulsification damage model presented in this study is sensitive to phacoemulsification energy and may reliably be used to investigate various factors involved in phacoemulsification with regard to their influence on corneal endothelial cells. This method is able to replace animal experiments or in vitro cell culture experiments that often do not translate well to the in vivo situation in humans.
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Affiliation(s)
- Berenike C. Kunzmann
- University Eye Hospital Centre for Ophthalmology University Hospital Tübingen Tübingen Germany
| | - Daniel A. Wenzel
- Department of Ophthalmology University Medical Center Hamburg‐Eppendorf (UKE) Hamburg Germany
| | - Karl U. Bartz‐Schmidt
- University Eye Hospital Centre for Ophthalmology University Hospital Tübingen Tübingen Germany
| | - Martin S. Spitzer
- Department of Ophthalmology University Medical Center Hamburg‐Eppendorf (UKE) Hamburg Germany
| | - Maximilian Schultheiss
- Department of Ophthalmology University Medical Center Hamburg‐Eppendorf (UKE) Hamburg Germany
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