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Surico PL, Barone V, Singh RB, Coassin M, Blanco T, Dohlman TH, Basu S, Chauhan SK, Dana R, Di Zazzo A. Potential applications of mesenchymal stem cells in ocular surface immune-mediated disorders. Surv Ophthalmol 2025; 70:467-479. [PMID: 39097173 DOI: 10.1016/j.survophthal.2024.07.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2024] [Revised: 07/29/2024] [Accepted: 07/29/2024] [Indexed: 08/05/2024]
Abstract
We explore the interaction between corneal immunity and mesenchymal stem/stromal cells (MSCs) and their potential in treating corneal and ocular surface disorders. We outline the cornea's immune privilege mechanisms and the immunomodulatory substances involved. In this realm, MSCs are characterized by their immunomodulatory properties and regenerative potential, making them promising for therapeutic application. Therefore, we focus on the role of MSCs in immune-mediated corneal diseases such as dry eye disease, corneal transplantation rejection, limbal stem cell deficiency, and ocular graft-versus-host disease. Preclinical and clinical studies demonstrate MSCs' efficacy in promoting corneal healing and reducing inflammation in these conditions. Overall, we emphasize the potential of MSCs as innovative therapies in ophthalmology, offering promising solutions for managing various ocular surface pathologies.
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Affiliation(s)
- Pier Luigi Surico
- Schepens Eye Research Institute of Massachusetts Eye and Ear, Harvard Medical School, Boston, MA 02114, USA; Department of Ophthalmology, Campus Bio-Medico University Hospital, Rome 00128, Italy; Cornea Rare Diseases Center, Fondazione Policlinico Campus Bio-Medico, Rome 00128, Italy
| | - Vincenzo Barone
- Department of Ophthalmology, Campus Bio-Medico University Hospital, Rome 00128, Italy; Cornea Rare Diseases Center, Fondazione Policlinico Campus Bio-Medico, Rome 00128, Italy
| | - Rohan Bir Singh
- Schepens Eye Research Institute of Massachusetts Eye and Ear, Harvard Medical School, Boston, MA 02114, USA
| | - Marco Coassin
- Department of Ophthalmology, Campus Bio-Medico University Hospital, Rome 00128, Italy; Cornea Rare Diseases Center, Fondazione Policlinico Campus Bio-Medico, Rome 00128, Italy
| | - Tomas Blanco
- Schepens Eye Research Institute of Massachusetts Eye and Ear, Harvard Medical School, Boston, MA 02114, USA
| | - Thomas H Dohlman
- Schepens Eye Research Institute of Massachusetts Eye and Ear, Harvard Medical School, Boston, MA 02114, USA
| | - Sayan Basu
- Brien Holden Eye Research Centre (BHERC), L. V. Prasad Eye Institute, Hyderabad, Telangana, India
| | - Sunil K Chauhan
- Schepens Eye Research Institute of Massachusetts Eye and Ear, Harvard Medical School, Boston, MA 02114, USA
| | - Reza Dana
- Schepens Eye Research Institute of Massachusetts Eye and Ear, Harvard Medical School, Boston, MA 02114, USA
| | - Antonio Di Zazzo
- Department of Ophthalmology, Campus Bio-Medico University Hospital, Rome 00128, Italy; Cornea Rare Diseases Center, Fondazione Policlinico Campus Bio-Medico, Rome 00128, Italy.
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Qi Q, Su D, Zhuang S, Yao S, Heindl LM, Fan X, Lin M, Li J, Pang Y. Progress in Nanotechnology for Treating Ocular Surface Chemical Injuries: Reflecting on Advances in Ophthalmology. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2407340. [PMID: 39755928 PMCID: PMC11809354 DOI: 10.1002/advs.202407340] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/02/2024] [Revised: 11/26/2024] [Indexed: 01/06/2025]
Abstract
Ocular surface chemical injuries often result in permanent visual impairment and necessitate complex, long-term treatments. Immediate and extensive irrigation serves as the first-line intervention, followed by various therapeutic protocols applied throughout different stages of the condition. To optimize outcomes, conventional regimens increasingly incorporate biological agents and surgical techniques. In recent years, nanotechnology has made significant strides, revolutionizing the management of ocular surface chemical injuries by enabling sustained drug release, enhancing treatment efficacy, and minimizing side effects. This review provides a comprehensive analysis of the etiology, epidemiology, classification, and conventional therapies for ocular chemical burns, with a special focus on nanotechnology-based drug delivery systems in managing ocular surface chemical injuries. Twelve categories of nanocarrier platforms are examined, including liposomes, nanoemulsions, nanomicelles, nanowafers, nanostructured lipid carriers, nanoparticles, hydrogels, dendrimers, nanocomplexes, nanofibers, nanozymes, and nanocomposite materials, highlighting their advantages in targeted delivery, biocompatibility, and improved healing efficacy. Additionally, current challenges and limitations in the field are discussed and the future potential of nanotechnology in treating ocular diseases is explored. This review presents the most extensive examination of this topic to date, aiming to link recent advancements with broader therapeutic strategies.
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Affiliation(s)
- Qiaoran Qi
- Department of OphthalmologyNinth People's HospitalShanghai Jiao Tong University School of MedicineShanghai200011China
- Shanghai Key Laboratory of Orbital Diseases and Ocular OncologyCenter for Basic Medical Research and Innovation in Visual System DiseasesMinistry of EducationShanghai200011China
| | - Dai Su
- Department of OphthalmologyNinth People's HospitalShanghai Jiao Tong University School of MedicineShanghai200011China
- Shanghai Key Laboratory of Orbital Diseases and Ocular OncologyCenter for Basic Medical Research and Innovation in Visual System DiseasesMinistry of EducationShanghai200011China
| | - Shuqin Zhuang
- Department of OphthalmologyNinth People's HospitalShanghai Jiao Tong University School of MedicineShanghai200011China
- Shanghai Key Laboratory of Orbital Diseases and Ocular OncologyCenter for Basic Medical Research and Innovation in Visual System DiseasesMinistry of EducationShanghai200011China
| | - Sunyuan Yao
- Department of OphthalmologyNinth People's HospitalShanghai Jiao Tong University School of MedicineShanghai200011China
- Shanghai Key Laboratory of Orbital Diseases and Ocular OncologyCenter for Basic Medical Research and Innovation in Visual System DiseasesMinistry of EducationShanghai200011China
| | - Ludwig M. Heindl
- Department of OphthalmologyFaculty of Medicine and University Hospital CologneUniversity of Cologne50937CologneGermany
- Center for Integrated Oncology (CIO)Aachen‐Bonn‐Cologne‐DuesseldorfCologneGermany
| | - Xianqun Fan
- Department of OphthalmologyNinth People's HospitalShanghai Jiao Tong University School of MedicineShanghai200011China
- Shanghai Key Laboratory of Orbital Diseases and Ocular OncologyCenter for Basic Medical Research and Innovation in Visual System DiseasesMinistry of EducationShanghai200011China
| | - Ming Lin
- Department of OphthalmologyNinth People's HospitalShanghai Jiao Tong University School of MedicineShanghai200011China
- Shanghai Key Laboratory of Orbital Diseases and Ocular OncologyCenter for Basic Medical Research and Innovation in Visual System DiseasesMinistry of EducationShanghai200011China
| | - Jin Li
- Department of OphthalmologyNinth People's HospitalShanghai Jiao Tong University School of MedicineShanghai200011China
- Shanghai Key Laboratory of Orbital Diseases and Ocular OncologyCenter for Basic Medical Research and Innovation in Visual System DiseasesMinistry of EducationShanghai200011China
| | - Yan Pang
- Department of OphthalmologyNinth People's HospitalShanghai Jiao Tong University School of MedicineShanghai200011China
- Shanghai Key Laboratory of Orbital Diseases and Ocular OncologyCenter for Basic Medical Research and Innovation in Visual System DiseasesMinistry of EducationShanghai200011China
- Shanghai Frontiers Science Center of Drug Target Identification and DeliverySchool of Pharmaceutical SciencesShanghai Jiao Tong UniversityShanghai200240China
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De Miguel MP, Cadenas-Martin M, Stokking M, Martin-Gonzalez AI. Biomedical Application of MSCs in Corneal Regeneration and Repair. Int J Mol Sci 2025; 26:695. [PMID: 39859409 PMCID: PMC11766311 DOI: 10.3390/ijms26020695] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2024] [Revised: 01/10/2025] [Accepted: 01/11/2025] [Indexed: 01/27/2025] Open
Abstract
The World Health Organization estimates that approximately 285 million people suffer from visual impairments, around 5% of which are caused by corneal pathologies. Currently, the most common clinical treatment consists of a corneal transplant (keratoplasty) from a human donor. However, worldwide demand for donor corneas amply exceeds the available supply. Lamellar keratoplasty (transplantation replacement of only one of the three layers of the cornea) is partially solving the problem of cornea undersupply. Obviously, cell therapy applied to every one of these layers will expand current therapeutic options, reducing the cost of ophthalmological interventions and increasing the effectiveness of surgery. Mesenchymal stem cells (MSCs) are adult stem cells with the capacity for self-renewal and differentiation into different cell lineages. They can be obtained from many human tissues, such as bone marrow, umbilical cord, adipose tissue, dental pulp, skin, and cornea. Their ease of collection and advantages over embryonic stem cells or induced pluripotent stem cells make them a very practical source for experimental and potential clinical applications. In this review, we focus on recent advances using MSCs from different sources to replace the damaged cells of the three corneal layers, at both the preclinical and clinical levels for specific corneal diseases.
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Affiliation(s)
- Maria P. De Miguel
- Cell Engineering Laboratory, La Paz University Hospital Health Research Institute, IdiPAZ, 28046 Madrid, Spain; (M.C.-M.); (M.S.); (A.I.M.-G.)
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Genna VG, Maurizi E, Rama P, Pellegrini G. Biology and medicine on ocular surface restoration: Advancements and limits of limbal stem cell deficiency treatments. Ocul Surf 2025; 35:57-67. [PMID: 39580144 DOI: 10.1016/j.jtos.2024.11.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2024] [Revised: 11/08/2024] [Accepted: 11/13/2024] [Indexed: 11/25/2024]
Abstract
Ocular vision can be hampered by corneal damages, sensibly reducing patients' quality of life and having important social and economic consequences. Ocular surface diseases, which often lead to corneal opacities with visual impairment are the most severe forms of the Limbal Stem Cell Deficiency (LSCD). The present review provides an updated perspective on the available treatments for LSCD, focusing on clinical and biological features, as well as critical points to monitor during clinical translation. Recently developed surgical treatments for LSCD are described, along with their benefits and limitations, with the aim of addressing the issue of correct patient selection. Autologous surgical approaches have been attempted, such as conjunctival limbal autograft (CLAU), simple limbal epithelial transplantation (SLET), and others. Allogeneic limbal stem cell transplantation represents an alternative but carries risk of rejection and requires immunosuppression. Other potential treatments are based on induced pluripotent stem cells (iPSCs), but they require further investigation. The development of advanced therapy medicinal products (ATMPs) such as cultivated limbal epithelial transplantation (CLET), or the use of other epithelia as cultivated oral mucosal epithelial cell transplantation (COMET), has opened additional therapeutic possibilities. Some common critical issues in clinical translation are described, such as patient selection, biopsy procurement, or the use of human/animal derived components, which require rigorous validation to ensure safety and efficacy. Personalized medicine is a promising field for ocular surface restoration, where long-term follow-up studies and standardized criteria are crucial to evaluate the efficacy of these treatments and their cost-effectiveness in providing high-value healthcare.
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Affiliation(s)
| | - Eleonora Maurizi
- Centre for Regenerative Medicine ''S. Ferrari'', University of Modena and Reggio Emilia, Modena, Italy
| | - Paolo Rama
- Department of Ophthalmology, IRCCS Policlinico San Matteo, Pavia, Italy
| | - Graziella Pellegrini
- Centre for Regenerative Medicine ''S. Ferrari'', University of Modena and Reggio Emilia, Modena, Italy.
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Suleman A, Aluyi-Osa G, Ashipa F, Spadea L, Gagliano C, D’Esposito F, Zeppieri M, Musa M. Autologous blood in the management of ocular surface disorders. World J Exp Med 2024; 14:96412. [PMID: 39713083 PMCID: PMC11551708 DOI: 10.5493/wjem.v14.i4.96412] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2024] [Revised: 09/23/2024] [Accepted: 10/22/2024] [Indexed: 10/31/2024] Open
Abstract
Autologous blood therapy has emerged as a promising modality in managing ocular surface disorders. This review provides a comprehensive overview of the current literature regarding the use of autologous blood in ocular surface disorders, encompassing its physiological basis, clinical applications, techniques, challenges, and future perspectives. The ocular surface, comprising the cornea, conjunctiva, and tear film, plays a critical role in maintaining visual function, and its disruption can lead to various pathological conditions. With its rich composition of growth factors, cytokines, and other bioactive molecules, autologous blood offers therapeutic potential in promoting corneal wound healing, reducing inflammation, and improving tear film stability. Clinical studies have demonstrated the efficacy and safety of autologous blood therapy in diverse ocular surface disorders, including persistent epithelial defects, neurotrophic keratopathy, and dry eye disease. However, challenges such as variability in treatment response, adverse effects, and optimal patient selection remain areas of concern. Further research is needed to elucidate the underlying mechanisms of action, refine treatment protocols, and explore synergistic approaches with other therapeutic modalities. Despite these challenges, autologous blood therapy holds promise as a valuable adjunctive treatment option for ocular surface disorders, offering new avenues for improving patient outcomes and quality of life. This review examines the mechanisms underlying ocular surface disorders while discussing existing autologous blood-based therapies for managing these disorders. Current clinical trials are also summarized, and a comparison between autologous blood therapy and conventional eyedrops is attempted. Finally, safe techniques and protocols for autologous blood medicine are elucidated, and adverse effects and future perspectives of this novel therapy are reviewed.
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Affiliation(s)
- Ayuba Suleman
- Department of Ophthalmology, Africa Eye Laser Centre, Km 7, Benin 300105, Nigeria
| | - Gladness Aluyi-Osa
- Department of Ophthalmology, Africa Eye Laser Centre, Km 7, Benin 300105, Nigeria
| | | | - Leopoldo Spadea
- Eye Clinic, Policlinico Umberto I, “Sapienza” University of Rome, Rome 00142, Italy
| | - Caterina Gagliano
- Department of Medicine and Surgery, University of Enna “Kore”, Enna 94100, Italy
- Mediterranean Foundation “G.B. Morgagni”, Catania 95125, Italy
| | - Fabiana D’Esposito
- Imperial College Ophthalmic Research Group Unit, Imperial College, London NW1 5QH, United Kingdom
| | - Marco Zeppieri
- Department of Ophthalmology, University Hospital of Udine, Udine 33100, Italy
| | - Mutali Musa
- Department of Optometry, University of Benin, Benin 3000283, Nigeria
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6
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Setiawan AM, Kamarudin TA. Differentiation of Human Mesenchymal Stem Cells into Corneal Epithelial Cells: Current Progress. Curr Issues Mol Biol 2024; 46:13281-13295. [PMID: 39727920 DOI: 10.3390/cimb46120792] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2024] [Revised: 11/13/2024] [Accepted: 11/17/2024] [Indexed: 12/28/2024] Open
Abstract
The limited availability of corneal tissue grafts poses significant challenges in the treatment of corneal blindness. Novel treatment utilizes stem cell grafts transplanted from the healthy side of the cornea to the damaged side. However, this procedure is only possible for those who have one-sided corneal blindness. Human stem cells offer promising potential for corneal tissue engineering, providing an alternative solution. Among the different types of stem cells, mesenchymal stem cells (MSCs) stand out due to their abundance and ease of isolation. Human MSCs can be derived from bone marrow, adipose, and umbilical cord tissues. Differentiating MSC toward corneal tissue can be achieved through several methods including chemical induction and co-culture with adult corneal cells such as human limbal epithelial stem cells (LESCs) and human corneal epithelial cells (hTCEpi). Adipose-derived stem cells (ADSCs) are the most common type of MSC that has been studied for corneal differentiation. Corneal epithelial cells are the most common corneal cell type targeted by researchers for corneal differentiation. Chemical induction with small molecules, especially bone morphogenetic protein 4 (BMP4), all-trans retinoic acid (ATRA), and epidermal growth factor (EGF), has gained more popularity in corneal epithelial cell differentiation. This review highlights the current progress in utilizing MSCs for corneal differentiation studies, showcasing their potential to revolutionize treatments for corneal blindness.
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Affiliation(s)
- Abdul Malik Setiawan
- Department of Anatomy, Faculty of Medicine, Universiti Kebangsaan Malaysia, Cheras, Kuala Lumpur 56000, Malaysia
- Department of Anatomy, Maulana Malik Ibrahim State Islamic University, Malang 65144, Indonesia
| | - Taty Anna Kamarudin
- Department of Anatomy, Faculty of Medicine, Universiti Kebangsaan Malaysia, Cheras, Kuala Lumpur 56000, Malaysia
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Kobal N, Marzidovšek M, Schollmayer P, Maličev E, Hawlina M, Marzidovšek ZL. Molecular and Cellular Mechanisms of the Therapeutic Effect of Mesenchymal Stem Cells and Extracellular Vesicles in Corneal Regeneration. Int J Mol Sci 2024; 25:11121. [PMID: 39456906 PMCID: PMC11507649 DOI: 10.3390/ijms252011121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2024] [Revised: 10/11/2024] [Accepted: 10/15/2024] [Indexed: 10/28/2024] Open
Abstract
The cornea is a vital component of the visual system, and its integrity is crucial for optimal vision. Damage to the cornea resulting from trauma, infection, or disease can lead to blindness. Corneal regeneration using mesenchymal stem cells (MSCs) and MSC-derived extracellular vesicles (MSC-EVs) offers a promising alternative to corneal transplantation. MSCs are multipotent stromal cells that can differentiate into various cell types, including corneal cells. They can also secrete a variety of anti-inflammatory cytokines and several growth factors, promoting wound healing and tissue reconstruction. This review summarizes the current understanding of the molecular and cellular mechanisms by which MSCs and MSC-EVs contribute to corneal regeneration. It discusses the potential of MSCs and MSC-EV for treating various corneal diseases, including corneal epithelial defects, dry eye disease, and keratoconus. The review also highlights finalized human clinical trials investigating the safety and efficacy of MSC-based therapy in corneal regeneration. The therapeutic potential of MSCs and MSC-EVs for corneal regeneration is promising; however, further research is needed to optimize their clinical application.
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Affiliation(s)
- Nina Kobal
- Eye Hospital, University Medical Centre Ljubljana, 1000 Ljubljana, Slovenia; (N.K.)
| | - Miha Marzidovšek
- Eye Hospital, University Medical Centre Ljubljana, 1000 Ljubljana, Slovenia; (N.K.)
| | - Petra Schollmayer
- Eye Hospital, University Medical Centre Ljubljana, 1000 Ljubljana, Slovenia; (N.K.)
| | - Elvira Maličev
- Blood Transfusion Centre of Slovenia, 1000 Ljubljana, Slovenia
- Biotechnical Faculty, University of Ljubljana, 1000 Ljubljana, Slovenia
| | - Marko Hawlina
- Eye Hospital, University Medical Centre Ljubljana, 1000 Ljubljana, Slovenia; (N.K.)
- Medical Faculty, Department of Ophthalmology, University of Ljubljana, 1000 Ljubljana, Slovenia
| | - Zala Lužnik Marzidovšek
- Eye Hospital, University Medical Centre Ljubljana, 1000 Ljubljana, Slovenia; (N.K.)
- Medical Faculty, Department of Ophthalmology, University of Ljubljana, 1000 Ljubljana, Slovenia
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Dadfar S, Yazdanpanah E, Pazoki A, Nemati MH, Eslami M, Haghmorad D, Oksenych V. The Role of Mesenchymal Stem Cells in Modulating Adaptive Immune Responses in Multiple Sclerosis. Cells 2024; 13:1556. [PMID: 39329740 PMCID: PMC11430382 DOI: 10.3390/cells13181556] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2024] [Revised: 09/12/2024] [Accepted: 09/14/2024] [Indexed: 09/28/2024] Open
Abstract
Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system, leading to significant disability through neurodegeneration. Despite advances in the understanding of MS pathophysiology, effective treatments remain limited. Mesenchymal stem cells (MSCs) have gained attention as a potential therapeutic option due to their immunomodulatory and regenerative properties. This review examines MS pathogenesis, emphasizing the role of immune cells, particularly T cells, in disease progression, and explores MSCs' therapeutic potential. Although preclinical studies in animal models show MSC efficacy, challenges such as donor variability, culture conditions, migratory capacity, and immunological compatibility hinder widespread clinical adoption. Strategies like genetic modification, optimized delivery methods, and advanced manufacturing are critical to overcoming these obstacles. Further research is needed to validate MSCs' clinical application in MS therapy.
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Affiliation(s)
- Sepehr Dadfar
- Student Research Committee, Semnan University of Medical Sciences, Semnan 35147-99442, Iran
- Department of Immunology, School of Medicine, Semnan University of Medical Sciences, Semnan 35147-99442, Iran
| | - Esmaeil Yazdanpanah
- Student Research Committee, Semnan University of Medical Sciences, Semnan 35147-99442, Iran
| | - Alireza Pazoki
- Student Research Committee, Semnan University of Medical Sciences, Semnan 35147-99442, Iran
- Department of Immunology, School of Medicine, Semnan University of Medical Sciences, Semnan 35147-99442, Iran
| | - Mohammad Hossein Nemati
- Student Research Committee, Semnan University of Medical Sciences, Semnan 35147-99442, Iran
- Department of Immunology, School of Medicine, Semnan University of Medical Sciences, Semnan 35147-99442, Iran
| | - Majid Eslami
- Cancer Research Center, Semnan University of Medical Sciences, Semnan 35147-99442, Iran
- Department of Bacteriology and Virology, Semnan University of Medical Sciences, Semnan 35147-99442, Iran
| | - Dariush Haghmorad
- Department of Immunology, School of Medicine, Semnan University of Medical Sciences, Semnan 35147-99442, Iran
- Cancer Research Center, Semnan University of Medical Sciences, Semnan 35147-99442, Iran
| | - Valentyn Oksenych
- Broegelmann Research Laboratory, Department of Clinical Science, University of Bergen, 5020 Bergen, Norway
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Aghazadeh S, Peng Q, Dardmeh F, Hjortdal JØ, Zachar V, Alipour H. Immunophenotypical Characterization of Limbal Mesenchymal Stromal Cell Subsets during In Vitro Expansion. Int J Mol Sci 2024; 25:8684. [PMID: 39201371 PMCID: PMC11354999 DOI: 10.3390/ijms25168684] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2024] [Revised: 07/26/2024] [Accepted: 08/02/2024] [Indexed: 09/02/2024] Open
Abstract
Limbal mesenchymal stromal cells (LMSCs) reside in the limbal niche, supporting corneal integrity and facilitating regeneration. While mesenchymal stem/stromal cells (MSCs) are used in regenerative therapies, there is limited knowledge about LMSC subpopulations and their characteristics. This study characterized human LMSC subpopulations through the flow cytometric assessment of fifteen cell surface markers, including MSC, wound healing, immune regulation, ASC, endothelial, and differentiation markers. Primary LMSCs were established from remnant human corneal transplant specimens and passaged eight times to observe changes during subculture. The results showed the consistent expression of typical MSC markers and distinct subpopulations with the passage-dependent expression of wound healing, immune regulation, and differentiation markers. High CD166 and CD248 expressions indicated a crucial role in ocular surface repair. CD29 expression suggested an immunoregulatory role. Comparable pigment-epithelial-derived factor (PEDF) expression supported anti-inflammatory and anti-angiogenic roles. Sustained CD201 expression indicated maintained differentiation capability, while VEGFR2 expression suggested potential endothelial differentiation. LMSCs showed higher VEGF expression than fibroblasts and endothelial cells, suggesting a potential contribution to ocular surface regeneration through the modulation of angiogenesis and inflammation. These findings highlight the heterogeneity and multipotent potential of LMSC subpopulations during in vitro expansion, informing the development of standardized protocols for regenerative therapies and improving treatments for ocular surface disorders.
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Affiliation(s)
- Sara Aghazadeh
- Regenerative Medicine, Department of Health Science and Technology, Aalborg University, 9260 Gistrup, Denmark; (S.A.); (Q.P.); (F.D.); (V.Z.)
| | - Qiuyue Peng
- Regenerative Medicine, Department of Health Science and Technology, Aalborg University, 9260 Gistrup, Denmark; (S.A.); (Q.P.); (F.D.); (V.Z.)
| | - Fereshteh Dardmeh
- Regenerative Medicine, Department of Health Science and Technology, Aalborg University, 9260 Gistrup, Denmark; (S.A.); (Q.P.); (F.D.); (V.Z.)
| | | | - Vladimir Zachar
- Regenerative Medicine, Department of Health Science and Technology, Aalborg University, 9260 Gistrup, Denmark; (S.A.); (Q.P.); (F.D.); (V.Z.)
| | - Hiva Alipour
- Regenerative Medicine, Department of Health Science and Technology, Aalborg University, 9260 Gistrup, Denmark; (S.A.); (Q.P.); (F.D.); (V.Z.)
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10
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Padinharayil H, Varghese J, Wilson C, George A. Mesenchymal stem cell-derived exosomes: Characteristics and applications in disease pathology and management. Life Sci 2024; 342:122542. [PMID: 38428567 DOI: 10.1016/j.lfs.2024.122542] [Citation(s) in RCA: 15] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Revised: 02/25/2024] [Accepted: 02/27/2024] [Indexed: 03/03/2024]
Abstract
Mesenchymal stem cells (MSCs) possess a role in tissue regeneration and homeostasis because of inherent immunomodulatory capacity and the production of factors that encourage healing. There is substantial evidence that MSCs' therapeutic efficacy is primarily determined by their paracrine function including in cancers. Extracellular vesicles (EVs) are basic paracrine effectors of MSCs that reside in numerous bodily fluids and cell homogenates and play an important role in bidirectional communication. MSC-derived EVs (MSC-EVs) offer a wide range of potential therapeutic uses that exceed cell treatment, while maintaining protocell function and having less immunogenicity. We describe characteristics and isolation methods of MSC-EVs, and focus on their therapeutic potential describing its roles in tissue repair, anti-fibrosis, and cancer with an emphasis on the molecular mechanism and immune modulation and clinical trials. We also explain current understanding and challenges in the clinical applications of MSC-EVs as a cell free therapy.
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Affiliation(s)
- Hafiza Padinharayil
- Jubilee Centre for Medical Research, Jubilee Mission Medical College and Research Institute, Thrissur 05, Kerala, India; PG & Research Department of Zoology, St. Thomas College, Kozhencherry, Pathanamthitta, Kerala 689641, India
| | - Jinsu Varghese
- PG & Research Department of Zoology, St. Thomas College, Kozhencherry, Pathanamthitta, Kerala 689641, India
| | - Cornelia Wilson
- Canterbury Christ Church University, Natural Applied Sciences, Life Science Industry Liaison Lab, Discovery Park, Sandwich CT139FF, United Kingdom.
| | - Alex George
- Jubilee Centre for Medical Research, Jubilee Mission Medical College and Research Institute, Thrissur 05, Kerala, India.
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11
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Atalay E, Altuğ B, Çalışkan ME, Ceylan S, Özler ZS, Figueiredo G, Lako M, Figueiredo F. Animal Models for Limbal Stem Cell Deficiency: A Critical Narrative Literature Review. Ophthalmol Ther 2024; 13:671-696. [PMID: 38280103 PMCID: PMC10853161 DOI: 10.1007/s40123-023-00880-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2023] [Accepted: 12/19/2023] [Indexed: 01/29/2024] Open
Abstract
This literature review will provide a critical narrative overview of the highlights and potential pitfalls of the reported animal models for limbal stem cell deficiency (LSCD) and will identify the neglected aspects of this research area. There exists significant heterogeneity in the literature regarding the methodology used to create the model and the predefined duration after the insult when the model is supposedly fully fit for evaluations and/or for testing various therapeutic interventions. The literature is also replete with examples wherein the implementation of a specific model varies significantly across different studies. For example, the concentration of the chemical, as well as its duration and technique of exposure in a chemically induced LSCD model, has a great impact not only on the validity of the model but also on the severity of the complications. Furthermore, while some models induce a full-blown clinical picture of total LSCD, some are hindered by their ability to yield only partial LSCD. Another aspect to consider is the nature of the damage induced by a specific method. As thermal methods cause more stromal scarring, they may be better suited for assessing the anti-fibrotic properties of a particular treatment. On the other hand, since chemical burns cause more neovascularisation, they provide the opportunity to tap into the potential treatments for anti-neovascularisation. The animal species (i.e., rats, mice, rabbits, etc.) is also a crucial factor in the validity of the model and its potential for clinical translation, with each animal having its unique set of advantages and disadvantages. This review will also elaborate on other overlooked aspects, such as the anaesthetic(s) used during experiments, the gender of the animals, care after LSCD induction, and model validation. The review will conclude by providing future perspectives and suggestions for further developments in this rather important area of research.
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Affiliation(s)
- Eray Atalay
- Department of Ophthalmology, Eskişehir Osmangazi University Medical School, Eskişehir, Turkey
| | - Burcugül Altuğ
- Cellular Therapy and Stem Cell Production Application, Research Centre (ESTEM), Eskişehir Osmangazi University, Eskişehir, Turkey
| | | | - Semih Ceylan
- Eskişehir Osmangazi University Medical School, Eskişehir, Turkey
| | | | | | - Majlinda Lako
- Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Francisco Figueiredo
- Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.
- Department of Ophthalmology, Royal Victoria Infirmary, Newcastle University, Newcastle upon Tyne, NE1 4LP, UK.
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Xiao Y, Zhong J, Yang J, Fu Z, Wang B, Peng L, Zuo X, Zhao X, He D, Yuan J. Myeloid-derived suppressor cells ameliorate corneal alkali burn through IL-10-dependent anti-inflammatory properties. Transl Res 2023; 262:25-34. [PMID: 37543286 DOI: 10.1016/j.trsl.2023.07.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2023] [Revised: 06/03/2023] [Accepted: 07/23/2023] [Indexed: 08/07/2023]
Abstract
This study aims to investigate the efficiency and the underlying mechanism of myeloid-derived suppressor cells (MDSCs) in corneal alkali burns (CAB). In the study, CD11b+ Gr-1+ cells from C57BL/6J mice bone marrow were cultured and induced. Cell activity and immunoregulatory function were assessed by flow cytometry in vitro. The optimal strategy of MDSCs therapy was assessed by slit-lamp microscopy, and flow cytometry in vivo. The therapeutic effects of MDSCs and the critical signaling pathway were investigated by hematoxylin-eosin (HE) staining, slit-lamp microscopy, flow cytometry, and immunofluorescence. The expression level of the NLRP3 inflammasome pathway was examined. The crucial biochemical parameters of MDSCs were examined by RNA-seq and qPCR to screen out the key regulators. The mechanism of MDSCs' therapeutic effects was explored using MDSCs with IL-10 knockout/rescue by slit-lamp microscopy, HE staining, and qPCR evaluation. The cell frequencies of macrophages and neutrophils in the cornea were examined by flow cytometry in vivo. The results demonstrated that the induced MDSCs meet the standard of phenotypic and functional characteristics. The treatment of 5 × 105 MDSCs conjunctival injection on alternate days significantly ameliorated the disease development, downregulated the NLRP3 inflammasome pathway, and decreased the cell frequencies of macrophages and neutrophils in vivo significantly. IL-10 was screened out to be the critical factor for MDSCs therapy. The therapeutic effects of MDSCs were impaired largely by IL-10 knock-out and saved by the IL-10 supplement. In conclusion, MDSCs therapy is a promising therapeutic solution for CAB. MDSCs fulfilled immunoregulatory roles for CAB by IL-10-dependent anti-inflammatory properties.
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Affiliation(s)
- Yichen Xiao
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, Guangdong, China
| | - Jing Zhong
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, Guangdong, China
| | - Jiahui Yang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, Guangdong, China
| | - Zhenyuan Fu
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, Guangdong, China
| | - Bowen Wang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, Guangdong, China
| | - Lulu Peng
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, Guangdong, China
| | - Xin Zuo
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, Guangdong, China
| | - Xuan Zhao
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, Guangdong, China
| | - Dalian He
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, Guangdong, China
| | - Jin Yuan
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, Guangdong, China.
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13
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Kang H, Feng J, Peng Y, Liu Y, Yang Y, Wu Y, Huang J, Jie Y, Chen B, He Y. Human mesenchymal stem cells derived from adipose tissue showed a more robust effect than those from the umbilical cord in promoting corneal graft survival by suppressing lymphangiogenesis. Stem Cell Res Ther 2023; 14:328. [PMID: 37957770 PMCID: PMC10644560 DOI: 10.1186/s13287-023-03559-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Accepted: 11/03/2023] [Indexed: 11/15/2023] Open
Abstract
BACKGROUND Mesenchymal stem cells (MSCs) have shown promising potential in allograft survival. However, few reports have focused on comparing the immunosuppressive capacity of MSCs from different sources and administered via different routes in inhibiting transplant rejection. Moreover, virtually nothing is known about the role of MSCs in the regulation of graft neovascularization and lymphangiogenesis. In this study, we compared the efficacy of human adipose MSCs (hAD-MSCs) and human umbilical cord MSCs (hUC-MSCs) in vitro and in corneal transplantation models to explore the underlying molecular mechanisms and provide a powerful strategy for future clinical applications. METHODS hAD-MSCs and hUC-MSCs were generated, and their self-renewal and multi-differentiation abilities were evaluated. The inhibitory effect of human MSCs (hMSCs) was examined by T-cell proliferation assays with or without transwell in vitro. Two MSCs from different sources were separately adoptively transferred in mice corneal transplantation (5 × 105 or 1 × 106/mouse) via topical subconjunctival or intravenous (IV) routes. Allograft survival was evaluated every other day, and angiogenesis and lymphomagenesis were quantitatively analyzed by immunofluorescence staining. The RNA expression profiles of hMSCs were revealed by RNA sequencing (RNA-seq) and verified by quantitative real-time PCR (qRT‒PCR), western blotting or ELISA. The function of the differentially expressed gene FAS was verified by a T-cell apoptosis assay. RESULTS hAD-MSCs induced stronger immunosuppression in vitro than hUC-MSCs. The inhibitory effect of hUC-MSCs but not hAD-MSCs was mediated by cell-cell contact-dependent mechanisms. Systemic administration of a lower dose of hAD-MSCs showed better performance in prolonging corneal allograft survival than hUC-MSCs, while subconjunctival administration of hMSCs was safer and further prolonged corneal allograft survival. Both types of hMSCs could inhibit corneal neovascularization, while hAD-MSCs showed greater superiority in suppressing graft lymphangiogenesis. RNA-seq analysis and confirmation experiments revealed the superior performance of hAD-MSCs in allografts based on the lower expression of vascular endothelial growth factor C (VEGF-C) and higher expression of FAS. CONCLUSIONS The remarkable inhibitory effects on angiogenesis/lymphangiogenesis and immunological transplantation effects support the development of hAD-MSCs as a cell therapy against corneal transplant rejection. Topical administration of hMSCs was a safer and more effective route for application than systemic administration.
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Affiliation(s)
- Huanmin Kang
- Department of Ophthalmology, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China
- Hunan Clinical Research Center of Ophthalmic Disease, Changsha, 410011, Hunan, China
| | - Jianing Feng
- Department of Ophthalmology, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China
- Hunan Clinical Research Center of Ophthalmic Disease, Changsha, 410011, Hunan, China
- Shanxi Eye Hospital, Xi'an People's Hospital (Xi'an Fourth Hospital), Affiliated People's Hospital of Northwest University, Xi'an, 710004, China
| | - Yingqian Peng
- Department of Ophthalmology, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China
- Hunan Clinical Research Center of Ophthalmic Disease, Changsha, 410011, Hunan, China
| | - Yingyi Liu
- Department of Ophthalmology, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China
- Hunan Clinical Research Center of Ophthalmic Disease, Changsha, 410011, Hunan, China
| | - Yalei Yang
- Department of Ophthalmology, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China
- Hunan Clinical Research Center of Ophthalmic Disease, Changsha, 410011, Hunan, China
| | - Ying Wu
- Department of Ophthalmology, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China
- Hunan Clinical Research Center of Ophthalmic Disease, Changsha, 410011, Hunan, China
| | - Jian Huang
- Department of Obstetrics and Gynecology, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China
| | - Ying Jie
- Beijing Ophthalmology and Visual Sciences Key Laboratory, Beijing Institute of Ophthalmology, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing, China
| | - Baihua Chen
- Department of Ophthalmology, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China
- Hunan Clinical Research Center of Ophthalmic Disease, Changsha, 410011, Hunan, China
| | - Yan He
- Beijing Ophthalmology and Visual Sciences Key Laboratory, Beijing Institute of Ophthalmology, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing, China.
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14
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Shadmani A, Jarin T, Meng XQ, Rajaendran Y, Uzun S, Wu AY. Evaluation of the Algerbrush II rotating burr as a tool for inducing ocular surface failure in a mouse model. Mol Vis 2023; 29:256-265. [PMID: 38222449 PMCID: PMC10784216] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2023] [Accepted: 11/01/2023] [Indexed: 01/16/2024] Open
Abstract
Purpose The Algerbrush II has been widely used to induce corneal and limbal injuries in animal models. The extent of injury varies with the duration of exposure, pressure from the placement of the burr, and the size of the burr. However, no study has explored the correlation between the duration of exposure and the severity of injury in mouse model with corneal and limbal stem cell deficiency (LSCD) induced using the Algerbrush II. Therefore, this study aimed to evaluate the variations in the severity of corneal and limbal injury with different durations of the Algerbrush II application. Methods The entire cornea and limbus of C57BL/6 mice were injured for 30-45 s, 60-75 s, 90-120 s, and 3-4 min. Photography and slit-lamp examination was performed on days 0, 2, 4, and 7, followed by hematoxylin & eosin, periodic acid-Schiff, and immunohistochemical staining. Statistical analysis was performed using one way ANOVA analysis. Results A duration of 30-45 s of injury was found to be sufficient to induce superficial corneal and limbal epithelial debridement and re-epithelialization was completed in all eyes by day 7; however, clinical signs of LSCD were not observed in all mice. Increasing the exposure time to 90-120 s resulted in central 2+ corneal opacity with limbal and paracentral corneal neovascularization. All eyes injured for 3-4 min displayed clinical signs of LSCD, such as persistent epithelial defects on day 7 after the injury, central corneal neovascularization, and 2.2+ diffuse corneal opacity. Histological signs of LSCD, including goblet cell metaplasia and K13 expression on the corneal surface, were observed in all injured eyes. Conclusions Our findings suggest that the duration of injury is an important factor influencing the severity of LSCD in a murine model of injury. A 1-mm rotating burr was found to be more effective for keratectomy and pigment release, whereas a 0.5-mm burr was more suitable for corneal epithelial debridement.
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Affiliation(s)
- Athar Shadmani
- Department of Ophthalmology, Stanford University School of Medicine, Stanford, CA
| | - Trent Jarin
- Department of Ophthalmology, Stanford University School of Medicine, Stanford, CA
| | - Xiang Qi Meng
- McGill University Faculty of Medicine and Health Sciences, Montreal, Quebec, Canada
| | - Yugendran Rajaendran
- Department of Bioengineering, Stanford University School of Engineering and School of Medicine, Stanford, CA
| | - Salih Uzun
- Department of Ophthalmology, Stanford University School of Medicine, Stanford, CA
| | - Albert Y. Wu
- Department of Ophthalmology, Stanford University School of Medicine, Stanford, CA
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15
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van Velthoven AJH, Utheim TP, Notara M, Bremond-Gignac D, Figueiredo FC, Skottman H, Aberdam D, Daniels JT, Ferrari G, Grupcheva C, Koppen C, Parekh M, Ritter T, Romano V, Ferrari S, Cursiefen C, Lagali N, LaPointe VLS, Dickman MM. Future directions in managing aniridia-associated keratopathy. Surv Ophthalmol 2023; 68:940-956. [PMID: 37146692 DOI: 10.1016/j.survophthal.2023.04.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Revised: 04/19/2023] [Accepted: 04/24/2023] [Indexed: 05/07/2023]
Abstract
Congenital aniridia is a panocular disorder that is typically characterized by iris hypoplasia and aniridia-associated keratopathy (AAK). AAK results in the progressive loss of corneal transparency and thereby loss of vision. Currently, there is no approved therapy to delay or prevent its progression, and clinical management is challenging because of phenotypic variability and high risk of complications after interventions; however, new insights into the molecular pathogenesis of AAK may help improve its management. Here, we review the current understanding about the pathogenesis and management of AAK. We highlight the biological mechanisms involved in AAK development with the aim to develop future treatment options, including surgical, pharmacological, cell therapies, and gene therapies.
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Affiliation(s)
- Arianne J H van Velthoven
- MERLN Institute for Technology-Inspired Regenerative Medicine, Maastricht University, Maastricht, the Netherlands; University Eye Clinic Maastricht, Maastricht University Medical Center+, Maastricht, the Netherlands
| | - Tor P Utheim
- Department of Medical Biochemistry, Oslo University Hospital, Oslo, Norway; Department of Ophthalmology, Oslo University Hospital, Oslo, Norway
| | - Maria Notara
- Department of Ophthalmology, Faculty of Medicine and University Hospital Cologne, Cologne, Germany
| | - Dominique Bremond-Gignac
- Ophthalmology Department, University Hospital Necker-Enfants Malades, APHP, Paris Cité University, Paris, France; Centre de Recherche des Cordeliers, Sorbonne Paris Cité University, Paris, France
| | - Francisco C Figueiredo
- Department of Ophthalmology, Royal Victoria Infirmary, Newcastle upon Tyne, UK; Biosciences Institute, Newcastle University, Newcastle upon Tyne, UK
| | - Heli Skottman
- Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | - Daniel Aberdam
- Centre de Recherche des Cordeliers, Sorbonne Paris Cité University, Paris, France
| | | | - Giulio Ferrari
- Cornea and Ocular Surface Unit, Eye Repair Lab, San Raffaele Hospital, Milan, Italy
| | - Christina Grupcheva
- Department of Ophthalmology and Visual Sciences, Medical University of Varna, Varna, Bulgaria
| | - Carina Koppen
- Department of Ophthalmology, Antwerp University Hospital, Edegem, Belgium
| | - Mohit Parekh
- Schepens Eye Research Institute, Harvard Medical School, Boston, MA, USA
| | - Thomas Ritter
- Regenerative Medicine Institute, University of Galway, Galway, Ireland
| | - Vito Romano
- Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, Ophthalmology Clinic, University of Brescia, Brescia, Italy
| | | | - Claus Cursiefen
- Department of Ophthalmology, Faculty of Medicine and University Hospital Cologne, Cologne, Germany; Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany
| | - Neil Lagali
- Division of Ophthalmology, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
| | - Vanessa L S LaPointe
- MERLN Institute for Technology-Inspired Regenerative Medicine, Maastricht University, Maastricht, the Netherlands
| | - Mor M Dickman
- MERLN Institute for Technology-Inspired Regenerative Medicine, Maastricht University, Maastricht, the Netherlands; University Eye Clinic Maastricht, Maastricht University Medical Center+, Maastricht, the Netherlands
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16
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Tian Y, Zhang T, Li J, Tao Y. Advances in development of exosomes for ophthalmic therapeutics. Adv Drug Deliv Rev 2023; 199:114899. [PMID: 37236425 DOI: 10.1016/j.addr.2023.114899] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Revised: 04/18/2023] [Accepted: 05/21/2023] [Indexed: 05/28/2023]
Abstract
Exosomes contain multiple bioactive molecules and maintain the connection between cells. Recent advances in exosome-based therapeutics have witnessed unprecedented opportunities in treating ophthalmic diseases, including traumatic diseases, autoimmune diseases, chorioretinal diseases and others. Utilization of exosomes as delivery vectors to encapsulate both drugs and therapeutic genes could yield higher efficacy and avoid the unnecessary immune responses. However, exosome-based therapies also come with some potential ocular risks. In this review, we first present a general introduction to exosomes. Then we provide an overview of available applications and discuss their potential risks. Moreover, we review recently reported exosomes as delivery vectors for ophthalmic diseases. Finally, we put forward future perspectives to grapple with its translation and underlying issues.
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Affiliation(s)
- Ying Tian
- Department of Ophthalmology, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, PR China
| | - Tao Zhang
- Department of Ophthalmology, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, PR China
| | - Jing Li
- Beijing Key Laboratory of DNA Damage Response, College of Life Sciences, Capital Normal University, Beijing 100048, PR China
| | - Yong Tao
- Department of Ophthalmology, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, PR China.
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17
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Sprogyte L, Park M, Di Girolamo N. Pathogenesis of Alkali Injury-Induced Limbal Stem Cell Deficiency: A Literature Survey of Animal Models. Cells 2023; 12:cells12091294. [PMID: 37174694 PMCID: PMC10177508 DOI: 10.3390/cells12091294] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Revised: 04/28/2023] [Accepted: 04/28/2023] [Indexed: 05/15/2023] Open
Abstract
Limbal stem cell deficiency (LSCD) is a debilitating ocular surface disease that eventuates from a depleted or dysfunctional limbal epithelial stem cell (LESC) pool, resulting in corneal epithelial failure and blindness. The leading cause of LSCD is a chemical burn, with alkali substances being the most common inciting agents. Characteristic features of alkali-induced LSCD include corneal conjunctivalization, inflammation, neovascularization and fibrosis. Over the past decades, animal models of corneal alkali burn and alkali-induced LSCD have been instrumental in improving our understanding of the pathophysiological mechanisms responsible for disease development. Through these paradigms, important insights have been gained with regards to signaling pathways that drive inflammation, neovascularization and fibrosis, including NF-κB, ERK, p38 MAPK, JNK, STAT3, PI3K/AKT, mTOR and WNT/β-catenin cascades. Nonetheless, the molecular and cellular events that underpin re-epithelialization and those that govern long-term epithelial behavior are poorly understood. This review provides an overview of the current mechanistic insights into the pathophysiology of alkali-induced LSCD. Moreover, we highlight limitations regarding existing animal models and knowledge gaps which, if addressed, would facilitate development of more efficacious therapeutic strategies for patients with alkali-induced LSCD.
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Affiliation(s)
- Lina Sprogyte
- Mechanisms of Disease and Translational Research, School of Biomedical Sciences, Faculty of Medicine and Health, University of New South Wales, Sydney, NSW 2052, Australia
| | - Mijeong Park
- Mechanisms of Disease and Translational Research, School of Biomedical Sciences, Faculty of Medicine and Health, University of New South Wales, Sydney, NSW 2052, Australia
| | - Nick Di Girolamo
- Mechanisms of Disease and Translational Research, School of Biomedical Sciences, Faculty of Medicine and Health, University of New South Wales, Sydney, NSW 2052, Australia
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18
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Uzel E, Durgun ME, Esentürk-Güzel İ, Güngör S, Özsoy Y. Nanofibers in Ocular Drug Targeting and Tissue Engineering: Their Importance, Advantages, Advances, and Future Perspectives. Pharmaceutics 2023; 15:pharmaceutics15041062. [PMID: 37111550 PMCID: PMC10145046 DOI: 10.3390/pharmaceutics15041062] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Revised: 03/17/2023] [Accepted: 03/23/2023] [Indexed: 03/29/2023] Open
Abstract
Nanofibers are frequently encountered in daily life as a modern material with a wide range of applications. The important advantages of production techniques, such as being easy, cost effective, and industrially applicable are important factors in the preference for nanofibers. Nanofibers, which have a broad scope of use in the field of health, are preferred both in drug delivery systems and tissue engineering. Due to the biocompatible materials used in their construction, they are also frequently preferred in ocular applications. The fact that they have a long drug release time as a drug delivery system and have been used in corneal tissue studies, which have been successfully developed in tissue engineering, stand out as important advantages of nanofibers. This review examines nanofibers, their production techniques and general information, nanofiber-based ocular drug delivery systems, and tissue engineering concepts in detail.
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Affiliation(s)
- Egemen Uzel
- Institute of Graduate Studies in Health Sciences, Istanbul University, Istanbul 34010, Türkiye
- Department of Pharmaceutical Technology, Faculty of Pharmacy, Istanbul University, Istanbul 34126, Türkiye
| | - Meltem Ezgi Durgun
- Department of Pharmaceutical Technology, Faculty of Pharmacy, Istanbul University, Istanbul 34126, Türkiye
| | - İmren Esentürk-Güzel
- Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Health Sciences, Istanbul 34668, Türkiye
| | - Sevgi Güngör
- Department of Pharmaceutical Technology, Faculty of Pharmacy, Istanbul University, Istanbul 34126, Türkiye
| | - Yıldız Özsoy
- Department of Pharmaceutical Technology, Faculty of Pharmacy, Istanbul University, Istanbul 34126, Türkiye
- Correspondence: ; Tel.: +90-212-4400000 (ext. 13498)
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19
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Corneal Reconstruction with EGFP-Labelled Limbal Mesenchymal Stem Cells in a Rabbit Model of Limbal Stem Cell Deficiency. Int J Mol Sci 2023; 24:ijms24065431. [PMID: 36982507 PMCID: PMC10051408 DOI: 10.3390/ijms24065431] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Revised: 03/07/2023] [Accepted: 03/10/2023] [Indexed: 03/14/2023] Open
Abstract
Ocular surface reconstruction is essential for treating corneal epithelial defects and vision recovery. Stem cell-based therapy demonstrates promising results but requires further research to elucidate stem cell survival, growth, and differentiation after transplantation in vivo. This study examined the corneal reconstruction promoted by EGFP-labeled limbal mesenchymal stem cells (L-MSCs-EGFP) and their fate after transplantation. EGFP labeling allowed us to evaluate the migration and survival rates of the transferred cells. L-MSCs-EGFP seeded onto decellularized human amniotic membrane (dHAM) were transplanted into rabbits with a modeled limbal stem cell deficiency. The localization and viability of the transplanted cells in animal tissue were analyzed using histology, immunohistochemistry, and confocal microscopy up to 3 months after transplantation. EGFP-labeled cells remained viable for the first 14 days after transplantation. By the 90th day, epithelialization of the rabbit corneas reached 90%, but the presence of viable labeled cells was not observed within the newly formed epithelium. Although labeled cells demonstrated low survivability in host tissue, the squamous corneal-like epithelium was partially restored by the 30th day after transplantation of the tissue-engineered graft. Overall, this study paves the way for further optimization of transplantation conditions and studying the mechanisms of corneal tissue restoration.
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20
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Rossner P, Cervena T, Echalar B, Palacka K, Milcova A, Novakova Z, Sima M, Simova Z, Vankova J, Holan V. Metal Nanoparticles with Antimicrobial Properties: The Toxicity Response in Mouse Mesenchymal Stem Cells. TOXICS 2023; 11:253. [PMID: 36977018 PMCID: PMC10057305 DOI: 10.3390/toxics11030253] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Revised: 03/01/2023] [Accepted: 03/07/2023] [Indexed: 06/18/2023]
Abstract
Some metal nanoparticles (NP) are characterized by antimicrobial properties with the potential to be used as alternative antibiotics. However, NP may negatively impact human organism, including mesenchymal stem cells (MSC), a cell population contributing to tissue growth and regeneration. To address these issues, we investigated the toxic effects of selected NP (Ag, ZnO, and CuO) in mouse MSC. MSC were treated with various doses of NP for 4 h, 24 h, and 48 h and multiple endpoints were analyzed. Reactive oxygen species were generated after 48 h CuO NP exposure. Lipid peroxidation was induced after 4 h and 24 h treatment, regardless of NP and/or tested dose. DNA fragmentation and oxidation induced by Ag NP showed dose responses for all the periods. For other NP, the effects were observed for shorter exposure times. The impact on the frequency of micronuclei was weak. All the tested NP increased the sensitivity of MSC to apoptosis. The cell cycle was most affected after 24 h, particularly for Ag NP treatment. In summary, the tested NP induced numerous adverse changes in MSC. These results should be taken into consideration when planning the use of NP in medical applications where MSC are involved.
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Affiliation(s)
- Pavel Rossner
- Department of Nanotoxicology and Molecular Epidemiology, Institute of Experimental Medicine CAS, 142 00 Prague, Czech Republic
| | - Tereza Cervena
- Department of Nanotoxicology and Molecular Epidemiology, Institute of Experimental Medicine CAS, 142 00 Prague, Czech Republic
- Department of Genetic Toxicology and Epigenetics, Institute of Experimental Medicine CAS, 142 00 Prague, Czech Republic
| | - Barbora Echalar
- Department of Nanotoxicology and Molecular Epidemiology, Institute of Experimental Medicine CAS, 142 00 Prague, Czech Republic
| | - Katerina Palacka
- Department of Nanotoxicology and Molecular Epidemiology, Institute of Experimental Medicine CAS, 142 00 Prague, Czech Republic
| | - Alena Milcova
- Department of Genetic Toxicology and Epigenetics, Institute of Experimental Medicine CAS, 142 00 Prague, Czech Republic
| | - Zuzana Novakova
- Department of Nanotoxicology and Molecular Epidemiology, Institute of Experimental Medicine CAS, 142 00 Prague, Czech Republic
| | - Michal Sima
- Department of Nanotoxicology and Molecular Epidemiology, Institute of Experimental Medicine CAS, 142 00 Prague, Czech Republic
| | - Zuzana Simova
- Department of Nanotoxicology and Molecular Epidemiology, Institute of Experimental Medicine CAS, 142 00 Prague, Czech Republic
| | - Jolana Vankova
- Department of Nanotoxicology and Molecular Epidemiology, Institute of Experimental Medicine CAS, 142 00 Prague, Czech Republic
| | - Vladimir Holan
- Department of Nanotoxicology and Molecular Epidemiology, Institute of Experimental Medicine CAS, 142 00 Prague, Czech Republic
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Chen P, Tang S, Li M, Wang D, Chen C, Qiu Y, Fang Z, Zhang H, Gao H, Weng H, Hu K, Lin J, Lin Q, Tan Y, Li S, Chen J, Chen L, Chen X. Single-Cell and Spatial Transcriptomics Decodes Wharton's Jelly-Derived Mesenchymal Stem Cells Heterogeneity and a Subpopulation with Wound Repair Signatures. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2023; 10:e2204786. [PMID: 36504438 PMCID: PMC9896049 DOI: 10.1002/advs.202204786] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Revised: 11/18/2022] [Indexed: 06/17/2023]
Abstract
The highly heterogeneous characteristics of Wharton's jelly mesenchymal stem cells (WJ-MSCs) may be responsible for the poor clinical outcomes and poor reproducibility of treatments based on WJ-MSCs. Exploration of WJ-MSC heterogeneity with multimodal single-cell technologies will aid in establishing accurate MSC subtyping and developing screening protocols for dominant functional subpopulations. Here, the characteristics of WJ-MSCs are systematically analyzed by single cell and spatial transcriptome sequencing. Single-cell transcriptomics analysis identifies four WJ-MSC subpopulations, namely proliferative_MSCs, niche-supporting_MSCs, metabolism-related_MSCs and biofunctional-type_MSCs. Furthermore, the transcriptome, cellular heterogeneity, and cell-state trajectories of these subpopulations are characterized. Intriguingly, the biofunctional-type MSCs (marked by S100A9, CD29, and CD142) selected in this study exhibit promising wound repair properties in vitro and in vivo. Finally, by integrating omics data, it has been found that the S100A9+ CD29+ CD142+ subpopulation is more enriched in the fetal segment of the umbilical cord, suggesting that this subpopulation deriving from the fetal segment may have potential for developing into an ideal therapeutic agent for wound healing. Overall, the presented study comprehensively maps the heterogeneity of WJ-MSCs and provides an essential resource for future development of WJ-MSC-based drugs.
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22
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Soleimani M, Cheraqpour K, Koganti R, Baharnoori SM, Djalilian AR. Concise Review: Bioengineering of Limbal Stem Cell Niche. Bioengineering (Basel) 2023; 10:111. [PMID: 36671683 PMCID: PMC9855097 DOI: 10.3390/bioengineering10010111] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Revised: 01/01/2023] [Accepted: 01/10/2023] [Indexed: 01/15/2023] Open
Abstract
The corneal epithelium is composed of nonkeratinized stratified squamous cells and has a significant turnover rate. Limbal integrity is vital to maintain the clarity and avascularity of the cornea as well as regeneration of the corneal epithelium. Limbal epithelial stem cells (LESCs) are located in the basal epithelial layer of the limbus and preserve this homeostasis. Proper functioning of LESCs is dependent on a specific microenvironment, known as the limbal stem cell niche (LSCN). This structure is made up of various cells, an extracellular matrix (ECM), and signaling molecules. Different etiologies may damage the LSCN, leading to limbal stem cell deficiency (LSCD), which is characterized by conjunctivalization of the cornea. In this review, we first summarize the basics of the LSCN and then focus on current and emerging bioengineering strategies for LSCN restoration to combat LSCD.
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Affiliation(s)
- Mohammad Soleimani
- Eye Research Center, Farabi Eye Hospital, Tehran University of Medical Sciences, Tehran 1336616351, Iran
- Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL 60612, USA
| | - Kasra Cheraqpour
- Eye Research Center, Farabi Eye Hospital, Tehran University of Medical Sciences, Tehran 1336616351, Iran
| | - Raghuram Koganti
- Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL 60612, USA
| | - Seyed Mahbod Baharnoori
- Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL 60612, USA
| | - Ali R. Djalilian
- Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL 60612, USA
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23
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Soleimani M, Masoumi A, Momenaei B, Cheraqpour K, Koganti R, Chang AY, Ghassemi M, Djalilian AR. Applications of mesenchymal stem cells in ocular surface diseases: sources and routes of delivery. Expert Opin Biol Ther 2023; 23:509-525. [PMID: 36719365 PMCID: PMC10313829 DOI: 10.1080/14712598.2023.2175605] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Accepted: 01/30/2023] [Indexed: 02/01/2023]
Abstract
INTRODUCTION Mesenchymal stem cells (MSCs) are novel, promising agents for treating ocular surface disorders. MSCs can be isolated from several tissues and delivered by local or systemic routes. They produce several trophic factors and cytokines, which affect immunomodulatory, transdifferentiating, angiogenic, and pro-survival pathways in their local microenvironment via paracrine secretion. Moreover, they exert their therapeutic effect through a contact-dependent manner. AREAS COVERED In this review, we discuss the characteristics, sources, delivery methods, and applications of MSCs in ocular surface disorders. We also explore the potential application of MSCs to inhibit senescence at the ocular surface. EXPERT OPINION Therapeutic application of MSCs in ocular surface disorders are currently under investigation. One major research area is corneal epitheliopathies, including chemical or thermal burns, limbal stem cell deficiency, neurotrophic keratopathy, and infectious keratitis. MSCs can promote corneal epithelial repair and prevent visually devastating sequelae of non-healing wounds. However, the optimal dosages and delivery routes have yet to be determined and further clinical trials are needed to address these fundamental questions.
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Affiliation(s)
- Mohammad Soleimani
- Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL, USA
- Eye Research Center, Farabi Eye Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Ahmad Masoumi
- Eye Research Center, Farabi Eye Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Bita Momenaei
- Eye Research Center, Farabi Eye Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Kasra Cheraqpour
- Eye Research Center, Farabi Eye Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Raghuram Koganti
- Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL, USA
| | - Arthur Y Chang
- Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL, USA
| | - Mahmoud Ghassemi
- Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL, USA
| | - Ali R Djalilian
- Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL, USA
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24
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The progress in techniques for culturing human limbal epithelial stem cells. Hum Cell 2023; 36:1-14. [PMID: 36181663 DOI: 10.1007/s13577-022-00794-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Accepted: 09/11/2022] [Indexed: 01/07/2023]
Abstract
In vitro culture of human limbal epithelial stem cells (hLESCs) is crucial to cell therapy in the treatment of limbal stem cell deficiency, a potentially vision-threatening disease that is characterized by persistent corneal epithelial defects and corneal epithelium conjunctivalization. Traditionally, hLESCs are cultivated based on either limbal tissue explants or single-cell suspensions in culture media containing xenogenous components, such as fetal bovine serum and murine 3T3 feeder cells. Plastic culture dishes and human amniotic membranes are classical growth substrates used in conventional hLESC culture systems. The past few decades have witnessed considerable progress and innovations in hLESC culture techniques to ensure a higher level of biosafety and lower immunogenicity for further cell treatment, including complete removal of xenogenous components from culture media, the application of human-derived feeder cells, and the development of novel scaffolds. Three-dimensional artificial niches and three-dimensional culture techniques have also been established to simulate the real microenvironment of limbal crypts for better cell outgrowth and proliferation. All these progresses ensure that in vitro cultured hLESCs are more adaptable to translational stem cell therapy for limbal stem cell deficiency.
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Jiang Y, Lin S, Gao Y. Mesenchymal Stromal Cell-Based Therapy for Dry Eye: Current Status and Future Perspectives. Cell Transplant 2022; 31:9636897221133818. [PMID: 36398793 PMCID: PMC9679336 DOI: 10.1177/09636897221133818] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
Dry eye is one of the most common chronic diseases in ophthalmology. It affects quality of life and has become a public health problem that cannot be ignored. The current treatment methods mainly include artificial tear replacement therapy, anti-inflammatory therapy, and local immunosuppressive therapy. These treatments are mainly limited to improvement of ocular surface discomfort and other symptoms. In recent years, regenerative medicine has developed rapidly, and ophthalmologists are working on new methods to treat dry eye. Mesenchymal stromal cells (MSCs) have anti-inflammatory, tissue repair, and immune regulatory effects, and have become a promising tool for the treatment of dry eye. These effects can also be produced by MSC-derived exosomes (MSC-Exos). As a cell-free therapy, MSC-Exos are hypoimmunogenic, serve more stable entities, and compared with MSCs, reduce the safety risks associated with the injection of live cells. This article reviews current knowledge about MSCs and MSC-Exos, and highlights the latest progress and future prospects of MSC-based therapy in dry eye treatment.
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Affiliation(s)
- Yuting Jiang
- Department of Ophthalmology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
| | - Shu Lin
- Diabetes and Metabolism Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
| | - Yingying Gao
- Department of Ophthalmology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China,Yingying Gao, The Second Affiliated Hospital of Fujian Medical University, No. 34 North Zhongshan Road, Quanzhou 362000, Fujian, China.
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26
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He X, Li X, Du X, Han J, Zhang H, Zhu Y, Ma H. Rs420137, rs386360 and rs7763726 polymorphisms in fibronectin type III domain containing 1 are associated with susceptibility to coronary heart disease: Analysis in the Han population. Front Cardiovasc Med 2022; 9:964978. [PMID: 36277792 PMCID: PMC9583258 DOI: 10.3389/fcvm.2022.964978] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Accepted: 09/20/2022] [Indexed: 11/13/2022] Open
Abstract
Background Numerous genetic studies have shown that genes are related to the pathogenesis of coronary heart disease (CHD). The main aim of this study was to confirm whether fibronectin type III domain containing 1 (FNDC1) polymorphisms correlate with the risk of CHD. Methods In this study, in order to assess the association between three FNDC1 single nucleotide polymorphisms (SNPs) and the risk of CHD, we conducted a case-control study involving 630 patients with CHD and 568 healthy controls using Agena MassARRAY (Agena Bioscience, San Diego, CA, USA). Genotype distribution in case and control groups was analyzed by Chi square test. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by logistic regression models adjusted for age, sex, smoking, and alcohol consumption to assess the correlation between SNPs and CHD risk. Results Our results indicated that FNDC1-rs420137, -rs386360, and -rs7763726 played important roles in enhancing the risk of CHD. Subgroup analysis revealed that rs420137 increased the susceptibility to CHD in males, smokers, and patients aged ≤62 years. Rs360 had an increased risk of CHD in males, patients at aged ≤62 years, smokers, and non-drinkers. Furthermore, the association of rs7763726 with increased CHD risk was also observed in males, patients aged ≤62 years, smokers, and drinkers. Last but not least, these three SNPs we selected were protective factors against hypertension in CHD individuals. Conclusion Our research suggest that FNDC1-rs420137, -rs386360, and -rs7763726 variants may be regarded as novel biomarkers for predicting CHD risk and other specific mechanisms of action of CHD need to be further studied.
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Affiliation(s)
| | | | | | | | | | | | - Honghong Ma
- *Correspondence: Honghong Ma mhh1001@sohucom
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27
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Dias IE, Viegas CA, Requicha JF, Saavedra MJ, Azevedo JM, Carvalho PP, Dias IR. Mesenchymal Stem Cell Studies in the Goat Model for Biomedical Research-A Review of the Scientific Literature. BIOLOGY 2022; 11:1276. [PMID: 36138755 PMCID: PMC9495984 DOI: 10.3390/biology11091276] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Revised: 08/18/2022] [Accepted: 08/24/2022] [Indexed: 12/02/2022]
Abstract
Mesenchymal stem cells (MSCs) are multipotent cells, defined by their ability to self-renew, while maintaining the capacity to differentiate into different cellular lineages, presumably from their own germinal layer. MSCs therapy is based on its anti-inflammatory, immunomodulatory, and regenerative potential. Firstly, they can differentiate into the target cell type, allowing them to regenerate the damaged area. Secondly, they have a great immunomodulatory capacity through paracrine effects (by secreting several cytokines and growth factors to adjacent cells) and by cell-to-cell contact, leading to vascularization, cellular proliferation in wounded tissues, and reducing inflammation. Currently, MSCs are being widely investigated for numerous tissue engineering and regenerative medicine applications. Appropriate animal models are crucial for the development and evaluation of regenerative medicine-based treatments and eventual treatments for debilitating diseases with the hope of application in upcoming human clinical trials. Here, we summarize the latest research focused on studying the biological and therapeutic potential of MSCs in the goat model, namely in the fields of orthopedics, dermatology, ophthalmology, dentistry, pneumology, cardiology, and urology fields.
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Affiliation(s)
- Inês E. Dias
- CITAB—Centre for the Research and Technology of Agro-Environmental and Biological Sciences, Universidade de Trás-os-Montes e Alto Douro (UTAD), Quinta de Prados, 5000-801 Vila Real, Portugal
- Inov4Agro—Institute for Innovation, Capacity Building and Sustainability of Agri-Food Production, 5000-801 Vila Real, Portugal
| | - Carlos A. Viegas
- CITAB—Centre for the Research and Technology of Agro-Environmental and Biological Sciences, Universidade de Trás-os-Montes e Alto Douro (UTAD), Quinta de Prados, 5000-801 Vila Real, Portugal
- Inov4Agro—Institute for Innovation, Capacity Building and Sustainability of Agri-Food Production, 5000-801 Vila Real, Portugal
- Department of Veterinary Sciences, School of Agricultural and Veterinary Sciences (ECAV), UTAD, Quinta de Prados, 5000-801 Vila Real, Portugal
- CECAV—Centre for Animal Sciences and Veterinary Studies, UTAD, Quinta de Prados, 5000-801 Vila Real, Portugal
- AL4AnimalS—Associate Laboratory for Animal and Veterinary Sciences, 1300-477 Lisboa, Portugal
| | - João F. Requicha
- Department of Veterinary Sciences, School of Agricultural and Veterinary Sciences (ECAV), UTAD, Quinta de Prados, 5000-801 Vila Real, Portugal
- CECAV—Centre for Animal Sciences and Veterinary Studies, UTAD, Quinta de Prados, 5000-801 Vila Real, Portugal
- AL4AnimalS—Associate Laboratory for Animal and Veterinary Sciences, 1300-477 Lisboa, Portugal
| | - Maria J. Saavedra
- CITAB—Centre for the Research and Technology of Agro-Environmental and Biological Sciences, Universidade de Trás-os-Montes e Alto Douro (UTAD), Quinta de Prados, 5000-801 Vila Real, Portugal
- Inov4Agro—Institute for Innovation, Capacity Building and Sustainability of Agri-Food Production, 5000-801 Vila Real, Portugal
- Department of Veterinary Sciences, School of Agricultural and Veterinary Sciences (ECAV), UTAD, Quinta de Prados, 5000-801 Vila Real, Portugal
| | - Jorge M. Azevedo
- CECAV—Centre for Animal Sciences and Veterinary Studies, UTAD, Quinta de Prados, 5000-801 Vila Real, Portugal
- AL4AnimalS—Associate Laboratory for Animal and Veterinary Sciences, 1300-477 Lisboa, Portugal
- Department of Animal Science, ECAV, UTAD, Quinta de Prados, 5000-801 Vila Real, Portugal
| | - Pedro P. Carvalho
- CIVG—Vasco da Gama Research Center, University School Vasco da Gama (EUVG), Av. José R. Sousa Fernandes, Campus Universitário, Lordemão, 3020-210 Coimbra, Portugal
- Vetherapy—Research and Development in Biotechnology, 3020-210 Coimbra, Portugal
| | - Isabel R. Dias
- CITAB—Centre for the Research and Technology of Agro-Environmental and Biological Sciences, Universidade de Trás-os-Montes e Alto Douro (UTAD), Quinta de Prados, 5000-801 Vila Real, Portugal
- Inov4Agro—Institute for Innovation, Capacity Building and Sustainability of Agri-Food Production, 5000-801 Vila Real, Portugal
- Department of Veterinary Sciences, School of Agricultural and Veterinary Sciences (ECAV), UTAD, Quinta de Prados, 5000-801 Vila Real, Portugal
- CECAV—Centre for Animal Sciences and Veterinary Studies, UTAD, Quinta de Prados, 5000-801 Vila Real, Portugal
- AL4AnimalS—Associate Laboratory for Animal and Veterinary Sciences, 1300-477 Lisboa, Portugal
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Corneal Regeneration Using Adipose-Derived Mesenchymal Stem Cells. Cells 2022; 11:cells11162549. [PMID: 36010626 PMCID: PMC9406486 DOI: 10.3390/cells11162549] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Revised: 08/12/2022] [Accepted: 08/12/2022] [Indexed: 11/28/2022] Open
Abstract
Adipose-derived stem cells are a subtype of mesenchymal stem cell that offers the important advantage of being easily obtained (in an autologous manner) from low invasive procedures, rendering a high number of multipotent stem cells with the potential to differentiate into several cellular lineages, to show immunomodulatory properties, and to promote tissue regeneration by a paracrine action through the secretion of extracellular vesicles containing trophic factors. This secretome is currently being investigated as a potential source for a cell-free based regenerative therapy for human tissues, which would significantly reduce the involved costs, risks and law regulations, allowing for a broader application in real clinical practice. In the current article, we will review the existing preclinical and human clinical evidence regarding the use of such adipose-derived mesenchymal stem cells for the regeneration of the three main layers of the human cornea: the epithelium (derived from the surface ectoderm), the stroma (derived from the neural crest mesenchyme), and the endothelium (derived from the neural crest cells).
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Kou M, Huang L, Yang J, Chiang Z, Chen S, Liu J, Guo L, Zhang X, Zhou X, Xu X, Yan X, Wang Y, Zhang J, Xu A, Tse HF, Lian Q. Mesenchymal stem cell-derived extracellular vesicles for immunomodulation and regeneration: a next generation therapeutic tool? Cell Death Dis 2022; 13:580. [PMID: 35787632 PMCID: PMC9252569 DOI: 10.1038/s41419-022-05034-x] [Citation(s) in RCA: 254] [Impact Index Per Article: 84.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Revised: 06/08/2022] [Accepted: 06/22/2022] [Indexed: 02/06/2023]
Abstract
Mesenchymal stem cells (MSCs) can be widely isolated from various tissues including bone marrow, umbilical cord, and adipose tissue, with the potential for self-renewal and multipotent differentiation. There is compelling evidence that the therapeutic effect of MSCs mainly depends on their paracrine action. Extracellular vesicles (EVs) are fundamental paracrine effectors of MSCs and play a crucial role in intercellular communication, existing in various body fluids and cell supernatants. Since MSC-derived EVs retain the function of protocells and have lower immunogenicity, they have a wide range of prospective therapeutic applications with advantages over cell therapy. We describe some characteristics of MSC-EVs, and discuss their role in immune regulation and regeneration, with emphasis on the molecular mechanism and application of MSC-EVs in the treatment of fibrosis and support tissue repair. We also highlight current challenges in the clinical application of MSC-EVs and potential ways to overcome the problem of quality heterogeneity.
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Affiliation(s)
- Meng Kou
- Cord Blood Bank Centre, Guangzhou Women and Children's Medical Centre, Guangzhou Medical University, Guangzhou, China
| | - Li Huang
- Cord Blood Bank Centre, Guangzhou Women and Children's Medical Centre, Guangzhou Medical University, Guangzhou, China
| | - Jinjuan Yang
- Cord Blood Bank Centre, Guangzhou Women and Children's Medical Centre, Guangzhou Medical University, Guangzhou, China
| | - Zhixin Chiang
- Department of Allied Health Sciences Faculty of Science, Tunku Abdul Rahman University, Ipoh, Malaysia
| | - Shaoxiang Chen
- Cord Blood Bank Centre, Guangzhou Women and Children's Medical Centre, Guangzhou Medical University, Guangzhou, China
| | - Jie Liu
- State Key Laboratory of Pharmaceutical Biotechnology, the University of Hong Kong, Hong Kong SAR, China
- Department of Medicine, the University of Hong Kong, Hong Kong SAR, China
| | - Liyan Guo
- Cord Blood Bank Centre, Guangzhou Women and Children's Medical Centre, Guangzhou Medical University, Guangzhou, China
| | - Xiaoxian Zhang
- Cord Blood Bank Centre, Guangzhou Women and Children's Medical Centre, Guangzhou Medical University, Guangzhou, China
| | - Xiaoya Zhou
- Cord Blood Bank Centre, Guangzhou Women and Children's Medical Centre, Guangzhou Medical University, Guangzhou, China
| | - Xiang Xu
- Department of Stem Cell & Regenerative Medicine, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital, Army Medical University, Chongqing, 400042, China
| | - Xiaomei Yan
- Department of Chemical Biology, The MOE Key Laboratory of Spectrochemical Analysis & Instrumentation, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, Fujian, 361005, China
| | - Yan Wang
- Xiamen Cardiovascular Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
| | - Jinqiu Zhang
- Cord Blood Bank Centre, Guangzhou Women and Children's Medical Centre, Guangzhou Medical University, Guangzhou, China
| | - Aimin Xu
- State Key Laboratory of Pharmaceutical Biotechnology, the University of Hong Kong, Hong Kong SAR, China
- Department of Medicine, the University of Hong Kong, Hong Kong SAR, China
| | - Hung-Fat Tse
- Department of Medicine, the University of Hong Kong, Hong Kong SAR, China
- HKUMed Laboratory of Cellular Therapeutics, the University of Hong Kong, Hong Kong SAR, China
| | - Qizhou Lian
- Cord Blood Bank Centre, Guangzhou Women and Children's Medical Centre, Guangzhou Medical University, Guangzhou, China.
- State Key Laboratory of Pharmaceutical Biotechnology, the University of Hong Kong, Hong Kong SAR, China.
- Department of Medicine, the University of Hong Kong, Hong Kong SAR, China.
- HKUMed Laboratory of Cellular Therapeutics, the University of Hong Kong, Hong Kong SAR, China.
- Department of Surgery, Shenzhen Hong Kong University Hospital, Shenzhen, 518053, China.
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Fu YS, Chen PR, Yeh CC, Pan JY, Kuo WC, Tseng KW. Human Umbilical Mesenchymal Stem Cell Xenografts Repair UV-Induced Photokeratitis in a Rat Model. Biomedicines 2022; 10:biomedicines10051125. [PMID: 35625862 PMCID: PMC9138504 DOI: 10.3390/biomedicines10051125] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Revised: 05/09/2022] [Accepted: 05/10/2022] [Indexed: 01/04/2023] Open
Abstract
Most patients with a corneal injury are administered anti-inflammatory medications and antibiotics, but no other treatments are currently available. Thus, the corneal injury healing is unsatisfactory, affects the vision, and has a risk of blindness in severe cases. Human umbilical mesenchymal stem cells exhibit pluripotent and anti-inflammatory properties and do not cause immunological rejection in the host. Rats were irradiated with type B ultraviolet (UVB) light to generate a stable animal model of photokeratitis. After irradiation-induced photokeratitis, human umbilical mesenchymal stem cells were implanted into the subconjunctival space of the lateral sclera, and the changes in the corneal pathology were evaluated. Three weeks after implantation, many mesenchymal stem cells were visible in the subconjunctival space. These mesenchymal stem cells effectively reduced the extent of injury to the adjacent corneal tissue. They accelerated the epithelial layer repair, reduced the inflammatory response and neovascularization, and improved the disorganization of collagen and fibronectin in the corneal stroma caused by the injury. In conclusion, xenografted human umbilical mesenchymal stem cells can survive in rat eye tissues for a long time, effectively support the structural integrity of injured corneal tissues, restore corneal permeability, and reduce abnormal neovascularization. This study provides a new approach to the treatment of photokeratitis.
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Affiliation(s)
- Yu-Show Fu
- Department of Anatomy and Cell Biology, School of Medicine, National Yang Ming Chiao Tung University, Taipei 112, Taiwan;
| | - Po-Ru Chen
- Institute of Anatomy and Cell Biology, School of Medicine, National Yang Ming Chiao Tung University, Taipei 112, Taiwan;
| | - Chang-Ching Yeh
- Department of Obstetrics and Gynecology, Taipei Veterans General Hospital, Taipei 112, Taiwan;
- Department of Obstetrics and Gynecology, National Yang Ming Chiao Tung University, Taipei 112, Taiwan
- Department of Nurse-Midwifery and Women Health, National Taipei University of Nursing and Health Sciences, Taipei 112, Taiwan
| | - Jian-Yu Pan
- Institute of Biophotonics, National Yang Ming Chiao Tung University, Taipei 112, Taiwan;
| | - Wen-Chuan Kuo
- Institute of Biophotonics, National Yang Ming Chiao Tung University, Taipei 112, Taiwan;
- Correspondence: (W.-C.K.); (K.-W.T.); Tel.: +886-2-2826-7000 (ext. 7950) (W.-C.K.); +886-2-2636-0303 (ext. 1227) (K.-W.T.)
| | - Kuang-Wen Tseng
- Department of Medicine, Mackay Medical College, New Taipei 252, Taiwan
- Correspondence: (W.-C.K.); (K.-W.T.); Tel.: +886-2-2826-7000 (ext. 7950) (W.-C.K.); +886-2-2636-0303 (ext. 1227) (K.-W.T.)
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Retracted: The Favorable Effect of Mesenchymal Stem Cell Treatment on the Antioxidant Protective Mechanism in the Corneal Epithelium and Renewal of Corneal Optical Properties Changed after Alkali Burns. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:9854827. [PMID: 35602103 PMCID: PMC9117029 DOI: 10.1155/2022/9854827] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Accepted: 04/06/2022] [Indexed: 11/17/2022]
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Retracted: An Immunohistochemical Study of the Increase in Antioxidant Capacity of Corneal Epithelial Cells by Molecular Hydrogen, Leading to the Suppression of Alkali-Induced Oxidative Stress. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:9831406. [PMID: 35585882 PMCID: PMC9110204 DOI: 10.1155/2022/9831406] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Accepted: 04/06/2022] [Indexed: 11/18/2022]
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33
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Retracted: Molecular Hydrogen Effectively Heals Alkali-Injured Cornea via Suppression of Oxidative Stress. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:9846572. [PMID: 35585887 PMCID: PMC9110205 DOI: 10.1155/2022/9846572] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Accepted: 04/06/2022] [Indexed: 11/18/2022]
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The Inability of Ex Vivo Expanded Mesenchymal Stem/Stromal Cells to Survive in Newborn Mice and to Induce Transplantation Tolerance. Stem Cell Rev Rep 2022; 18:2365-2375. [PMID: 35288846 DOI: 10.1007/s12015-022-10363-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/07/2022] [Indexed: 11/09/2022]
Abstract
An encounter of the developing immune system with an antigen results in the induction of immunological areactivity to this antigen. In the case of transplantation antigens, the application of allogeneic hematopoietic cells induces a state of neonatal transplantation tolerance. This tolerance depends on the establishment of cellular chimerism, when allogeneic cells survive in the neonatally treated recipient. Since mesenchymal stem/stromal cells (MSCs) have been shown to have low immunogenicity and often survive in allogeneic recipients, we attempted to use these cells for induction of transplantation tolerance. Newborn (less than 24 h old) C57BL/6 mice were injected intraperitoneally with 5 × 106 adipose tissue-derived MSCs isolated from allogeneic donors and the fate and survival of these cells were monitored. The impact of MSC application on the proportion of cell populations of the immune system and immunological reactivity was assessed. In addition, the survival of skin allografts in neonatally treated recipients was tested. We found that in vitro expanded MSCs did not survive in neonatal recipients, and the living MSCs were not detected few days after their application. Furthermore, there were no significant changes in the proportion of individual immune cell populations including CD4+ cell lineages, but we detected an apparent shift to the production of Th1 cytokines IL-2 and IFN-γ in neonatally treated mice. However, skin allografts in the MSC-treated recipients were promptly rejected. These results therefore show that in vitro expanded MSCs do not survive in neonatal recipients, but induce a cytokine imbalance without induction of transplantation tolerance.
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Zeb1 Regulation of Wound Healing-Induced Inflammation in Alkali-Damaged Corneas. iScience 2022; 25:104038. [PMID: 35340433 PMCID: PMC8941209 DOI: 10.1016/j.isci.2022.104038] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2021] [Revised: 12/24/2021] [Accepted: 03/03/2022] [Indexed: 11/22/2022] Open
Abstract
The cornea is an avascular tissue for vision clarity. Alkali burn could cause severe traumatic damage on the cornea with inflammation and neovascularization (NV), leading to vision reduction and blindness. Mechanisms underlying corneal inflammation and NV are not as clear. We previously reported that Zeb1 is an important factor in corneal NV, and we sought to clarify whether it is also involved in regulation of corneal inflammation. We analyzed the alkali burn-induced corneal inflammation and wound healing in both Zeb1+/+ and Zeb1−/+ littermates through a multidisciplinary approach. We provide evidence that Zeb1 forms a positive regulatory loop with Tgfb to regulate early corneal inflammation by maintenance of immune cell viability and mobility and later wound healing by activation of both Nf-κb and Tgfb-related Stat3 signaling pathways. We believe that ZEB1 is a potential therapeutic target, and inactivation of ZEB1 could be a strategy to treat severe corneal inflammation condition.
Traumatic wound induces inflammation in the cornea, resulting in vision reduction Zeb1 is a key factor to retain immune cell viability, mobility, and cytokine expression Zeb1 regulates cytokine gene expression through both Nf-κb and Stat3 pathways Inactivation of ZEB1 could be a strategy to treat severe corneal inflammation condition
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MIC-1 Antlerogenic Stem Cells Homogenate from Cervus elaphus Accelerate Corneal Burn Reepithelization in Rabbits. APPLIED SCIENCES-BASEL 2022. [DOI: 10.3390/app12052468] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
Deer antler is the only mammalian organ that can fully grow back once lost from its pedicle. Antler regeneration is a stem cell-based process. Therefore, antlers probably offer the most pertinent model for studying organ regeneration in mammals. Evaluation of the effect of deer antler stem cells on the healing of superficial and deep rabbit corneal wounds was performed. Thirty-six New Zealeand White rabbits were used in this study in superficial and deep denaturation models, and corneal erosion was performed with n-heptanol placed on the cornea for 30 and NaOH for 90 s. Antler stem cells in drop formulation with hyaluronate was used. As a control, sodium hyaluronate in the superficial model and protein-free calf blood dialysate (Solcoseryl) in the deep model were administered. In superficial corneal damage, a reduction in the area of the damaged cornea was observed from day 3 of the experiment to an adequate level: 45% in the test group and 52% in the control group relative to the baseline damage (100%). Between days 3 and 7, on average, a smaller lesion area was observed in the group receiving antler stem cells. The use of antler stem cells has resulted in a marked improvement in cornea clarity. According to the 5-point scale of corneal opacity evaluation, where 1 is completely clear and 5 is completely opaque, the first statistically significant changes were observed after 4 weeks of treatment: 3.0 in the study group, 4.1 in the control with Solcoseryl, and 4.4 in the control group. After 9 weeks, these values were, 2.5, 3.8, and 4.1, respectively. The present preliminary study shows the promising results of antlerogenic stem cells of Cervus elaphus topically applied for the treatment of corneal injury. A deeper understanding of the developmental mechanisms involved in antler renewal can be useful for controlling regeneration cornea processes.
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Tichotová L, Studenovska H, Petrovski G, Popelka Š, Nemesh Y, Sedláčková M, Drutovič S, Rohiwal S, Jendelová P, Erceg S, Brymová A, Artero‐Castro A, Lytvynchuk L, Straňák Z, Ellederová Z, Motlík J, Ardan T. Advantages of nanofibrous membranes for culturing of primary RPE cells compared to commercial scaffolds. Acta Ophthalmol 2021; 100:e1172-e1185. [PMID: 34687141 DOI: 10.1111/aos.15034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Accepted: 09/22/2021] [Indexed: 10/20/2022]
Abstract
PURPOSE Dysfunction of the retinal pigment epithelium (RPE) causes numerous forms of retinal degeneration. RPE replacement is a modern option to save vision. We aimed to test the results of transplanting cultured RPEs on biocompatible membranes. METHODS We cultivated porcine primary RPE cells isolated from cadaver eyes from the slaughterhouse on two types of membranes: commercial polyester scaffolds Transwell (Corning Inc., Kenneburg, ME, USA) with 0.4 µm pore size and prepared Poly (L-lactide-co-DL-lactide) (PDLLA) nanofibrous membranes with an average pore size of 0.4 µm. RESULTS Five types of assays were used for the analysis: immunocytochemistry (ICC), phagocytosis assay, Western blotting, real-time qPCR (RT-qPCR) and electron microscopy. RT-qPCR demonstrated that RPEs cultured on nanofibrous membranes have higher expressions of BEST1 (bestrophin 1), RLBP1 (retinaldehyde-binding protein 1), RPE65 (retinal pigment epithelium-specific 65 kDa protein), PAX6 (transcription factor PAX6), SOX9 (transcription factor SOX9), DCT (dopachrome tautomerase) and MITF (microphthalmia-associated transcription factor). ICC of the RPEs cultured on nanofibrous membranes showed more intensive staining of markers such as BEST1, MCT1 (monocarboxylate transporter 1), Na+ /K+ ATPase, RPE65 and acetylated tubulin in comparison with commercial ones. Additionally, the absence of α-SMA proved the stability of the RPE polarization state and the absence of epithelial-to-mesenchymal transition. RPE possessed high phagocytic activity. Electron microscopy of both membranes confirmed a confluent layer of RPE cells and their genuine morphological structure, which was comparable to native RPEs. CONCLUSIONS Retinal pigment epitheliums cultured on polylactide nanofibrous membranes improved the final quality of the cell product by having better maturation and long-term survival of the RPE monolayer compared to those cultured on commercial polyester scaffolds. PDLLA-cultured RPEs are a plausible source for the replacement of non-functioning RPEs during cell therapy.
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Affiliation(s)
- Lucie Tichotová
- Institute of Animal Physiology and Genetics Academy of Sciences of the Czech Republic Libechov Czech Republic
- Department of Cell Biology Faculty of Science Charles University Prague Czech Republic
| | - Hana Studenovska
- Institute of Macromolecular Chemistry Academy of Sciences of the Czech Republic Prague Czech Republic
| | - Goran Petrovski
- Center for Eye Research Department of Ophthalmology Oslo University Hospital and Institute for Clinical Medicine University of Oslo Oslo Norway
| | - Štěpán Popelka
- Institute of Macromolecular Chemistry Academy of Sciences of the Czech Republic Prague Czech Republic
| | - Yaroslav Nemesh
- Institute of Animal Physiology and Genetics Academy of Sciences of the Czech Republic Libechov Czech Republic
- Department of Cell Biology Faculty of Science Charles University Prague Czech Republic
| | - Miroslava Sedláčková
- Department of Histology and Embryology Faculty of Medicine Masaryk University Brno Czech Republic
| | - Saskia Drutovič
- Institute of Animal Physiology and Genetics Academy of Sciences of the Czech Republic Libechov Czech Republic
| | - Sonali Rohiwal
- Institute of Animal Physiology and Genetics Academy of Sciences of the Czech Republic Libechov Czech Republic
| | - Pavla Jendelová
- Institute of Experimental Medicine Academy of Sciences of the Czech Republic Prague Czech Republic
| | - Slaven Erceg
- Institute of Experimental Medicine Academy of Sciences of the Czech Republic Prague Czech Republic
- Stem Cell Therapies in Neurodegenerative Diseases Lab Research Center ‘Principe Felipe’ Valencia Spain
| | - Anna Brymová
- Institute of Animal Physiology and Genetics Academy of Sciences of the Czech Republic Libechov Czech Republic
- Department of Cell Biology Faculty of Science Charles University Prague Czech Republic
| | - Ana Artero‐Castro
- Stem Cell Therapies in Neurodegenerative Diseases Lab Research Center ‘Principe Felipe’ Valencia Spain
| | - Lyubomyr Lytvynchuk
- Department of Ophthalmology Justus‐Liebig‐University Giessen University Hospital Giessen and Marburg Giessen Germany
| | - Zbyněk Straňák
- Ophthalmology Department of 3rd Faculty of Medicine Charles University and University Hospital Kralovske Vinohrady Prague Czech Republic
- Third Faculty of Medicine Charles University Prague Czech Republic
| | - Zdeňka Ellederová
- Institute of Animal Physiology and Genetics Academy of Sciences of the Czech Republic Libechov Czech Republic
| | - Jan Motlík
- Institute of Animal Physiology and Genetics Academy of Sciences of the Czech Republic Libechov Czech Republic
| | - Taras Ardan
- Institute of Animal Physiology and Genetics Academy of Sciences of the Czech Republic Libechov Czech Republic
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Evaluating the clinical translational relevance of animal models for limbal stem cell deficiency: A systematic review. Ocul Surf 2021; 23:169-183. [PMID: 34583088 DOI: 10.1016/j.jtos.2021.09.006] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2021] [Revised: 09/20/2021] [Accepted: 09/23/2021] [Indexed: 12/13/2022]
Abstract
PURPOSE Animal models are pivotal for elucidating pathophysiological mechanisms and evaluating novel therapies. This systematic review identified studies that developed or adapted animal models of limbal stem cell deficiency (LSCD), assessed their reporting quality, summarized their key characteristics, and established their clinical translational relevance to human disease. METHODS The protocol was prospectively registered (PROSPERO CRD42020203937). Searches were conducted in PubMed, Ovid EMBASE and Web of Science in August 2020. Two authors screened citations, extracted data, assessed the reporting quality of eligible studies using the ARRIVE guidelines, and judged the clinical translational relevance of each model using a custom matrix. RESULTS 105 studies were included. Rabbits were the most common animal species. Overall, 97% of studies recapitulated LSCD to a clinical etiology, however 62% did not provide sufficient methodological detail to enable independent reproduction of the model. Adverse events and/or exclusion of animals were infrequently (20%) reported. Approximately one-quarter of studies did not produce the intended severity of LSCD; 34% provided insufficient information to assess the fidelity of disease induction. Adjunctive diagnostic confirmation of LSCD induction was performed in 13% of studies. CONCLUSIONS This is the first systematic review to assess the reporting quality and clinical translational relevance of animal models of LSCD. Models of LSCD have evolved over time, resulting in variable reporting of the characteristics of animals, experimental procedures and adverse events. In most studies, validation of LSCD was made using clinical tests; newer adjunctive techniques would enhance diagnostic validation. As most studies sought to evaluate novel therapies for LSCD, animal models should ideally recapitulate all features of the condition that develop in patients.
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Gu C, Feng J, Waqas A, Deng Y, Zhang Y, Chen W, Long J, Huang S, Chen L. Technological Advances of 3D Scaffold-Based Stem Cell/Exosome Therapy in Tissues and Organs. Front Cell Dev Biol 2021; 9:709204. [PMID: 34568322 PMCID: PMC8458970 DOI: 10.3389/fcell.2021.709204] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Accepted: 08/05/2021] [Indexed: 12/12/2022] Open
Abstract
Recently, biomaterial scaffolds have been widely applied in the field of tissue engineering and regenerative medicine. Due to different production methods, unique types of three-dimensional (3D) scaffolds can be fabricated to meet the structural characteristics of tissues and organs, and provide suitable 3D microenvironments. The therapeutic effects of stem cell (SC) therapy in tissues and organs are considerable and have attracted the attention of academic researchers worldwide. However, due to the limitations and challenges of SC therapy, exosome therapy can be used for basic research and clinical translation. The review briefly introduces the materials (nature or polymer), shapes (hydrogels, particles and porous solids) and fabrication methods (crosslinking or bioprinting) of 3D scaffolds, and describes the recent progress in SC/exosome therapy with 3D scaffolds over the past 5 years (2016-2020). Normal SC/exosome therapy can improve the structure and function of diseased and damaged tissues and organs. In addition, 3D scaffold-based SC/exosome therapy can significantly improve the structure and function cardiac and neural tissues for the treatment of various refractory diseases. Besides, exosome therapy has the same therapeutic effects as SC therapy but without the disadvantages. Hence, 3D scaffold therapy provides an alternative strategy for treatment of refractory and incurable diseases and has entered a transformation period from basic research into clinical translation as a viable therapeutic option in the future.
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Affiliation(s)
- Chenyang Gu
- Department of Neurosurgery, Neuroscience Center, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
| | - Jia Feng
- Department of Neurosurgery, Neuroscience Center, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
- School of Medicine, Southeast University, Nanjing, China
| | - Ahmed Waqas
- School of Medicine, Southeast University, Nanjing, China
| | - Yushu Deng
- Department of Neurosurgery, Neuroscience Center, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
| | - Yifan Zhang
- Department of Neurosurgery, Neuroscience Center, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
| | - Wanghao Chen
- Department of Neurosurgery, Ninth People Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jun Long
- Department of Neurosurgery, Neuroscience Center, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
| | - Shiying Huang
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
| | - Lukui Chen
- Department of Neurosurgery, Neuroscience Center, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
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Derivation and Characterization of EGFP-Labeled Rabbit Limbal Mesenchymal Stem Cells and Their Potential for Research in Regenerative Ophthalmology. Biomedicines 2021; 9:biomedicines9091134. [PMID: 34572321 PMCID: PMC8465718 DOI: 10.3390/biomedicines9091134] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Revised: 08/24/2021] [Accepted: 08/28/2021] [Indexed: 12/13/2022] Open
Abstract
The development of cell-based approaches to the treatment of various cornea pathologies, including limbal stem cell deficiency (LSCD), is an area of current interest in regenerative biomedicine. In this context, the shortage of donor material is urgent, and limbal mesenchymal stem cells (L-MSCs) may become a promising cell source for the development of these novel approaches, being established mainly within the rabbit model. In this study, we obtained and characterized rabbit L-MSCs and modified them with lentiviral transduction to express the green fluorescent protein EGFP (L-MSCs-EGFP). L-MSCs and L-MSCs-EGFP express not only stem cell markers specific for mesenchymal stem cells but also ABCG2, ABCB5, ALDH3A1, PAX6, and p63a specific for limbal epithelial stem cells (LESCs), as well as various cytokeratins (3/12, 15, 19). L-MSCs-EGFP have been proven to differentiate into adipogenic, osteogenic, and chondrogenic directions, as well as to transdifferentiate into epithelial cells. The possibility of using L-MSCs-EGFP to study the biocompatibility of various scaffolds developed to treat corneal pathologies was demonstrated. L-MSCs-EGFP may become a useful tool for studying regenerative processes occurring during the treatment of various corneal pathologies, including LSCD, with the use of cell-based technologies.
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Adak S, Magdalene D, Deshmukh S, Das D, Jaganathan BG. A Review on Mesenchymal Stem Cells for Treatment of Retinal Diseases. Stem Cell Rev Rep 2021; 17:1154-1173. [PMID: 33410097 PMCID: PMC7787584 DOI: 10.1007/s12015-020-10090-x] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/16/2020] [Indexed: 12/12/2022]
Abstract
Mesenchymal Stem Cells (MSCs) have been studied extensively for the treatment of several retinal diseases. The therapeutic potential of MSCs lies in its ability to differentiate into multiple lineages and secretome enriched with immunomodulatory, anti-angiogenic and neurotrophic factors. Several studies have reported the role of MSCs in repair and regeneration of the damaged retina where the secreted factors from MSCs prevent retinal degeneration, improve retinal morphology and function. MSCs also donate mitochondria to rescue the function of retinal cells and exosomes secreted by MSCs were found to have anti-apoptotic and anti-inflammatory effects. Based on several promising results obtained from the preclinical studies, several clinical trials were initiated to explore the potential advantages of MSCs for the treatment of retinal diseases. This review summarizes the various properties of MSCs that help to repair and restore the damaged retinal cells and its potential for the treatment of retinal degenerative diseases.
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Affiliation(s)
- Sanjucta Adak
- Stem Cells and Cancer Biology Research Group, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam, 781039, India
| | - Damaris Magdalene
- Department of Strabismus, Sri Sankaradeva Nethralaya Hospital, Guwahati, Assam, India
| | - Saurabh Deshmukh
- Department of Strabismus, Sri Sankaradeva Nethralaya Hospital, Guwahati, Assam, India
| | - Dipankar Das
- Department of Pathology, Sri Sankaradeva Nethralaya Hospital, Guwahati, Assam, India
| | - Bithiah Grace Jaganathan
- Stem Cells and Cancer Biology Research Group, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam, 781039, India.
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Abdul-Al M, Kyeremeh GK, Saeinasab M, Heidari Keshel S, Sefat F. Stem Cell Niche Microenvironment: Review. Bioengineering (Basel) 2021; 8:bioengineering8080108. [PMID: 34436111 PMCID: PMC8389324 DOI: 10.3390/bioengineering8080108] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Revised: 07/14/2021] [Accepted: 07/16/2021] [Indexed: 12/13/2022] Open
Abstract
The cornea comprises a pool of self-regenerating epithelial cells that are crucial to preserving clarity and visibility. Limbal epithelial stem cells (LESCs), which live in a specialized stem cell niche (SCN), are crucial for the survival of the human corneal epithelium. They live at the bottom of the limbal crypts, in a physically enclosed microenvironment with a number of neighboring niche cells. Scientists also simplified features of these diverse microenvironments for more analysis in situ by designing and recreating features of different SCNs. Recent methods for regenerating the corneal epithelium after serious trauma, including burns and allergic assaults, focus mainly on regenerating the LESCs. Mesenchymal stem cells, which can transform into self-renewing and skeletal tissues, hold immense interest for tissue engineering and innovative medicinal exploration. This review summarizes all types of LESCs, identity and location of the human epithelial stem cells (HESCs), reconstruction of LSCN and artificial stem cells for self-renewal.
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Affiliation(s)
- Mohamed Abdul-Al
- Department of Biomedical and Electronics Engineering, School of Engineering, University of Bradford, Bradford BD71DP, UK; (M.A.-A.); (G.K.K.)
| | - George Kumi Kyeremeh
- Department of Biomedical and Electronics Engineering, School of Engineering, University of Bradford, Bradford BD71DP, UK; (M.A.-A.); (G.K.K.)
| | - Morvarid Saeinasab
- Department of Biology, Faculty of Science, Ferdowsi University of Mashhad, Mashhad 91779 48974, Iran;
| | - Saeed Heidari Keshel
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran 19839 69411, Iran;
| | - Farshid Sefat
- Department of Biomedical and Electronics Engineering, School of Engineering, University of Bradford, Bradford BD71DP, UK; (M.A.-A.); (G.K.K.)
- Interdisciplinary Research Centre in Polymer Science & Technology (Polymer IRC), University of Bradford, Bradford BD71DP, UK
- Correspondence:
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Can Human Oral Mucosa Stem Cells Differentiate to Corneal Epithelia? Int J Mol Sci 2021; 22:ijms22115976. [PMID: 34205905 PMCID: PMC8198937 DOI: 10.3390/ijms22115976] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Revised: 05/27/2021] [Accepted: 05/28/2021] [Indexed: 12/25/2022] Open
Abstract
Human oral mucosa stem cells (hOMSCs) arise from the neural crest, they can self-renew, proliferate, and differentiate to several cell lines and could represent a good source for application in tissue engineering. Because of their anatomical location, hOMSCs are easy to isolate, have multilineage differentiation capacity and express embryonic stem cells markers such as—Sox2, Oct3/4 and Nanog. We have used SHEM (supplemented hormonal epithelial medium) media and cultured hOMSCs over human amniotic membrane and determined the cell’s capacity to differentiate to an epithelial-like phenotype and to express corneal specific epithelial markers—CK3, CK12, CK19, Pan-cadherin and E-cadherin. Our results showed that hOMSCs possess the capacity to attach to the amniotic membrane and express CK3, CK19, Pan-Cadherin and E-Cadherin without induction with SHEM media and expressed CK12 or changed the expression pattern of E-Cadherin to a punctual-like feature when treated with SHEM media. The results observed in this study show that hOMSCs possess the potential to differentiate toward epithelial cells. In conclusion, our results revealed that hOMSCs readily express markers for corneal determination and could provide the ophthalmology field with a therapeutic alternative for tissue engineering to achieve corneal replacement when compared with other techniques. Nevertheless, further studies are needed to develop a predictable therapeutic alternative for cornea replacement.
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Sánchez-Ávila RM, Vázquez N, Chacón M, Persinal-Medina M, Brea-Pastor A, Berisa-Prado S, Fernández-Vega-Cueto L, Anitua E, Meana Á, Merayo-Lloves J. Fibrin-Plasma Rich in Growth Factors Membrane for the Treatment of a Rabbit Alkali-Burn Lesion. Int J Mol Sci 2021; 22:ijms22115564. [PMID: 34070266 PMCID: PMC8197415 DOI: 10.3390/ijms22115564] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Revised: 05/17/2021] [Accepted: 05/20/2021] [Indexed: 11/16/2022] Open
Abstract
The purpose of this work is to describe the use of Fibrin-Plasma Rich in Growth Factors (PRGF) membranes for the treatment of a rabbit alkali-burn lesion. For this purpose, an alkali-burn lesion was induced in 15 rabbits. A week later, clinical events were evaluated and rabbits were divided into five treatment groups: rabbits treated with medical treatment, with a fibrin-PRGF membrane cultured with autologous or heterologous rabbit Limbal Epithelial Progenitor Cells (LEPCs), with a fibrin-PRGF membrane in a Simple Limbal Epithelial Transplantation and with a fibrin-PRGF membrane without cultured LEPCs. After 40 days of follow-up, corneas were subjected to histochemical examination and immunostaining against corneal or conjunctival markers. Seven days after alkali-burn lesion, it was observed that rabbits showed opaque cornea, new blood vessels across the limbus penetrating the cornea and epithelial defects. At the end of the follow-up period, an improvement of the clinical parameters analyzed was observed in transplanted rabbits. However, only rabbits transplanted with cultured LEPCs were positive for corneal markers. Otherwise, rabbits in the other three groups showed positive staining against conjunctival markers. In conclusion, fibrin-PRGF membrane improved the chemically induced lesions. Nonetheless, only fibrin-PRGF membranes cultured with rabbit LEPCs were able to restore the corneal surface.
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Affiliation(s)
- Ronald M. Sánchez-Ávila
- Instituto Universitario Fernández-Vega, Fundación de Investigación Oftalmológica, Universidad de Oviedo, 33071 Oviedo, Spain; (R.M.S.-Á.); (N.V.); (M.C.); (M.P.-M.); (S.B.-P.); (L.F.-V.-C.); (J.M.-L.)
- Biotechnology Institute (BTI), 01007 Vitoria, Spain;
| | - Natalia Vázquez
- Instituto Universitario Fernández-Vega, Fundación de Investigación Oftalmológica, Universidad de Oviedo, 33071 Oviedo, Spain; (R.M.S.-Á.); (N.V.); (M.C.); (M.P.-M.); (S.B.-P.); (L.F.-V.-C.); (J.M.-L.)
- Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), 33071 Oviedo, Spain
| | - Manuel Chacón
- Instituto Universitario Fernández-Vega, Fundación de Investigación Oftalmológica, Universidad de Oviedo, 33071 Oviedo, Spain; (R.M.S.-Á.); (N.V.); (M.C.); (M.P.-M.); (S.B.-P.); (L.F.-V.-C.); (J.M.-L.)
- Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), 33071 Oviedo, Spain
| | - Mairobi Persinal-Medina
- Instituto Universitario Fernández-Vega, Fundación de Investigación Oftalmológica, Universidad de Oviedo, 33071 Oviedo, Spain; (R.M.S.-Á.); (N.V.); (M.C.); (M.P.-M.); (S.B.-P.); (L.F.-V.-C.); (J.M.-L.)
- Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), 33071 Oviedo, Spain
| | - Agustín Brea-Pastor
- Unidad de Bioterio e imagen Preclínica, Universidad de Oviedo, 33071 Oviedo, Spain;
| | - Silvia Berisa-Prado
- Instituto Universitario Fernández-Vega, Fundación de Investigación Oftalmológica, Universidad de Oviedo, 33071 Oviedo, Spain; (R.M.S.-Á.); (N.V.); (M.C.); (M.P.-M.); (S.B.-P.); (L.F.-V.-C.); (J.M.-L.)
| | - Luis Fernández-Vega-Cueto
- Instituto Universitario Fernández-Vega, Fundación de Investigación Oftalmológica, Universidad de Oviedo, 33071 Oviedo, Spain; (R.M.S.-Á.); (N.V.); (M.C.); (M.P.-M.); (S.B.-P.); (L.F.-V.-C.); (J.M.-L.)
- Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), 33071 Oviedo, Spain
| | - Eduardo Anitua
- Biotechnology Institute (BTI), 01007 Vitoria, Spain;
- University Institute for Regenerative Medicine and Oral Implantology (UIRMI), 01007 Vitoria, Spain
| | - Álvaro Meana
- Instituto Universitario Fernández-Vega, Fundación de Investigación Oftalmológica, Universidad de Oviedo, 33071 Oviedo, Spain; (R.M.S.-Á.); (N.V.); (M.C.); (M.P.-M.); (S.B.-P.); (L.F.-V.-C.); (J.M.-L.)
- Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), 33071 Oviedo, Spain
- Centro de Investigación Biomédica en Red en Enfermedades Raras (CIBERER) (U714), ISCII, 28029 Madrid, Spain
- Correspondence: ; Tel.: +34-985-240-141; Fax: +34-985-233-288
| | - Jesús Merayo-Lloves
- Instituto Universitario Fernández-Vega, Fundación de Investigación Oftalmológica, Universidad de Oviedo, 33071 Oviedo, Spain; (R.M.S.-Á.); (N.V.); (M.C.); (M.P.-M.); (S.B.-P.); (L.F.-V.-C.); (J.M.-L.)
- Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), 33071 Oviedo, Spain
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Gorodetsky R, Aicher WK. Allogenic Use of Human Placenta-Derived Stromal Cells as a Highly Active Subtype of Mesenchymal Stromal Cells for Cell-Based Therapies. Int J Mol Sci 2021; 22:5302. [PMID: 34069909 PMCID: PMC8157571 DOI: 10.3390/ijms22105302] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Revised: 05/14/2021] [Accepted: 05/14/2021] [Indexed: 12/13/2022] Open
Abstract
The application of mesenchymal stromal cells (MSCs) from different sources, including bone marrow (BM, bmMSCs), adipose tissue (atMSCs), and human term placenta (hPSCs) has been proposed for various clinical purposes. Accumulated evidence suggests that the activity of the different MSCs is indirect and associated with paracrine release of pro-regenerative and anti-inflammatory factors. A major limitation of bmMSCs-based treatment for autologous application is the limited yield of cells harvested from BM and the invasiveness of the procedure. Similar effects of autologous and allogeneic MSCs isolated from various other tissues were reported. The easily available fresh human placenta seems to represent a preferred source for harvesting abundant numbers of human hPSCs for allogenic use. Cells derived from the neonate tissues of the placenta (f-hPSC) can undergo extended expansion with a low risk of senescence. The low expression of HLA class I and II on f-hPSCs reduces the risk of rejection in allogeneic or xenogeneic applications in normal immunocompetent hosts. The main advantage of hPSCs-based therapies seems to lie in the secretion of a wide range of pro-regenerative and anti-inflammatory factors. This renders hPSCs as a very competent cell for therapy in humans or animal models. This review summarizes the therapeutic potential of allogeneic applications of f-hPSCs, with reference to their indirect pro-regenerative and anti-inflammatory effects and discusses clinical feasibility studies.
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Affiliation(s)
- Raphael Gorodetsky
- Biotechnology and Radiobiology Laboratory, Sharett Institute of Oncology, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel
| | - Wilhelm K. Aicher
- Center of Medical Research, Department of Urology at UKT, Eberhard-Karls-University, 72076 Tuebingen, Germany
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Nieto-Nicolau N, Martínez-Conesa EM, Fuentes-Julián S, Arnalich-Montiel F, García-Tuñón I, De Miguel MP, Casaroli-Marano RP. Priming human adipose-derived mesenchymal stem cells for corneal surface regeneration. J Cell Mol Med 2021; 25:5124-5137. [PMID: 33951289 PMCID: PMC8178265 DOI: 10.1111/jcmm.16501] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2019] [Revised: 03/17/2021] [Accepted: 03/18/2021] [Indexed: 12/13/2022] Open
Abstract
Limbal stem cells (LSC) maintain the transparency of the corneal epithelium. Chemical burns lead the loss of LSC inducing an up-regulation of pro-inflammatory and pro-angiogenic factors, triggering corneal neovascularization and blindness. Adipose tissue-derived mesenchymal stem cells (AT-MSC) have shown promise in animal models to treat LSC deficiency (LSCD), but there are not studies showing their efficacy when primed with different media before transplantation. We cultured AT-MSC with standard medium and media used to culture LSC for clinical application. We demonstrated that different media changed the AT-MSC paracrine secretion showing different paracrine effector functions in an in vivo model of chemical burn and in response to a novel in vitro model of corneal inflammation by alkali induction. Treatment of LSCD with AT-MSC changed the angiogenic and inflammatory cytokine profile of mice corneas. AT-MSC cultured with the medium that improved their cytokine secretion, enhanced the anti-angiogenic and anti-inflammatory profile of the treated corneas. Those corneas also presented better outcome in terms of corneal transparency, neovascularization and histologic reconstruction. Priming human AT-MSC with LSC specific medium can potentiate their ability to improve corneal wound healing, decrease neovascularization and inflammation modulating paracrine effector functions in an in vivo optimized rat model of LSCD.
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Affiliation(s)
- Núria Nieto-Nicolau
- CellTec-UB, Department of Cell Biology, University of Barcelona, Barcelona, Spain.,Barcelona Tissue Bank (BTB), Banc de Sang I Teixits (BST), Barcelona, Spain.,Institute of Biomedical Research IIB-Sant Pau (SGR1113), Barcelona, Spain
| | - Eva M Martínez-Conesa
- Barcelona Tissue Bank (BTB), Banc de Sang I Teixits (BST), Barcelona, Spain.,Institute of Biomedical Research IIB-Sant Pau (SGR1113), Barcelona, Spain
| | | | | | - Ignacio García-Tuñón
- Cell Engineering Laboratory, La Paz Hospital Research Institute (IdiPAZ), Madrid, Spain
| | - María P De Miguel
- Cell Engineering Laboratory, La Paz Hospital Research Institute (IdiPAZ), Madrid, Spain
| | - Ricardo P Casaroli-Marano
- CellTec-UB, Department of Cell Biology, University of Barcelona, Barcelona, Spain.,Barcelona Tissue Bank (BTB), Banc de Sang I Teixits (BST), Barcelona, Spain.,Institute of Biomedical Research IIB-Sant Pau (SGR1113), Barcelona, Spain.,Department of Surgery & Hospital Clinic de Barcelona, School of Medicine, University of Barcelona, Barcelona, Spain
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Kossl J, Bohacova P, Hermankova B, Javorkova E, Zajicova A, Holan V. Antiapoptotic Properties of Mesenchymal Stem Cells in a Mouse Model of Corneal Inflammation. Stem Cells Dev 2021; 30:418-427. [PMID: 33607933 DOI: 10.1089/scd.2020.0195] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Mesenchymal stem cells (MSCs) represent a population of adult stem cells that have potent immunoregulatory, anti-inflammatory, and antiapoptotic properties. In addition, they have ability to migrate to the site of inflammation or injury, where they contribute to the regeneration and healing process. For these properties, MSCs have been used as therapeutic cells in several models, including treatment of damages or disorders of the ocular surface. If the damage of the ocular surface is extensive and involves a limbal region where limbal stem cell reside, MSC therapy has been proved as the effective treatment approach. Although the anti-inflammatory properties of MSCs have been well characterized, mechanisms of antiapoptotic action of MSCs are not well recognized. Using a chemically damaged cornea in a mouse model, we showed that the injury decreases expression of the gene for antiapoptotic molecule Bcl-2 and increases the expression of proapoptotic genes Bax and p53. These changes were attenuated by local transplantation of MSCs after corneal damage. The antiapoptotic effect of MSCs was tested in an in vitro model of co-cultivation of corneal explants with MSCs. The apoptosis of corneal cells in the explants was induced by proinflammatory cytokines and was significantly inhibited in the presence of MSCs. The antiapoptotic effect of MSCs was mediated by paracrine action, as confirmed by separation of the explants in inserts or by supernatants from MSCs. In addition, MSCs decreased the expression of genes for the molecules associated with endoplasmic reticulum stress Atf4, Bip, and p21, which are associated with apoptosis. The results show that MSCs inhibit the expression of proapoptotic genes and decrease the number of apoptotic cells in the damaged corneas, and this action might be one of the mechanisms of the therapeutic action of MSCs.
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Affiliation(s)
- Jan Kossl
- Department of Cell Biology, Faculty of Science, Charles University, Prague, Czech Republic
- Department of Nanotoxicology and Molecular Epidemiology, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, Czech Republic
| | - Pavla Bohacova
- Department of Cell Biology, Faculty of Science, Charles University, Prague, Czech Republic
- Department of Nanotoxicology and Molecular Epidemiology, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, Czech Republic
| | - Barbora Hermankova
- Department of Nanotoxicology and Molecular Epidemiology, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, Czech Republic
| | - Eliska Javorkova
- Department of Cell Biology, Faculty of Science, Charles University, Prague, Czech Republic
- Department of Nanotoxicology and Molecular Epidemiology, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, Czech Republic
| | - Alena Zajicova
- Department of Nanotoxicology and Molecular Epidemiology, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, Czech Republic
| | - Vladimir Holan
- Department of Cell Biology, Faculty of Science, Charles University, Prague, Czech Republic
- Department of Nanotoxicology and Molecular Epidemiology, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, Czech Republic
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Corneal reconstruction in chemically damaged cornea using temperature responsive surface assisted mesenchymal stem cell transplantation in rabbits. Graefes Arch Clin Exp Ophthalmol 2021; 259:1859-1870. [PMID: 33754210 DOI: 10.1007/s00417-021-05132-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Revised: 02/11/2021] [Accepted: 02/16/2021] [Indexed: 10/21/2022] Open
Abstract
PURPOSE Transplantation of autologous stem cells over damaged cornea seems to be a promising approach for corneal reconstruction. Use of a biocompatible carrier is still a challenge in bedside translation of transplantation. We investigated corneal reconstruction and tissue remodelling by transplantation of mesenchymal stem cells (MSCs) using temperature responsive membranes in chemically damaged rabbit cornea model. METHODS MSCs were cultured from rabbit's bone marrow and transplanted over alkali injured cornea, using either temperature responsive membrane or fibrin glue method. Endogenous levels of MSCs were assessed to decide the optimal time point for transplanting cells. MSC transplanted corneas were harvested at different time points post-transplantation. Corneal repair markers were evaluated using histopathology, immunohistochemistry (IHC) and real time qPCR. The quality of cornea reconstructed was evaluated and compared using corneal opacity scoring and immunohistochemistry (IHC). RESULTS Use of temperature responsive surface as carrier resulted in uniform and homogenous delivery of MSCs sheet over the damaged corneal surface. Corneal transparency improved day 7 onwards post-MSC transplantation in rabbit chemically injured cornea. Complete re-epithelialization of injured cornea was observed 15 days after MSC transplantation. Restoration of vimentin, α-smooth muscle actin and collagen levels in MSC transplanted cornea was observed post-transplantation. Further, differentiation of MSCs into mature corneal epithelial cells was also observed upon transplantation. CONCLUSIONS The extent of corneal repair was apparently better using temperature responsive surfaces. The surface provides biocompatible niche for MSCs and can be a method of choice in clinics for cell transplantation over the damaged ocular surfaces.
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Mesenchymal Stem Cell-Based Therapy for Retinal Degenerative Diseases: Experimental Models and Clinical Trials. Cells 2021; 10:cells10030588. [PMID: 33799995 PMCID: PMC8001847 DOI: 10.3390/cells10030588] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Revised: 02/26/2021] [Accepted: 03/02/2021] [Indexed: 12/13/2022] Open
Abstract
Retinal degenerative diseases, such as age-related macular degeneration, retinitis pigmentosa, diabetic retinopathy or glaucoma, represent the main causes of a decreased quality of vision or even blindness worldwide. However, despite considerable efforts, the treatment possibilities for these disorders remain very limited. A perspective is offered by cell therapy using mesenchymal stem cells (MSCs). These cells can be obtained from the bone marrow or adipose tissue of a particular patient, expanded in vitro and used as the autologous cells. MSCs possess potent immunoregulatory properties and can inhibit a harmful inflammatory reaction in the diseased retina. By the production of numerous growth and neurotrophic factors, they support the survival and growth of retinal cells. In addition, MSCs can protect retinal cells by antiapoptotic properties and could contribute to the regeneration of the diseased retina by their ability to differentiate into various cell types, including the cells of the retina. All of these properties indicate the potential of MSCs for the therapy of diseased retinas. This view is supported by the recent results of numerous experimental studies in different preclinical models. Here we provide an overview of the therapeutic properties of MSCs, and their use in experimental models of retinal diseases and in clinical trials.
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