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An W, Zhang W, Qi J, Xu W, Long Y, Qin H, Yao K. Mesenchymal stem cells and mesenchymal stem cell-derived exosomes: a promising strategy for treating retinal degenerative diseases. Mol Med 2025; 31:75. [PMID: 39984849 PMCID: PMC11846226 DOI: 10.1186/s10020-025-01120-w] [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: 12/30/2024] [Accepted: 02/07/2025] [Indexed: 02/23/2025] Open
Abstract
Mesenchymal stem cells (MSCs) have emerged as a promising therapeutic strategy in regenerative medicine, demonstrating significant potential for clinical applications. Evidence suggests that MSCs not only exhibit multipotent differentiation potential but also exert critical therapeutic effects in retinal degenerative diseases via robust paracrine mechanisms. MSCs protect retinal cells from degenerative damage by modulating inflammation, inhibiting apoptosis, alleviating oxidative stress, and suppressing cell death pathways. Furthermore, MSCs contribute to retinal structural and functional stability by facilitating vascular remodeling and donating mitochondria to retinal cells. Of particular interest, MSC-derived exosomes have gained widespread attention as a compelling cell-free therapy. Owing to their potent anti-inflammatory, anti-apoptotic, and vascular-stabilizing properties, exosomes show significant promise for the treatment of retinal degenerative diseases.
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Affiliation(s)
- Wenjing An
- Institute of Visual Neuroscience and Stem Cell Engineering, Wuhan University of Science and Technology, Wuhan, 430065, China
- College of Life Sciences and Health, Wuhan University of Science and Technology, Wuhan, 430065, China
| | - Wenliang Zhang
- Institute of Visual Neuroscience and Stem Cell Engineering, Wuhan University of Science and Technology, Wuhan, 430065, China
- College of Life Sciences and Health, Wuhan University of Science and Technology, Wuhan, 430065, China
| | - Jia Qi
- Institute of Visual Neuroscience and Stem Cell Engineering, Wuhan University of Science and Technology, Wuhan, 430065, China
- College of Life Sciences and Health, Wuhan University of Science and Technology, Wuhan, 430065, China
| | - Weihui Xu
- Institute of Visual Neuroscience and Stem Cell Engineering, Wuhan University of Science and Technology, Wuhan, 430065, China
- College of Life Sciences and Health, Wuhan University of Science and Technology, Wuhan, 430065, China
| | - Yushan Long
- Institute of Visual Neuroscience and Stem Cell Engineering, Wuhan University of Science and Technology, Wuhan, 430065, China
- College of Life Sciences and Health, Wuhan University of Science and Technology, Wuhan, 430065, China
| | - Huan Qin
- Institute of Visual Neuroscience and Stem Cell Engineering, Wuhan University of Science and Technology, Wuhan, 430065, China.
- College of Life Sciences and Health, Wuhan University of Science and Technology, Wuhan, 430065, China.
| | - Kai Yao
- Institute of Visual Neuroscience and Stem Cell Engineering, Wuhan University of Science and Technology, Wuhan, 430065, China.
- College of Life Sciences and Health, Wuhan University of Science and Technology, Wuhan, 430065, China.
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Alatas FS, Yamaza T, Matsuura T, Ongko L, Kadim M, Ohga S, Taguchi T, Tajiri T. Potential role of stem cells from human exfoliated deciduous teeth in inducing liver regeneration. J Gastroenterol Hepatol 2024; 39:2190-2196. [PMID: 38859685 DOI: 10.1111/jgh.16651] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2023] [Revised: 04/11/2024] [Accepted: 05/28/2024] [Indexed: 06/12/2024]
Abstract
BACKGROUND AND AIM Even with advancement of medical technologies, liver transplantation still faces several major challenges. Hence, other treatment modalities are urgently needed for patients with end-stage liver disease. Stem cells from human exfoliated deciduous teeth (SHED) was discovered to have highly proliferative and pluripotent properties; including differentiation into hepatocyte-like cells. This study aims to investigate the capability of intrasplenic transplanted SHED and SHED-Hep cells in inducing proliferation of stem cells and native hepatocytes in order to accelerate liver regeneration in liver fibrosis mice models. METHODS Three carbon tetrachloride (CCl4)-injured male mice groups were used in this study. Two of those groups were transplanted with either SHED or SHED-Hep, while the other did not undergo transplantation. One age- and sex- matched healthy mice group was used as control. All specimens were immunohistochemically stained with anti-Ki-67 antibodies and anti-proliferating cell nuclear antigen (PCNA) antibodies before counter stained with hematoxylin-eosin. RESULTS Anti-Ki-67 antibodies staining: at both 8 and 12 weeks, proliferating activity was predominantly seen on both SHED- and SHED-Hep-transplanted CCl4-injured mice groups, while control and non-transplanted CCl4-injured mice group showed little to no sign of proliferation activity. Anti-PCNA staining: at both 8 and 12 weeks, significant proliferating activity was detected by PCNA staining, mainly on stem cells population area on SHED- and SHED-Hep-treated group. CONCLUSIONS In conclusion, this study has provided the evidence that transplantation of SHED or SHED-Hep on liver-injured mice induced proliferation of both transplanted stem cells and native liver cells in order to accelerate liver regeneration.
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Affiliation(s)
- Fatima Safira Alatas
- Department of Pediatric Surgery, Reproductive and Developmental Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
- Department of Child Health, Faculty of Medicine, Universitas Indonesia, Cipto Mangunkusumo Hospital, Jakarta, Indonesia
| | - Takayoshi Yamaza
- Departments of Molecular Cell Biology and Oral Anatomy, Kyushu University Graduate School of Dental Science, Fukuoka, Japan
| | - Toshiharu Matsuura
- Department of Pediatric Surgery, Reproductive and Developmental Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Lukito Ongko
- Department of Child Health, Faculty of Medicine, Universitas Indonesia, Cipto Mangunkusumo Hospital, Jakarta, Indonesia
| | - Muzal Kadim
- Department of Child Health, Faculty of Medicine, Universitas Indonesia, Cipto Mangunkusumo Hospital, Jakarta, Indonesia
| | - Shouichi Ohga
- Departments of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Tomoaki Taguchi
- Department of Pediatric Surgery, Reproductive and Developmental Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
- Fukuoka College of Health Sciences, Fukuoka, Japan
| | - Tatsuro Tajiri
- Department of Pediatric Surgery, Reproductive and Developmental Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
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Bugara K, Pacwa A, Smedowski A. Molecular pathways in experimental glaucoma models. Front Neurosci 2024; 18:1363170. [PMID: 38562304 PMCID: PMC10982327 DOI: 10.3389/fnins.2024.1363170] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2023] [Accepted: 03/05/2024] [Indexed: 04/04/2024] Open
Abstract
Glaucoma is a complex and progressive disease that primarily affects the optic nerve axons, leading to irreversible vision loss. Although the exact molecular mechanisms underlying glaucoma pathogenesis are not fully understood, it is believed that except increased intraocular pressure, a combination of genetic and environmental factors play a role in the development of the disease. Animal models have been widely used in the study of glaucoma, allowing researchers to better understand the underlying mechanisms of the disease and test potential treatments. Several molecular pathways have been implicated in the pathogenesis of glaucoma, including oxidative stress, inflammation, and excitotoxic-induced neurodegeneration. This review summarizes the most important knowledge about molecular mechanisms involved in the glaucoma development. Although much research has been done to better understand the molecular mechanisms underlying this disease, there is still much to be learned to develop effective treatments and prevent vision loss in those affected by glaucoma.
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Affiliation(s)
- Klaudia Bugara
- Department of Physiology, Faculty of Medical Sciences in Katowice, Medical University of Silesia, Katowice, Poland
| | - Anna Pacwa
- Department of Physiology, Faculty of Medical Sciences in Katowice, Medical University of Silesia, Katowice, Poland
- GlaucoTech Co., Katowice, Poland
| | - Adrian Smedowski
- GlaucoTech Co., Katowice, Poland
- Department of Ophthalmology, Faculty of Medical Sciences in Katowice, Medical University of Silesia, Katowice, Poland
- Department of Ophthalmology, Professor K. Gibinski University Clinical Center, Medical University of Silesia, Katowice, Poland
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4
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Erythropoietin in Glaucoma: From Mechanism to Therapy. Int J Mol Sci 2023; 24:ijms24032985. [PMID: 36769310 PMCID: PMC9917746 DOI: 10.3390/ijms24032985] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2022] [Revised: 01/26/2023] [Accepted: 01/27/2023] [Indexed: 02/05/2023] Open
Abstract
Glaucoma can cause irreversible vision loss and is the second leading cause of blindness worldwide. The disease mechanism is complex and various factors have been implicated in its pathogenesis, including ischemia, excessive oxidative stress, neurotropic factor deprivation, and neuron excitotoxicity. Erythropoietin (EPO) is a hormone that induces erythropoiesis in response to hypoxia. However, studies have shown that EPO also has neuroprotective effects and may be useful for rescuing apoptotic retinal ganglion cells in glaucoma. This article explores the relationship between EPO and glaucoma and summarizes preclinical experiments that have used EPO to treat glaucoma, with an aim to provide a different perspective from the current view that glaucoma is incurable.
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Sanie-Jahromi F, Mahmoudi A, Khalili MR, Nowroozzadeh MH. A Review on the Application of Stem Cell Secretome in the Protection and Regeneration of Retinal Ganglion Cells; a Clinical Prospect in the Treatment of Optic Neuropathies. Curr Eye Res 2022; 47:1463-1471. [PMID: 35876610 DOI: 10.1080/02713683.2022.2103153] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
PURPOSE Retinal ganglion cells (RGCs) are one the most specialized neural tissues in the body. They transmit (and further process) chemoelectrical information originating in outer retinal layers to the central nervous system. In fact, the optic nerve is composed of RGC axons. Like other neural cells, RGCs will not completely heal after the injury, leading to irreversible vision loss from disorders such as glaucoma that primarily affect these cells. Several methods have been developed to protect or regenerate RGCs during or after the insult has occurred. This study aims to review the most recent clinical, animal and laboratory experiments designed for the regeneration of RGC that apply the stem cell-derived secretome. METHODS We extracted the studies from Web of Science (ISI), Medline (PubMed), Scopus, Embase, and Google scholar from the first record to the last report registered in 2022, using the following keywords; "secretome" OR "conditioned medium" OR "exosome" OR "extracellular vesicle" AND "stem cell" AND "RGC" OR "optic neuropathy". Any registered clinical trials related to the subject were also extracted from clinicaltrial.gov. All published original studies that express the effect of stem cell secretome on RGC cells in optic neuropathy, whether in vitro, in animal studies, or in clinical trials were included in this survey. RESULTS In this review, we provided an update on the existing reports, and a brief description of the details applied in the procedure. Compared to cell transplant, applying stem cell-derived secretome has the advantage of minimized immunogenicity yet preserving efficacy via its rich content of growth factors. CONCLUSIONS Different sources of stem cell secretomes have distinct implications in the management of RGC injury, which is the main subject of the present article.
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Affiliation(s)
- Fatemeh Sanie-Jahromi
- Poostchi Ophthalmology Research Center, Department of Ophthalmology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Ahmad Mahmoudi
- Poostchi Ophthalmology Research Center, Department of Ophthalmology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mohammad Reza Khalili
- Poostchi Ophthalmology Research Center, Department of Ophthalmology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - M Hossein Nowroozzadeh
- Poostchi Ophthalmology Research Center, Department of Ophthalmology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
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Bacci GM, Becherucci V, Marziali E, Sodi A, Bambi F, Caputo R. Treatment of Inherited Retinal Dystrophies with Somatic Cell Therapy Medicinal Product: A Review. Life (Basel) 2022; 12:life12050708. [PMID: 35629375 PMCID: PMC9147057 DOI: 10.3390/life12050708] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Revised: 05/05/2022] [Accepted: 05/06/2022] [Indexed: 01/06/2023] Open
Abstract
Inherited retinal dystrophies and retinal degenerations related to more common diseases (i.e., age-related macular dystrophy) are a major issue and one of the main causes of low vision in pediatric and elderly age groups. Advancement and understanding in molecular biology and the possibilities raised by gene-editing techniques opened a new era for clinicians and patients due to feasible possibilities of treating disabling diseases and the reduction in their complications burden. The scope of this review is to focus on the state-of-the-art in somatic cell therapy medicinal products as the basis of new insights and possibilities to use this approach to treat rare eye diseases.
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Affiliation(s)
- Giacomo Maria Bacci
- Pediatric Ophthalmology Unit, Children’s Hospital A. Meyer-University of Florence, 50139 Florence, Italy; (E.M.); (R.C.)
- Correspondence:
| | - Valentina Becherucci
- Cell Factory Meyer, Children’s Hospital A. Meyer-University of Florence, 50139 Florence, Italy; (V.B.); (F.B.)
| | - Elisa Marziali
- Pediatric Ophthalmology Unit, Children’s Hospital A. Meyer-University of Florence, 50139 Florence, Italy; (E.M.); (R.C.)
| | - Andrea Sodi
- Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, 50139 Florence, Italy;
| | - Franco Bambi
- Cell Factory Meyer, Children’s Hospital A. Meyer-University of Florence, 50139 Florence, Italy; (V.B.); (F.B.)
| | - Roberto Caputo
- Pediatric Ophthalmology Unit, Children’s Hospital A. Meyer-University of Florence, 50139 Florence, Italy; (E.M.); (R.C.)
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Brown C, Agosta P, McKee C, Walker K, Mazzella M, Alamri A, Svinarich D, Chaudhry GR. Human primitive mesenchymal stem cell-derived retinal progenitor cells improved neuroprotection, neurogenesis, and vision in rd12 mouse model of retinitis pigmentosa. Stem Cell Res Ther 2022; 13:148. [PMID: 35395806 PMCID: PMC8994263 DOI: 10.1186/s13287-022-02828-w] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Accepted: 03/20/2022] [Indexed: 01/05/2023] Open
Abstract
Background Currently, there is no treatment for retinal degenerative diseases (RDD) such as retinitis pigmentosa (RP). Stem cell-based therapies could provide promising opportunities to repair the damaged retina and restore vision. Thus far, primarily adult mesenchymal stem cells (MSCs) have been investigated in preclinical and clinical studies, and the results have not been convincing. We applied a new approach in which primitive (p) MSC-derived retinal progenitor cells (RPCs) were examined to treat retinal degeneration in an rd12 mouse model of RP. Methods Well-characterized pMSCs and RPCs labeled with PKH26 were intravitreally injected into rd12 mice. The vision and retinal function of transplanted animals were analyzed using electroretinography. Animals were killed 4 and 8 weeks after cell transplantation for histological, immunological, molecular, and transcriptomic analyses of the retina. Results Transplanted RPCs significantly improved vision and retinal thickness as well as function in rd12 mice. pMSCs and RPCs homed to distinct retinal layers. pMSCs homed to the retinal pigment epithelium, and RPCs migrated to the neural layers of the retina, where they improved the thickness of the respective layers and expressed cell-specific markers. RPCs induced anti-inflammatory and neuroprotective responses as well as upregulated the expression of genes involved in neurogenesis. The transcriptomic analysis showed that RPCs promoted neurogenesis and functional recovery of the retina through inhibition of BMP and activation of JAK/STAT and MAPK signaling pathways. Conclusions Our study demonstrated that RPCs countered inflammation, provided retinal protection, and promoted neurogenesis resulting in improved retinal structure and physiological function in rd12 mice. Supplementary Information The online version contains supplementary material available at 10.1186/s13287-022-02828-w.
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Affiliation(s)
- Christina Brown
- Department of Biological Sciences, Oakland University, Rochester, MI, 48309, USA.,OU-WB Institute for Stem Cell and Regenerative Medicine, Rochester, MI, 48309, USA
| | - Patrina Agosta
- Ascension Providence Hospital, Southfield, MI, 48075, USA
| | - Christina McKee
- Department of Biological Sciences, Oakland University, Rochester, MI, 48309, USA.,OU-WB Institute for Stem Cell and Regenerative Medicine, Rochester, MI, 48309, USA
| | - Keegan Walker
- Department of Biological Sciences, Oakland University, Rochester, MI, 48309, USA.,OU-WB Institute for Stem Cell and Regenerative Medicine, Rochester, MI, 48309, USA
| | - Matteo Mazzella
- Department of Biological Sciences, Oakland University, Rochester, MI, 48309, USA.,OU-WB Institute for Stem Cell and Regenerative Medicine, Rochester, MI, 48309, USA
| | - Ali Alamri
- Department of Biological Sciences, Oakland University, Rochester, MI, 48309, USA.,OU-WB Institute for Stem Cell and Regenerative Medicine, Rochester, MI, 48309, USA
| | | | - G Rasul Chaudhry
- Department of Biological Sciences, Oakland University, Rochester, MI, 48309, USA. .,OU-WB Institute for Stem Cell and Regenerative Medicine, Rochester, MI, 48309, USA.
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8
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Shalaby WS, Ahmed OM, Waisbourd M, Katz LJ. A Review of Potential Novel Glaucoma Therapeutic Options Independent of Intraocular Pressure. Surv Ophthalmol 2021; 67:1062-1080. [PMID: 34890600 DOI: 10.1016/j.survophthal.2021.12.003] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Revised: 12/01/2021] [Accepted: 12/06/2021] [Indexed: 02/06/2023]
Abstract
Glaucoma, a progressive optic neuropathy characterized by retinal ganglion cell degeneration and visual field loss, is the leading cause of irreversible blindness worldwide. Intraocular pressure (IOP) is presently the only modifiable risk factor demonstrated to slow or halt disease progression; however, glaucomatous damage persists in almost 50% of patients despite significant IOP reduction. Many studies have investigated the non-IOP-related risk factors that contribute to glaucoma progression as well as interventions that can prevent or delay glaucomatous neurodegeneration and preserve vision throughout life, independently of IOP. A vast number of experimental studies have reported effective neuroprotection in glaucoma, and clinical studies are ongoing attempting to provide strong evidence of effectiveness of these interventions. In this review, we look into the current understanding of the pathophysiology of glaucoma and explore the recent advances in non-IOP related strategies for neuroprotection and neuroregeneration in glaucoma.
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Key Words
- AMD, Age-related macular degeneration
- BDNF, Brain derived neurotrophic factor
- CNTF, Ciliary neurotrophic factor
- GDNF, Glial‐derived neurotrophic factor
- Glaucoma
- IOP, Intraocular pressure
- LoGTS, Low-Pressure Glaucoma Treatment Study
- MRI, Magnetic resonance imaging
- MSCs, Mesenchymal stem cells
- NGF, Nerve growth factor
- NTG, Normal tension glaucoma
- OCTA, Optical coherence tomography angiography
- PBM, hotobiomodulation
- PDGF, Platelet derived growth factor
- POAG, Primary open angle glaucoma
- RGCs, Retinal ganglion cells
- TNF-α, Tumor necrosis factor- α
- bFGF, Basic fibroblast growth factor
- gene therapy
- intracranial pressure
- intraocular pressure
- neuroprotection
- ocular blood flow
- oxidative stress
- retinal ganglion cells
- stem cell therapy
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Affiliation(s)
- Wesam Shamseldin Shalaby
- Glaucoma Research Center, Wills Eye Hospital, Philadelphia, PA, USA; Department of Ophthalmology, Tanta Medical School, Tanta University, Tanta, Gharbia, Egypt
| | - Osama M Ahmed
- Glaucoma Research Center, Wills Eye Hospital, Philadelphia, PA, USA; Yale University School of Medicine, New Haven, CT, USA
| | - Michael Waisbourd
- Glaucoma Research Center, Wills Eye Hospital, Philadelphia, PA, USA; Department of Ophthalmology, Tel Aviv Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Israel
| | - L Jay Katz
- Glaucoma Research Center, Wills Eye Hospital, Philadelphia, PA, USA.
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Cell-Based Neuroprotection of Retinal Ganglion Cells in Animal Models of Optic Neuropathies. BIOLOGY 2021; 10:biology10111181. [PMID: 34827174 PMCID: PMC8615038 DOI: 10.3390/biology10111181] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Revised: 11/10/2021] [Accepted: 11/11/2021] [Indexed: 11/16/2022]
Abstract
Retinal ganglion cells (RGCs) comprise a heterogenous group of projection neurons that transmit visual information from the retina to the brain. Progressive degeneration of these cells, as it occurs in inflammatory, ischemic, traumatic or glaucomatous optic neuropathies, results in visual deterioration and is among the leading causes of irreversible blindness. Treatment options for these diseases are limited. Neuroprotective approaches aim to slow down and eventually halt the loss of ganglion cells in these disorders. In this review, we have summarized preclinical studies that have evaluated the efficacy of cell-based neuroprotective treatment strategies to rescue retinal ganglion cells from cell death. Intraocular transplantations of diverse genetically nonmodified cell types or cells engineered to overexpress neurotrophic factors have been demonstrated to result in significant attenuation of ganglion cell loss in animal models of different optic neuropathies. Cell-based combinatorial neuroprotective approaches represent a potential strategy to further increase the survival rates of retinal ganglion cells. However, data about the long-term impact of the different cell-based treatment strategies on retinal ganglion cell survival and detailed analyses of potential adverse effects of a sustained intraocular delivery of neurotrophic factors on retina structure and function are limited, making it difficult to assess their therapeutic potential.
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Martinez Velazquez LA, Ballios BG. The Next Generation of Molecular and Cellular Therapeutics for Inherited Retinal Disease. Int J Mol Sci 2021; 22:ijms222111542. [PMID: 34768969 PMCID: PMC8583900 DOI: 10.3390/ijms222111542] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2021] [Revised: 10/13/2021] [Accepted: 10/14/2021] [Indexed: 12/26/2022] Open
Abstract
Inherited retinal degenerations (IRDs) are a diverse group of conditions that are often characterized by the loss of photoreceptors and blindness. Recent innovations in molecular biology and genomics have allowed us to identify the causative defects behind these dystrophies and to design therapeutics that target specific mechanisms of retinal disease. Recently, the FDA approved the first in vivo gene therapy for one of these hereditary blinding conditions. Current clinical trials are exploring new therapies that could provide treatment for a growing number of retinal dystrophies. While the field has had early success with gene augmentation strategies for treating retinal disease based on loss-of-function mutations, many novel approaches hold the promise of offering therapies that span the full spectrum of causative mutations and mechanisms. Here, we provide a comprehensive review of the approaches currently in development including a discussion of retinal neuroprotection, gene therapies (gene augmentation, gene editing, RNA modification, optogenetics), and regenerative stem or precursor cell-based therapies. Our review focuses on technologies that are being developed for clinical translation or are in active clinical trials and discusses the advantages and limitations for each approach.
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Affiliation(s)
| | - Brian G. Ballios
- Department of Ophthalmology and Vision Sciences, Temerty Faculty of Medicine, University of Toronto, Toronto, ON M5T 3A9, Canada
- Correspondence:
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11
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Bammidi S, Bali P, Kalra J, Anand A. Transplantation Efficacy of Human Ciliary Epithelium Cells from Fetal Eye and Lin-ve Stem Cells from Umbilical Cord Blood in the Murine Retinal Degeneration Model of Laser Injury. Cell Transplant 2021; 29:963689720946031. [PMID: 33023312 PMCID: PMC7784603 DOI: 10.1177/0963689720946031] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
A number of degenerative conditions affecting the neural retina including age-related macular degeneration have no successful treatment, resulting in partial or complete vision loss. There are a number of stem cell replacement strategies for recovery of retinal damage using cells from variable sources. However, literature is still deficit in the comparison of efficacy of types of stem cells. The purpose of the study was to compare the therapeutic efficacy of undifferentiated cells, i.e., lineage negative stem cells (Lin-ve SC) with differentiated neurosphere derived from ciliary epithelium (CE) cells on retinal markers associated with laser-induced retinal injury. Laser-induced photocoagulation was carried out to disrupt Bruch’s membrane and retinal pigmented epithelium in C57BL/6 mouse model. Lineage negative cells were isolated from human umbilical cord blood, whereas neurospheres were derived from CE of post-aborted human eyeballs. The cells were then transplanted into subretinal space to study their effect on injury. Markers of neurotropic factors, retina, apoptosis, and proliferation were analyzed after injury and transplantation. mRNA expression was also analyzed by real-time polymerase chain reaction at 1 week, and 3-month immunohistochemistry was evaluated at 1-week time point. CE cell transplantation showed enhanced differentiation of rods and retinal glial cells. However, Lin-ve cells exerted paracrine-dependent modulation of neurotrophic factors, which is possibly mediated by antiapoptotic and proliferative effects. In conclusion, CE transplantation showed superior regenerative outcome in comparison to Lin-ve SC for rescue of artificially injured rodent retinal cells. It is imperative that this source for transplantation may be extensively studied in various doses and additional retinal degeneration models for prospective clinical applications.
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Affiliation(s)
- Sridhar Bammidi
- Neuroscience Research Lab, Department of Neurology, 29751Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Parul Bali
- Neuroscience Research Lab, Department of Neurology, 29751Post Graduate Institute of Medical Education and Research, Chandigarh, India.,Department of Biophysics, 29751Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Jaswinder Kalra
- Department of Obstetrics and Gynaecology, 29751Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Akshay Anand
- Neuroscience Research Lab, Department of Neurology, 29751Post Graduate Institute of Medical Education and Research, Chandigarh, India
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12
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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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13
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da Silva-Junior AJ, Mesentier-Louro LA, Nascimento-Dos-Santos G, Teixeira-Pinheiro LC, Vasques JF, Chimeli-Ormonde L, Bodart-Santos V, de Carvalho LRP, Santiago MF, Mendez-Otero R. Human mesenchymal stem cell therapy promotes retinal ganglion cell survival and target reconnection after optic nerve crush in adult rats. Stem Cell Res Ther 2021; 12:69. [PMID: 33468246 PMCID: PMC7814601 DOI: 10.1186/s13287-020-02130-7] [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: 11/22/2020] [Accepted: 12/28/2020] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Optic-nerve injury results in impaired transmission of visual signals to central targets and leads to the death of retinal ganglion cells (RGCs) and irreversible vision loss. Therapies with mesenchymal stem cells (MSCs) from different sources have been used experimentally to increase survival and regeneration of RGCs. METHODS We investigated the efficacy of human umbilical Wharton's jelly-derived MSCs (hWJ-MSCs) and their extracellular vesicles (EVs) in a rat model of optic nerve crush. RESULTS hWJ-MSCs had a sustained neuroprotective effect on RGCs for 14, 60, and 120 days after optic nerve crush. The same effect was obtained using serum-deprived hWJ-MSCs, whereas transplantation of EVs obtained from those cells was ineffective. Treatment with hWJ-MSCs also promoted axonal regeneration along the optic nerve and reinnervation of visual targets 120 days after crush. CONCLUSIONS The observations showed that this treatment with human-derived MSCs promoted sustained neuroprotection and regeneration of RGCs after optic nerve injury. These findings highlight the possibility to use cell therapy to preserve neurons and to promote axon regeneration, using a reliable source of human MSCs.
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Affiliation(s)
- Almir Jordão da Silva-Junior
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, 21941-902, Brazil. .,Instituto Nacional de Ciência e Tecnologia em Medicina Regenerativa-REGENERE, Rio de Janeiro, RJ, Brazil. .,Rede NanoSaúde, Rio de Janeiro, RJ, Brazil.
| | - Louise Alessandra Mesentier-Louro
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, 21941-902, Brazil.,Department of Ophthalmology, Stanford University, Palo Alto, CA, USA
| | - Gabriel Nascimento-Dos-Santos
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, 21941-902, Brazil.,Instituto Nacional de Ciência e Tecnologia em Medicina Regenerativa-REGENERE, Rio de Janeiro, RJ, Brazil
| | - Leandro Coelho Teixeira-Pinheiro
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, 21941-902, Brazil.,Instituto Nacional de Ciência e Tecnologia em Medicina Regenerativa-REGENERE, Rio de Janeiro, RJ, Brazil
| | - Juliana F Vasques
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, 21941-902, Brazil.,Instituto Nacional de Ciência e Tecnologia em Medicina Regenerativa-REGENERE, Rio de Janeiro, RJ, Brazil
| | - Luiza Chimeli-Ormonde
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, 21941-902, Brazil.,Instituto Nacional de Ciência e Tecnologia em Medicina Regenerativa-REGENERE, Rio de Janeiro, RJ, Brazil
| | - Victor Bodart-Santos
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, 21941-902, Brazil.,Instituto Nacional de Ciência e Tecnologia em Medicina Regenerativa-REGENERE, Rio de Janeiro, RJ, Brazil
| | - Luiza Rachel Pinheiro de Carvalho
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, 21941-902, Brazil.,Instituto Nacional de Ciência e Tecnologia em Medicina Regenerativa-REGENERE, Rio de Janeiro, RJ, Brazil
| | - Marcelo Felippe Santiago
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, 21941-902, Brazil.,Instituto Nacional de Ciência e Tecnologia em Medicina Regenerativa-REGENERE, Rio de Janeiro, RJ, Brazil
| | - Rosalia Mendez-Otero
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, 21941-902, Brazil.,Instituto Nacional de Ciência e Tecnologia em Medicina Regenerativa-REGENERE, Rio de Janeiro, RJ, Brazil.,Rede NanoSaúde, Rio de Janeiro, RJ, Brazil
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14
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Xiao Z, Lei T, Liu Y, Yang Y, Bi W, Du H. The potential therapy with dental tissue-derived mesenchymal stem cells in Parkinson's disease. Stem Cell Res Ther 2021; 12:5. [PMID: 33407864 PMCID: PMC7789713 DOI: 10.1186/s13287-020-01957-4] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Accepted: 09/27/2020] [Indexed: 12/19/2022] Open
Abstract
Parkinson’s disease (PD), the second most common neurodegenerative disease worldwide, is caused by the loss of dopaminergic (DAergic) neurons in the substantia nigra resulting in a series of motor or non-motor disorders. Current treatment methods are unable to stop the progression of PD and may bring certain side effects. Cell replacement therapy has brought new hope for the treatment of PD. Recently, human dental tissue-derived mesenchymal stem cells have received extensive attention. Currently, dental pulp stem cells (DPSCs) and stem cells from human exfoliated deciduous teeth (SHED) are considered to have strong potential for the treatment of these neurodegenerative diseases. These cells are considered to be ideal cell sources for the treatment of PD on account of their unique characteristics, such as neural crest origin, immune rejection, and lack of ethical issues. In this review, we briefly describe the research investigating cell therapy for PD and discuss the application and progress of DPSCs and SHED in the treatment of PD. This review offers significant and comprehensive guidance for further clinical research on PD.
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Affiliation(s)
- Zhuangzhuang Xiao
- 112 Lab, School of Chemistry and Biological Engineering, University of Science and Technology Beijing, 30 XueYuan Road, Haidian District, Beijing, 100083, China
| | - Tong Lei
- 112 Lab, School of Chemistry and Biological Engineering, University of Science and Technology Beijing, 30 XueYuan Road, Haidian District, Beijing, 100083, China
| | - Yanyan Liu
- Kangyanbao (Beijing) Stem Cell Technology Co., Ltd, Beijing, 102600, China
| | - Yanjie Yang
- 112 Lab, School of Chemistry and Biological Engineering, University of Science and Technology Beijing, 30 XueYuan Road, Haidian District, Beijing, 100083, China
| | - Wangyu Bi
- 112 Lab, School of Chemistry and Biological Engineering, University of Science and Technology Beijing, 30 XueYuan Road, Haidian District, Beijing, 100083, China
| | - Hongwu Du
- 112 Lab, School of Chemistry and Biological Engineering, University of Science and Technology Beijing, 30 XueYuan Road, Haidian District, Beijing, 100083, China.
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15
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Amore G, Romagnoli M, Carbonelli M, Barboni P, Carelli V, La Morgia C. Therapeutic Options in Hereditary Optic Neuropathies. Drugs 2021; 81:57-86. [PMID: 33159657 PMCID: PMC7843467 DOI: 10.1007/s40265-020-01428-3] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Options for the effective treatment of hereditary optic neuropathies have been a long time coming. The successful launch of the antioxidant idebenone for Leber's Hereditary Optic Neuropathy (LHON), followed by its introduction into clinical practice across Europe, was an important step forward. Nevertheless, other options, especially for a variety of mitochondrial optic neuropathies such as dominant optic atrophy (DOA), are needed, and a number of pharmaceutical agents, acting on different molecular pathways, are currently under development. These include gene therapy, which has reached Phase III development for LHON, but is expected to be developed also for DOA, whilst most of the other agents (other antioxidants, anti-apoptotic drugs, activators of mitobiogenesis, etc.) are almost all at Phase II or at preclinical stage of research. Here, we review proposed target mechanisms, preclinical evidence, available clinical trials with primary endpoints and results, of a wide range of tested molecules, to give an overview of the field, also providing the landscape of future scenarios, including gene therapy, gene editing, and reproductive options to prevent transmission of mitochondrial DNA mutations.
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Affiliation(s)
- Giulia Amore
- Dipartimento di Scienze Biomediche e Neuromotorie, Università di Bologna, Bologna, Italy
| | - Martina Romagnoli
- IRCCS Istituto delle Scienze Neurologiche di Bologna, UOC Clinica Neurologica, Bologna, Via Altura 3, 40139, Bologna, Italy
| | - Michele Carbonelli
- IRCCS Istituto delle Scienze Neurologiche di Bologna, UOC Clinica Neurologica, Bologna, Via Altura 3, 40139, Bologna, Italy
| | | | - Valerio Carelli
- Dipartimento di Scienze Biomediche e Neuromotorie, Università di Bologna, Bologna, Italy
- IRCCS Istituto delle Scienze Neurologiche di Bologna, UOC Clinica Neurologica, Bologna, Via Altura 3, 40139, Bologna, Italy
| | - Chiara La Morgia
- IRCCS Istituto delle Scienze Neurologiche di Bologna, UOC Clinica Neurologica, Bologna, Via Altura 3, 40139, Bologna, Italy.
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16
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Li J, Bai X, Guan X, Yuan H, Xu X. Treatment of Optic Canal Decompression Combined with Umbilical Cord Mesenchymal Stem (Stromal) Cells for Indirect Traumatic Optic Neuropathy: A Phase 1 Clinical Trial. Ophthalmic Res 2020; 64:398-404. [PMID: 33091914 DOI: 10.1159/000512469] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Accepted: 10/21/2020] [Indexed: 11/19/2022]
Abstract
PURPOSE This study was aimed to investigate the safety and feasibility of umbilical cord-derived mesenchymal stem cell (MSC) transplantation in patients with traumatic optic neuropathy (TON). METHODS This is a single-center, prospective, open-labeled phase 1 study that enrolled 20 patients with TON. Patients consecutively underwent either optic canal decompression combined with MSC local implantation treatment (group 1) or only optic canal decompression (group 2). Patients were evaluated on the first day, seventh day, first month, third month, and sixth month postoperatively. Adverse events, such as fever, urticarial lesions, nasal infection, and death, were recorded at each visit. The primary outcome was changes in best-corrected visual acuity. The secondary outcomes were changes in color vision, relative afferent pupillary defect, and flash visual evoked potential. RESULTS All 20 patients completed the 6-month follow-up. None of them had any systemic or ocular complications. The change in best-corrected visual acuity at follow-up was not significantly different between group 1 and group 2 (p > 0.05); however, group 1 showed better visual outcome than group 2. Both groups showed significant improvements in vision compared with the baseline (p < 0.05); however, there were no statistically significant differences between the groups (p > 0.05). In addition, no adverse events related to local transplantation were observed in the patients. CONCLUSIONS A single, local MSC transplantation in the optic nerve is safe for patients with TON.
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Affiliation(s)
- Jia Li
- Department of Stem Cell and Regenerative Medicine, State Key Laboratory of Trauma, Burns and Combined Injury, Daping Hospital, Army Medical University, Chongqing, China
- Department of Ophthalmology, Daping Hospital, Army Medical University, Chongqing, China
| | - Xu Bai
- Department of Ophthalmology, Daping Hospital, Army Medical University, Chongqing, China
| | - Xiaoyue Guan
- Department of Ophthalmology, Daping Hospital, Army Medical University, Chongqing, China
| | - Hongfeng Yuan
- Department of Ophthalmology, Daping Hospital, Army Medical University, Chongqing, China
| | - Xiang Xu
- Department of Stem Cell and Regenerative Medicine, State Key Laboratory of Trauma, Burns and Combined Injury, Daping Hospital, Army Medical University, Chongqing, China,
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17
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Suri R, Neupane YR, Jain GK, Kohli K. Recent theranostic paradigms for the management of Age-related macular degeneration. Eur J Pharm Sci 2020; 153:105489. [PMID: 32717428 DOI: 10.1016/j.ejps.2020.105489] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2020] [Revised: 07/07/2020] [Accepted: 07/23/2020] [Indexed: 12/21/2022]
Abstract
Degenerative diseases of eye like Age-related macular degeneration (AMD), that affects the central portion of the retina (macula), is one of the leading causes of blindness worldwide especially in the elderly population. It is classified mainly as wet and dry form. With expanding knowledge about the underlying pathophysiology of the disease, various treatment strategies are being employed to halt the course of the disease progression. Hitherto, there is no ideal therapy which can cure the disease completely, and targeting the posterior segment of the eye is yet another challenge. The purpose of this review is to summarize the recent advances in the management and treatment stratagems (therapies, delivery systems and diagnostic tools) pertaining to AMD viz. molecular targeting, stem cell therapy, nanotechnology and exosomes with special reference to newer technologies like artificial intelligence and 3D printing. Furthermore, the role of diet and nutritional supplements in the prevention and treatment of the disease has also been highlighted. The alarming increase in the said disorder around the globe demands exhaustive research and investigations in the treatment zone. This review thus additionally directs the attention towards the challenges and future perspectives of different treatment approaches for AMD.
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Affiliation(s)
- Reshal Suri
- Department of Pharmaceutics, School of Pharmaceutical Education & Research, Jamia Hamdard, New Delhi, 110062, India
| | - Yub Raj Neupane
- Department of Pharmacy, National University of Singapore, 117559, Singapore
| | - Gaurav Kumar Jain
- Department of Pharmaceutics, School of Pharmaceutical Education & Research, Jamia Hamdard, New Delhi, 110062, India
| | - Kanchan Kohli
- Department of Pharmaceutics, School of Pharmaceutical Education & Research, Jamia Hamdard, New Delhi, 110062, India.
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18
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Wang L, Kang Y, Yan H, Zhu X, Zhu T, Jiang J, Zhao J. Tendon regeneration induced by umbilical cord graft in a rabbit tendon defect model. J Tissue Eng Regen Med 2020; 14:1009-1018. [PMID: 32336031 DOI: 10.1002/term.3052] [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: 12/16/2019] [Revised: 04/16/2020] [Accepted: 04/21/2020] [Indexed: 11/06/2022]
Abstract
Whether tendon regeneration can be induced using the umbilical cord as a whole-graft structure is unknown. In this study, we explored the potential for tendon regeneration induction using an umbilical cord graft in a rabbit model of patella tendon defects. In 52 of 54 New Zealand White rabbits, the central third of the patella tendons of both hind legs was removed to create tendon defects. The rabbits were randomly divided into four groups, nonfilling (empty defect), refilling (defect refilled with resected tendon portion), Wharton's jelly (WJ) outside (WJO; defect filled with umbilical cord graft, WJ side facing outward), and WJ inside (WJI; same as WJO with WJ side facing inward) groups. Four rabbits from WJO and WJI groups were sacrificed for human CD 105 evaluation 1 month after surgery. Further histological, biomechanical, and gene expression analyses were performed at 3 and 6 months after surgery. The untreated patella tendons in the remaining two rabbits were harvested as normal biomechanical controls. Histological evaluation showed that the formed tissue structure fibers in the tendon defect area were much denser and more mature in the WJI group than in all other groups. Biomechanical testing showed that the failure load of the final tissue structure was the highest in the WJI group. Real-time polymerase chain reaction indicated that the expression of most tendon-related genes was upregulated in the WJI group at 6 months after surgery. We concluded that umbilical cord grafting induces effective tendon regeneration, particularly when the WJ side faces inward.
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Affiliation(s)
- Liren Wang
- Department of Sports Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Yuhao Kang
- Department of Sports Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Hexin Yan
- Department of Research and Development, Shanghai Cryowise Medical Technology Co. Ltd., Shanghai, China
| | - Xuejing Zhu
- Department of Research and Development, Shanghai Cryowise Medical Technology Co. Ltd., Shanghai, China
| | - Tonghe Zhu
- Department of Sports Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Jia Jiang
- Department of Sports Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Jinzhong Zhao
- Department of Sports Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
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19
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Holan V, Hermankova B, Krulova M, Zajicova A. Cytokine interplay among the diseased retina, inflammatory cells and mesenchymal stem cells - a clue to stem cell-based therapy. World J Stem Cells 2019; 11:957-967. [PMID: 31768222 PMCID: PMC6851013 DOI: 10.4252/wjsc.v11.i11.957] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2019] [Revised: 09/02/2019] [Accepted: 09/14/2019] [Indexed: 02/06/2023] Open
Abstract
Retinal degenerative disorders, such as diabetic retinopathy, retinitis pigmentosa, age-related macular degeneration or glaucoma, represent the most common causes of loss of vision and blindness. In spite of intensive research, treatment options to prevent, stop or cure these diseases are limited. Newer therapeutic approaches are offered by stem cell-based therapy. To date, various types of stem cells have been evaluated in a range of models. Among them, mesenchymal stem/stromal cells (MSCs) derived from bone marrow or adipose tissue and used as autologous cells have been proposed to have the potential to attenuate the negative manifestations of retinal diseases. MSCs delivered to the vicinity of the diseased retina can exert local anti-inflammatory and repair-promoting/regenerative effects on retinal cells. However, MSCs also produce numerous factors that could have negative impacts on retinal regeneration. The secretory activity of MSCs is strongly influenced by the cytokine environment. Therefore, the interactions among the molecules produced by the diseased retina, cytokines secreted by inflammatory cells and factors produced by MSCs will decide the development and propagation of retinal diseases. Here we discuss the interactions among cytokines and other factors in the environment of the diseased retina treated by MSCs, and we present results supporting immunoregulatory and trophic roles of molecules secreted in the vicinity of the retina during MSC-based therapy.
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Affiliation(s)
- Vladimir Holan
- Department of Transplantation Immunology, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague 14220, Czech Republic
- Department of Cell Biology, Faculty of Science, Charles University, Prague 12843, Czech Republic
| | - Barbora Hermankova
- Department of Transplantation Immunology, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague 14220, Czech Republic
- Department of Cell Biology, Faculty of Science, Charles University, Prague 12843, Czech Republic
| | - Magdalena Krulova
- Department of Transplantation Immunology, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague 14220, Czech Republic
- Department of Cell Biology, Faculty of Science, Charles University, Prague 12843, Czech Republic
| | - Alena Zajicova
- Department of Transplantation Immunology, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague 14220, Czech Republic
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20
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Human Umbilical Cord Mesenchymal Stem Cells Attenuate Ocular Hypertension-Induced Retinal Neuroinflammation via Toll-Like Receptor 4 Pathway. Stem Cells Int 2019; 2019:9274585. [PMID: 31737079 PMCID: PMC6815608 DOI: 10.1155/2019/9274585] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2019] [Revised: 07/30/2019] [Accepted: 08/07/2019] [Indexed: 12/26/2022] Open
Abstract
Glaucoma is characterized by progressive, irreversible damage to the retinal ganglion cells (RGCs) and their axons. Our previous study has shown that the intravitreal transplantation of human umbilical cord mesenchymal stem cells (hUC-MSCs) reveals a neuroprotective role in microsphere injection-induced ocular hypertension (OHT) rat models. The protection is related to the modulation of glial cells, but the mechanisms are still unknown. The purpose of the present study is to clarify the potential neuroinflammatory mechanisms involved in the neuroprotective role of hUC-MSCs. OHT models were established with SD rats through intracameral injection of polystyrene microbeads. The animals were randomly divided into three groups: the normal group, the OHT+phosphate-buffered saline (PBS) group, and the OHT+hUC-MSC group. Retinal morphology was evaluated by measuring the inner retinal thickness via optical coherence tomography (OCT). Retinal cell apoptosis was examined by TUNEL staining and Bax expression 14 days following hUC-MSC transplantation. The expression levels of glial fibrillary acidic protein (GFAP), ionized calcium binding adapter molecule 1 (iba-1), and toll-like receptor 4 (TLR4) were assessed via immunohistochemistry, real-time quantitative PCR, and Western blot. RNA and proteins were extracted 14 days following transplantation, and the expression levels of the TLR4 signaling pathways and proinflammatory cytokines—myeloid differentiation factor 88 (MyD88), IL-1β, IL-6, and TNF-α—were determined. OCT showed that the intravitreal transplantation of hUC-MSCs significantly increased the inner thickness of the retina. A TUNEL assay and the expression of Bax suggested that the apoptosis of retinal cells was decreased by hUC-MSCs 14 days following transplantation. Intravitreal hUC-MSC transplantation resulted in a decreased expression of GFAP, iba-1, TLR4, MyD88, IL-1β, IL-6, and TNF-α 14 days following transplantation. In addition, via in vitro experiments, we found that the increased expression of the TLR4 signaling pathway induced by lipopolysaccharide (LPS) was markedly decreased after hUC-MSCs were cocultured with rMC-1 and BV2 cells. These findings indicate that hUC-MSC transplantation attenuates OHT-induced retinal neuroinflammation via the TLR4 pathway.
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21
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Borkowska-Kuczkowska A, Sługocka D, Świątkowska-Flis B, Boruczkowski D. The use of mesenchymal stem cells for the treatment of progressive retinal diseases: a review. Regen Med 2019; 14:321-329. [PMID: 30977436 DOI: 10.2217/rme-2019-0022] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Some ocular diseases, such as dystrophies, retinal and macular degeneration, optic nerve atrophy, and Stargardt disease, are progressive and irreversible. In this review, we focus on the use of mesenchymal stem cells (MSCs) in the treatment of these diseases. In animal studies, MSC transplantation significantly delayed retinal degeneration, led to the regeneration of cone cells, and supported the survival of retinal ganglion cells and axon regeneration. In clinical practice, patients with Behcet's disease with retinal vasculitis who received MSC injections experienced a decrease in retinal vasculitis but no improvement in vision acuity. Nonetheless, there is no evidence that MSCs are carcinogenic, and they even reduce the size of tumors in vitro. Furthermore, MSCs do not trigger the immune response.
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Affiliation(s)
- Agnieszka Borkowska-Kuczkowska
- Polish Center of Cell Therapy & Immunotherapy in Częstochowa, Waly Dwernickiego 43/45, 42-202 Częstochowa, Poland.,Agamed Center of Ophthalmology, Jasnogórska 4, 42-202 Częstochowa, Poland
| | - Dominika Sługocka
- Polish Center of Cell Therapy & Immunotherapy in Częstochowa, Waly Dwernickiego 43/45, 42-202 Częstochowa, Poland
| | - Beata Świątkowska-Flis
- Polish Center of Cell Therapy & Immunotherapy in Częstochowa, Waly Dwernickiego 43/45, 42-202 Częstochowa, Poland
| | - Dariusz Boruczkowski
- Polski Bank Komórek Macierzystych SA (FamiCord Group), Jana Pawła II 29, 00-867 Warsaw, Poland
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22
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Millán-Rivero JE, Nadal-Nicolás FM, García-Bernal D, Sobrado-Calvo P, Blanquer M, Moraleda JM, Vidal-Sanz M, Agudo-Barriuso M. Human Wharton's jelly mesenchymal stem cells protect axotomized rat retinal ganglion cells via secretion of anti-inflammatory and neurotrophic factors. Sci Rep 2018; 8:16299. [PMID: 30389962 PMCID: PMC6214908 DOI: 10.1038/s41598-018-34527-z] [Citation(s) in RCA: 52] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2018] [Accepted: 10/15/2018] [Indexed: 12/15/2022] Open
Abstract
Mesenchymal stem cell (MSC) transplantation is emerging as an ideal tool to restore the wounded central nervous system (CNS). MSCs isolated from extra-embryonic tissues have some advantages compared to MSCs derived from adult ones, such as an improved proliferative capacity, life span, differentiation potential and immunomodulatory properties. In addition, they are more immunoprivileged, reducing the probability of being rejected by the recipient. Umbilical cords (UCs) are a good source of MSCs because they are abundant, safe, non-invasively harvested after birth and, importantly, they are not encumbered with ethical problems. Here we show that the intravitreal transplant of Wharton´s jelly mesenchymal stem cells isolated from three different human UCs (hWJMSCs) delays axotomy-induced retinal ganglion cell (RGC) loss. In vivo, hWJMSCs secrete anti-inflammatory molecules and trophic factors, the latter alone may account for the elicited neuroprotection. Interestingly, this expression profile differs between naive and injured retinas, suggesting that the environment in which the hWJMSCs are modulates their secretome. Finally, even though the transplant itself is not toxic for RGCs, it is not innocuous as it triggers a transient but massive infiltration of Iba1+cells from the choroid to the retina that alters the retinal structure.
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Affiliation(s)
- Jose E Millán-Rivero
- Unidad de Terapia Celular y Trasplante Hematopoyético. Instituto Murciano de Investigación Biosanitaria Virgen de la Arrixaca (IMIB-Arrixaca), Murcia, Spain.,Dpto Medicina Interna, Universidad de Murcia, Murcia, Spain
| | - Francisco M Nadal-Nicolás
- Dpto Oftalmología, Universidad de Murcia, Murcia, Spain.,Grupo de Oftalmología Experimental, Instituto Murciano de Investigación Biosanitaria Virgen de la Arrixaca (IMIB-Arrixaca), Murcia, Spain.,Retinal Neurophysiology Section, National Eye Institute, National Institutes of Health, Bethesda, MD, USA
| | - David García-Bernal
- Unidad de Terapia Celular y Trasplante Hematopoyético. Instituto Murciano de Investigación Biosanitaria Virgen de la Arrixaca (IMIB-Arrixaca), Murcia, Spain.,Dpto Medicina Interna, Universidad de Murcia, Murcia, Spain
| | - Paloma Sobrado-Calvo
- Dpto Oftalmología, Universidad de Murcia, Murcia, Spain.,Grupo de Oftalmología Experimental, Instituto Murciano de Investigación Biosanitaria Virgen de la Arrixaca (IMIB-Arrixaca), Murcia, Spain
| | - Miguel Blanquer
- Unidad de Terapia Celular y Trasplante Hematopoyético. Instituto Murciano de Investigación Biosanitaria Virgen de la Arrixaca (IMIB-Arrixaca), Murcia, Spain.,Dpto Medicina Interna, Universidad de Murcia, Murcia, Spain
| | - Jose M Moraleda
- Unidad de Terapia Celular y Trasplante Hematopoyético. Instituto Murciano de Investigación Biosanitaria Virgen de la Arrixaca (IMIB-Arrixaca), Murcia, Spain.,Dpto Medicina Interna, Universidad de Murcia, Murcia, Spain
| | - Manuel Vidal-Sanz
- Dpto Oftalmología, Universidad de Murcia, Murcia, Spain.,Grupo de Oftalmología Experimental, Instituto Murciano de Investigación Biosanitaria Virgen de la Arrixaca (IMIB-Arrixaca), Murcia, Spain
| | - Marta Agudo-Barriuso
- Dpto Oftalmología, Universidad de Murcia, Murcia, Spain. .,Grupo de Oftalmología Experimental, Instituto Murciano de Investigación Biosanitaria Virgen de la Arrixaca (IMIB-Arrixaca), Murcia, Spain.
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23
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Guymer C, Wood JPM, Chidlow G, Casson RJ. Neuroprotection in glaucoma: recent advances and clinical translation. Clin Exp Ophthalmol 2018; 47:88-105. [DOI: 10.1111/ceo.13336] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2018] [Revised: 05/21/2018] [Accepted: 06/06/2018] [Indexed: 02/06/2023]
Affiliation(s)
- Chelsea Guymer
- Ophthalmic Research Laboratory, South Australian Institute of Ophthalmology; University of Adelaide; Adelaide South Australia Australia
| | - John PM Wood
- Ophthalmic Research Laboratory, South Australian Institute of Ophthalmology; University of Adelaide; Adelaide South Australia Australia
| | - Glyn Chidlow
- Ophthalmic Research Laboratory, South Australian Institute of Ophthalmology; University of Adelaide; Adelaide South Australia Australia
| | - Robert J Casson
- Ophthalmic Research Laboratory, South Australian Institute of Ophthalmology; University of Adelaide; Adelaide South Australia Australia
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Cislo-Pakuluk A, Marycz K. A Promising Tool in Retina Regeneration: Current Perspectives and Challenges When Using Mesenchymal Progenitor Stem Cells in Veterinary and Human Ophthalmological Applications. Stem Cell Rev Rep 2018. [PMID: 28643176 PMCID: PMC5602072 DOI: 10.1007/s12015-017-9750-4] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
Visual impairment is a common ailment of the current world population, with more exposure to CCD screens and fluorescent lighting, approximately 285 billion people suffer from this deficiency and 13% of those are considered clinically blind. More common causes for visual impairment include age-related macular degeneration (AMD), glaucoma and diabetic retinopathy (Zhu et al. Molecular Medicine Reports, 2015; Kolb et al. 2007; Machalińska et al. Current Eye Research, 34(9),748-760, 2009) among a few. As cases of retinal and optic nerve diseases rise, it is vital to find a treatment, which has led to investigation of the therapeutic potential of various stem cells types (Bull et al. Investigative Opthalmology & Visual Science, 50(9), 4244, 2009; Bull et al. Investigative Opthalmology & Visual Science, 49(8), 3449, 2008; Yu et al. Biochemical and Biophysical Research Communications, 344(4), 1071-1079, 2006; Na et al. Graefe's Archive for Clinical and Experimental Ophthalmology, 247(4), 503-514, 2008). In previous studies, some of the stem cell variants used include human Muller SCs and bone marrow derived SCs. Some of the regenerative potential characteristics of mesenchymal progenitor stem cells (MSCs) include their multilineage differentiation potential, their immunomodulatory effects, their high proliferative activity, they can be easily cultured in vitro, and finally their potential to synthesize and secrete membrane derived vesicles rich in growth factors, mRNA and miRNA which possibly aid in regulation of tissue damage regeneration. These facts alone, explain why MSCs are so widely used in clinical trials, 350 up to date (Switonski, Reproductive Biology, 14(1), 44-50, 2014). Animal studies have demonstrated that sub-retinal transplantation of MSCs delays retinal degeneration and preserves retinal function through trophic response (Inoue et al. Experimental Eye Research, 85(2), 234-241, 2007). Umbilical cord derived MSCs (UC/MSCs) have also been shown to contain neuroprotective features of ganglion cells in rat studies (Zwart et al. Experimental Neurology, 216(2), 439-448, 2009). This review aims to present current MSC therapies in practice, as well as their retinal regeneration potential in animal models, and their innovative prospects for treatment of human retinal diseases.
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Affiliation(s)
- Anna Cislo-Pakuluk
- Veterinary Clinic, Trzebnicka", Kościuszki 18, 55-100, Trzebnica, Poland
| | - Krzysztof Marycz
- Department of Experimental Biology, Wrocław University of Environmental and Life Sciences, C. K. Norwida 25, 50-375, Wrocław, Poland.
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Intrastriatal transplantation of stem cells from human exfoliated deciduous teeth reduces motor defects in Parkinsonian rats. Cytotherapy 2018; 20:670-686. [PMID: 29576501 DOI: 10.1016/j.jcyt.2018.02.371] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2017] [Revised: 02/11/2018] [Accepted: 02/21/2018] [Indexed: 12/20/2022]
Abstract
BACKGROUND This study explored the neural differentiation and therapeutic effects of stem cells from human exfoliated deciduous teeth (SHED) in a rat model of Parkinson's disease (PD). METHODS The SHED were isolated from fresh dental pulp and were induced to differentiate to neurons and dopamine neurons by inhibiting similar mothers against dpp (SMAD) signaling with Noggin and increase conversion of dopamine neurons from SHED with CHIR99021, Sonic Hedgehog (SHH) and FGF8 in vitro. The neural-primed SHED were transplanted to the striatum of 6-hydroxydopamine (6-OHDA)-induced PD rats to evaluate their neural differentiation and functions in vivo. RESULTS These SHED were efficiently differentiated to neurons (62.7%) and dopamine neurons (42.3%) through a newly developed method. After transplantation, the neural-induced SHED significantly improved recovery of the motor deficits of the PD rats. The grafted SHED were differentiated into neurons (61%), including dopamine neurons (22.3%), and integrated into the host rat brain by forming synaptic connections. Patch clamp analysis showed that neurons derived from grafted SHED have the same membrane potential profile as dopamine neurons, indicating these cells are dopamine neuron-like cells. The potential molecular mechanism of SHED transplantation in alleviating motor deficits of the rats is likely to be mediated by neuronal replacement and immune-modulation as we detected the transplanted dopamine neurons and released immune cytokines from SHED. CONCLUSION Using neural-primed SHED to treat PD showed significant restorations of motor deficits in 6-OHDA-induced rats. These observations provide further evidence that SHED can be used for cell-based therapy of PD.
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Ji S, Lin S, Chen J, Huang X, Wei CC, Li Z, Tang S. Neuroprotection of Transplanting Human Umbilical Cord Mesenchymal Stem Cells in a Microbead Induced Ocular Hypertension Rat Model. Curr Eye Res 2018; 43:810-820. [PMID: 29505314 DOI: 10.1080/02713683.2018.1440604] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
PURPOSE The purpose of this study is to investigate the potential therapeutic benefits of intravitreally transplanted human umbilical cord mesenchymal stem cells (UC-MSCs) in an animal model of microbead-injection-induced ocular hypertension (OHT). METHODS UC-MSCs were isolated from human umbilical cords and then cultured. The OHT model was induced via intracameral injection of polystyrene microbeads in Sprague-Dawley adult rat eyes. Fifty-four healthy adult rats were randomly divided into three groups: normal control, OHT model treated with intravitreal transplantation of UC-MSCs, or phosphate-buffered saline (PBS). Two days after OHT was induced, either 5 µl 105 UC-MSCs suspension or PBS was injected into the vitreous cavity of rats. UC-MSCs localization and integration were examined via immunohistochemistry. Neuroprotection was quantified by counting retinal ganglion cells (RGCs) and axons 2 weeks following transplantation. The expression levels of glial-derived neurotrophic factor (GDNF), brain-derived neurotrophic factor (BDNF), and glial fibrillary acidic protein (GFAP) were assessed via immunohistochemistry and Western blot. Functional recovery was assessed 2 weeks after transplantation via scotopic threshold response (STR) electroretinography. RESULTS Elevated IOP levels were sustained at least 3 weeks after intracameral microbead injection and the number of β-III-tubulin+ RGCs significantly declined compared to PBS-injected eyes. UC-MSCs survived for at least 2 weeks after intravitreal transplantation and predominantly located in the vitreous cavity. A fraction of cells migrated into the ganglion cell layer of host retina, but without differentiation. Intravitreal UC-MSC transplantation resulted in increased number of RGCs, axons, and increased expression of GDNF and BDNF but decreased expression of GFAP. Intravitreal delivery of UC-MSCs significantly improved the recovery of the positive STR. CONCLUSIONS Intravitreal transplantation of UC-MSCs revealed the neuroprotection in the microbead-injection induced OHT. The effects could be related to the secretion of tropic factors (BDNF and GDNF) and the modulation of glial cell activation.
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Affiliation(s)
- Shangli Ji
- a Aier School of Ophthalmology , Central South University , Changsha , Hunan , China
| | - Saiyue Lin
- b Department of Anatomy and Neurobiology, Xiangya School of Medicine , Central South University , Changsha , Hunan , China
| | - Jiansu Chen
- a Aier School of Ophthalmology , Central South University , Changsha , Hunan , China
| | - Xinping Huang
- c Department of Biology , ShenzhenHornetcorn Biotechnology Co., Ltd , Shenzhen , Guangdong , China
| | - Chih-Chang Wei
- c Department of Biology , ShenzhenHornetcorn Biotechnology Co., Ltd , Shenzhen , Guangdong , China
| | - Zhiyuan Li
- b Department of Anatomy and Neurobiology, Xiangya School of Medicine , Central South University , Changsha , Hunan , China
| | - Shibo Tang
- a Aier School of Ophthalmology , Central South University , Changsha , Hunan , China
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Osborne A, Sanderson J, Martin KR. Neuroprotective Effects of Human Mesenchymal Stem Cells and Platelet-Derived Growth Factor on Human Retinal Ganglion Cells. Stem Cells 2017; 36:65-78. [PMID: 29044808 PMCID: PMC5765520 DOI: 10.1002/stem.2722] [Citation(s) in RCA: 57] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2017] [Revised: 09/29/2017] [Accepted: 10/07/2017] [Indexed: 12/17/2022]
Abstract
Optic neuropathies such as glaucoma occur when retinal ganglion cells (RGCs) in the eye are injured. Strong evidence suggests mesenchymal stem cells (MSCs) could be a potential therapy to protect RGCs; however, little is known regarding their effect on the human retina. We, therefore, investigated if human MSCs (hMSCs), or platelet‐derived growth factor (PDGF) as produced by hMSC, could delay RGC death in a human retinal explant model of optic nerve injury. Our results showed hMSCs and the secreted growth factor PDGF‐AB could substantially reduce human RGC loss and apoptosis following axotomy. The neuroprotective pathways AKT, ERK, and STAT3 were activated in the retina shortly after treatments with labeling seen in the RGC layer. A dose dependent protective effect of PDGF‐AB was observed in human retinal explants but protection was not as substantial as that achieved by culturing hMSCs on the retina surface which resulted in RGC cell counts similar to those immediately post dissection. These results demonstrate that hMSCs and PDGF have strong neuroprotective action on human RGCs and may offer a translatable, therapeutic strategy to reduce degenerative visual loss. Stem Cells2018;36:65–78
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Affiliation(s)
- Andrew Osborne
- John van Geest Centre for Brain Repair, University of Cambridge, Cambridge, United Kingdom
| | - Julie Sanderson
- School of Pharmacy, University of East Anglia, Norwich, United Kingdom
| | - Keith R Martin
- John van Geest Centre for Brain Repair, University of Cambridge, Cambridge, United Kingdom.,Cambridge NIHR Biomedical Research Centre, Cambridge, United Kingdom.,Eye Department, Addenbrooke's Hospital, Cambridge, United Kingdom.,Wellcome Trust-Medical Research Council, Stem Cell Institute, Cambridge, United Kingdom
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Takahama S, Adetunji MO, Zhao T, Chen S, Li W, Tomarev SI. Retinal Astrocytes and GABAergic Wide-Field Amacrine Cells Express PDGFRα: Connection to Retinal Ganglion Cell Neuroprotection by PDGF-AA. Invest Ophthalmol Vis Sci 2017; 58:4703-4711. [PMID: 28910446 PMCID: PMC5606213 DOI: 10.1167/iovs.21783] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Purpose Our previous experiments demonstrated that intravitreal injection of platelet-derived growth factor-AA (PDGF-AA) provides retinal ganglion cell (RGC) neuroprotection in a rodent model of glaucoma. Here we used PDGFRα-enhanced green fluorescent protein (EGFP) mice to identify retinal cells that may be essential for RGC protection by PDGF-AA. Methods PDGFRα-EGFP mice expressing nuclear-targeted EGFP under the control of the PDGFRα promoter were used. Localization of PDGFRα in the neural retina was investigated by confocal imaging of EGFP fluorescence and immunofluorescent labeling with a panel of antibodies recognizing different retinal cell types. Primary cultures of mouse RGCs were produced by immunopanning. Neurobiotin injection of amacrine cells in a flat-mounted retina was used for the identification of EGFP-positive amacrine cells in the inner nuclear layer. Results In the mouse neural retina, PDGFRα was preferentially localized in the ganglion cell and inner nuclear layers. Immunostaining of the retina demonstrated that astrocytes in the ganglion cell layer and a subpopulation of amacrine cells in the inner nuclear layer express PDGFRα, whereas RGCs (in vivo or in vitro) did not. PDGFRα-positive amacrine cells are likely to be Type 45 gamma-aminobutyric acidergic (GABAergic) wide-field amacrine cells. Conclusions These data indicate that the neuroprotective effect of PDGF-AA in a rodent model of glaucoma could be mediated by astrocytes and/or a subpopulation of amacrine cells. We suggest that after intravitreal injection of PDGF-AA, these cells secrete factors protecting RGCs.
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Affiliation(s)
- Shokichi Takahama
- Section on Retinal Ganglion Cell Biology, Laboratory of Retinal Cell and Molecular Biology, National Institutes of Health, Bethesda, Maryland, United States
| | - Modupe O Adetunji
- Section on Retinal Ganglion Cell Biology, Laboratory of Retinal Cell and Molecular Biology, National Institutes of Health, Bethesda, Maryland, United States
| | - Tantai Zhao
- Retinal Neurophysiology Section, National Eye Institute, National Institutes of Health, Bethesda, Maryland, United States
| | - Shan Chen
- Retinal Neurophysiology Section, National Eye Institute, National Institutes of Health, Bethesda, Maryland, United States
| | - Wei Li
- Retinal Neurophysiology Section, National Eye Institute, National Institutes of Health, Bethesda, Maryland, United States
| | - Stanislav I Tomarev
- Section on Retinal Ganglion Cell Biology, Laboratory of Retinal Cell and Molecular Biology, National Institutes of Health, Bethesda, Maryland, United States
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29
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Nuzzi R, Tridico F. Glaucoma: Biological Trabecular and Neuroretinal Pathology with Perspectives of Therapy Innovation and Preventive Diagnosis. Front Neurosci 2017; 11:494. [PMID: 28928631 PMCID: PMC5591842 DOI: 10.3389/fnins.2017.00494] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2017] [Accepted: 08/22/2017] [Indexed: 12/14/2022] Open
Abstract
Glaucoma is a common degenerative disease affecting retinal ganglion cells (RGC) and optic nerve axons, with progressive and chronic course. It is one of the most important reasons of social blindness in industrialized countries. Glaucoma can lead to the development of irreversible visual field loss, if not treated. Diagnosis may be difficult due to lack of symptoms in early stages of disease. In many cases, when patients arrive at clinical evaluation, a severe neuronal damage may have already occurred. In recent years, newer perspective in glaucoma treatment have emerged. The current research is focusing on finding newer drugs and associations or better delivery systems in order to improve the pharmacological treatment and patient compliance. Moreover, the application of various stem cell types with restorative and neuroprotective intent may be found appealing (intravitreal autologous cellular therapy). Advances are made also in terms of parasurgical treatment, characterized by various laser types and techniques. Moreover, recent research has led to the development of central and peripheral retinal rehabilitation (featuring residing cells reactivation and replacement of defective elements), as well as innovations in diagnosis through more specific and refined methods and inexpensive tests.
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Affiliation(s)
- Raffaele Nuzzi
- Eye Clinic Section, Department of Surgical Sciences, University of Turin, Ophthalmic HospitalTurin, Italy
| | - Federico Tridico
- Eye Clinic Section, Department of Surgical Sciences, University of Turin, Ophthalmic HospitalTurin, Italy
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Hermankova B, Kossl J, Javorkova E, Bohacova P, Hajkova M, Zajicova A, Krulova M, Holan V. The Identification of Interferon-γ as a Key Supportive Factor for Retinal Differentiation of Murine Mesenchymal Stem Cells. Stem Cells Dev 2017; 26:1399-1408. [PMID: 28728472 DOI: 10.1089/scd.2017.0111] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Retinal disorders represent the main cause of decreased quality of vision and even blindness worldwide. The loss of retinal cells causes irreversible damage of the retina, and there are currently no effective treatment protocols for most retinal degenerative diseases. A promising approach for the treatment of retinal disorders is represented by stem cell-based therapy. The perspective candidates are mesenchymal stem cells (MSCs), which can differentiate into multiple cell types and produce a number of trophic and growth factors. In this study, we show the potential of murine bone marrow-derived MSCs to differentiate into cells expressing retinal markers and we identify the key supportive role of interferon-γ (IFN-γ) in the differentiation process. MSCs were cultured for 7 days with retinal extract and supernatant from T-cell mitogen concanavalin A-stimulated splenocytes, simulating the inflammatory site of retinal damage. MSCs cultured in such conditions differentiated to the cells expressing retinal cell markers such as rhodopsin, S antigen, retinaldehyde-binding protein, calbindin 2, recoverin, and retinal pigment epithelium 65. To identify a supportive molecule in the supernatants from activated spleen cells, MSCs were cultured with retinal extract in the presence of various T-cell cytokines. The expression of retinal markers was enhanced only in the presence of IFN-γ, and the supportive role of spleen cell supernatants was abrogated with the neutralization antibody anti-IFN-γ. In addition, differentiated MSCs were able to express a number of neurotrophic factors, which are important for retinal regeneration. Taken together, the results show that MSCs can differentiate into cells expressing retinal markers and that this differentiation process is supported by IFN-γ.
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Affiliation(s)
- Barbora Hermankova
- 1 Department of Transplantation Immunology, Institute of Experimental Medicine , Czech Academy of Sciences, Prague, Czech Republic .,2 Department of Cell Biology, Faculty of Science, Charles University , Prague, Czech Republic
| | - Jan Kossl
- 1 Department of Transplantation Immunology, Institute of Experimental Medicine , Czech Academy of Sciences, Prague, Czech Republic .,2 Department of Cell Biology, Faculty of Science, Charles University , Prague, Czech Republic
| | - Eliska Javorkova
- 1 Department of Transplantation Immunology, Institute of Experimental Medicine , Czech Academy of Sciences, Prague, Czech Republic .,2 Department of Cell Biology, Faculty of Science, Charles University , Prague, Czech Republic
| | - Pavla Bohacova
- 1 Department of Transplantation Immunology, Institute of Experimental Medicine , Czech Academy of Sciences, Prague, Czech Republic .,2 Department of Cell Biology, Faculty of Science, Charles University , Prague, Czech Republic
| | - Michaela Hajkova
- 1 Department of Transplantation Immunology, Institute of Experimental Medicine , Czech Academy of Sciences, Prague, Czech Republic .,2 Department of Cell Biology, Faculty of Science, Charles University , Prague, Czech Republic
| | - Alena Zajicova
- 1 Department of Transplantation Immunology, Institute of Experimental Medicine , Czech Academy of Sciences, Prague, Czech Republic
| | - Magdalena Krulova
- 1 Department of Transplantation Immunology, Institute of Experimental Medicine , Czech Academy of Sciences, Prague, Czech Republic .,2 Department of Cell Biology, Faculty of Science, Charles University , Prague, Czech Republic
| | - Vladimir Holan
- 1 Department of Transplantation Immunology, Institute of Experimental Medicine , Czech Academy of Sciences, Prague, Czech Republic .,2 Department of Cell Biology, Faculty of Science, Charles University , Prague, Czech Republic
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Gokuladhas K, Sivapriya N, Barath M, NewComer CH. Ocular progenitor cells and current applications in regenerative medicines - Review. Genes Dis 2017; 4:88-99. [PMID: 30258910 PMCID: PMC6136601 DOI: 10.1016/j.gendis.2017.01.002] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2016] [Accepted: 01/31/2017] [Indexed: 12/31/2022] Open
Abstract
The recent emerging field of regenerative medicine is to present solutions for chronic diseases which cannot be sufficiently repaired by the body's own mechanisms. Stem cells are undifferentiated biological cells and have the potential to develop into many different cell types in the body during early life and growth. Self renewal and totipotency are the characteristic features of stem cells and it holds a promising result for treating various diseases like diabetic foot ulcer, heart diseases, lung diseases, Autism, Skin diseases, arthritis including eye disease. Failure of complete recovery of eye diseases and complications that follow conventional treatments have shifted search to a new form of regenerative medicine using Stem cells. The ocular progenitor cells are remarkable in stem cell biology and replenishing degenerated cells despite being present in low quantity and quiescence in our body has a high therapeutic value. In this paper we have review the applications on ocular progenitor stem cells in treatment of human eye diseases and address the strategies that have been exploited in an effort to regain visual function in the advance treatment of stem cells without any side effects and also present the significance in advance stem cell research.
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Affiliation(s)
- K Gokuladhas
- World Stem Cell Clinic India LLP (ISO 9001:2015 Certified Clinic), #6, 9th Cross Street, Kapaleeshwar Nagar, Neelankarai, Chennai 600115, India
| | - N Sivapriya
- World Stem Cell Clinic India LLP (ISO 9001:2015 Certified Clinic), #6, 9th Cross Street, Kapaleeshwar Nagar, Neelankarai, Chennai 600115, India
| | - M Barath
- World Stem Cell Clinic India LLP (ISO 9001:2015 Certified Clinic), #6, 9th Cross Street, Kapaleeshwar Nagar, Neelankarai, Chennai 600115, India
| | - Charles H NewComer
- World Stem Cell Clinic India LLP (ISO 9001:2015 Certified Clinic), #6, 9th Cross Street, Kapaleeshwar Nagar, Neelankarai, Chennai 600115, India
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Mohamed EM, Abdelrahman SA, Hussein S, Shalaby SM, Mosaad H, Awad AMB. Effect of human umbilical cord blood mesenchymal stem cells administered by intravenous or intravitreal routes on cryo-induced retinal injury. IUBMB Life 2017; 69:188-201. [PMID: 28164440 DOI: 10.1002/iub.1608] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2016] [Accepted: 01/17/2017] [Indexed: 01/17/2023]
Abstract
Traumatic optic neuropathy is an important cause of severe vision loss. So, many attempts were performed to transplant stem cells systemically or locally to regenerate the injured retina. In this study, we investigated the effect of human umbilical cord blood mesenchymal stem cells (hUBMSCs) on histological structure, apoptotic, antiapoptotic, oxidant and antioxidant markers in an experimental model of cryo-induced retinal damage in mice. Forty-eight mice were included with 4 major groups; group I contained 18 mice as controls. The others included 30 mice exposed to cryo-induced retinal injury and were subdivided into three equal groups: group II received no treatment after injury. Group III was intravenously injected with hUCBMSCs after injury and group IV received an intravitreal injection with hUCBMSCs into both eyes. Retinal tissues were used for histopathological, immunological and gene expression studies. Real time-PCR was performed to assess B-cell lymphoma 2 (bcl2), Bcl2-associated X protein (bax), heme oxygenase-1 (hmox-1) and thioredoxin-2 (tnx-2) expression and to assess the differentiation of the stem cells into the retinal tissue. Immunohistochemical analysis was performed to assess caspase-3, 3-nitrotyrosine (3-NT) and basic fibroblast growth factor (bFGF). Disturbed retinal structure was seen in cryo-injured mice while hUCBMSCs treated groups showed nearly normal structure. By real time-PCR, significantly reduced mRNA expressions of Bax and notably enhanced mRNA expression of Bcl-2, hmox-1 and txn-2 were demonstrated in retinal injured mice with hUCBMSCs treatment compared to those without. In addition, immunohistochemical analysis confirmed downregulation of 3-NT and caspase-3 and upregulation of bFGF after hUCBMSCs injection in injured retina. Furthermore, there was no differentiation of transplanted stem cells into the retinal tissue. In conclusions, hUCBMSCs could improve the morphological retinal structure in cryo-induced retinal damage model by modulation of the oxidant-apoptotic status and by increased the expression of bFGF. © 2017 IUBMB Life, 69(3):188-201, 2017.
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Affiliation(s)
- Eman M Mohamed
- Histology and Cell Biology Department, Faculty of Medicine, Zagazig University, Egypt
| | - Shaimaa A Abdelrahman
- Histology and Cell Biology Department, Faculty of Medicine, Zagazig University, Egypt
| | - Samia Hussein
- Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Zagazig University, Egypt
| | - Sally M Shalaby
- Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Zagazig University, Egypt
| | - Hala Mosaad
- Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Zagazig University, Egypt
| | - Ahmed M B Awad
- Ophthalmology Department, Faculty of Medicine, Zagazig University, Egypt
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Mead B, Tomarev S. Bone Marrow-Derived Mesenchymal Stem Cells-Derived Exosomes Promote Survival of Retinal Ganglion Cells Through miRNA-Dependent Mechanisms. Stem Cells Transl Med 2017; 6:1273-1285. [PMID: 28198592 PMCID: PMC5442835 DOI: 10.1002/sctm.16-0428] [Citation(s) in RCA: 331] [Impact Index Per Article: 41.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2016] [Accepted: 11/29/2016] [Indexed: 12/20/2022] Open
Abstract
The loss of retinal ganglion cells (RGC) and their axons is one of the leading causes of blindness and includes traumatic (optic neuropathy) and degenerative (glaucoma) eye diseases. Although no clinical therapies are in use, mesenchymal stem cells (MSC) have demonstrated significant neuroprotective and axogenic effects on RGC in both of the aforementioned models. Recent evidence has shown that MSC secrete exosomes, membrane enclosed vesicles (30–100 nm) containing proteins, mRNA and miRNA which can be delivered to nearby cells. The present study aimed to isolate exosomes from bone marrow‐derived MSC (BMSC) and test them in a rat optic nerve crush (ONC) model. Treatment of primary retinal cultures with BMSC‐exosomes demonstrated significant neuroprotective and neuritogenic effects. Twenty‐one days after ONC and weekly intravitreal exosome injections; optical coherence tomography, electroretinography, and immunohistochemistry was performed. BMSC‐derived exosomes promoted statistically significant survival of RGC and regeneration of their axons while partially preventing RGC axonal loss and RGC dysfunction. Exosomes successfully delivered their cargo into inner retinal layers and the effects were reliant on miRNA, demonstrated by the diminished therapeutic effects of exosomes derived from BMSC after knockdown of Argonaute‐2, a key miRNA effector molecule. This study supports the use of BMSC‐derived exosomes as a cell‐free therapy for traumatic and degenerative ocular disease. Stem Cells Translational Medicine2017;6:1273–1285
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Affiliation(s)
- Ben Mead
- Section of Retinal Ganglion Cell Biology, Laboratory of Retinal Cell and Molecular Biology, National Eye Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Stanislav Tomarev
- Section of Retinal Ganglion Cell Biology, Laboratory of Retinal Cell and Molecular Biology, National Eye Institute, National Institutes of Health, Bethesda, Maryland, USA
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Hu ZL, Li N, Wei X, Tang L, Wang TH, Chen XM. Neuroprotective effects of BDNF and GDNF in intravitreally transplanted mesenchymal stem cells after optic nerve crush in mice. Int J Ophthalmol 2017; 10:35-42. [PMID: 28149774 DOI: 10.18240/ijo.2017.01.06] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2016] [Accepted: 09/04/2016] [Indexed: 02/05/2023] Open
Abstract
AIM To assess the neuro-protective effect of bone marrow mesenchymal stem cells (BMSCs) on retinal ganglion cells (RGCs) following optic nerve crush in mice. METHODS C56BL/6J mice were treated with intravitreal injection of PBS, BMSCs, BDNF-interference BMSCs (BIM), and GDNF-interference BMSCs (GIM) following optic nerve crush, respectively. The number of surviving RGCs was determined by whole-mount retinas and frozen sections, while certain mRNA or protein was detected by q-PCR or ELISA, respectively. RESULTS The density (cell number/mm2) of RGCs was 410.77±56.70 in the retina 21d after optic nerve crush without any treatment, compared to 1351.39±195.97 in the normal control (P<0.05). RGCs in BMSCs treated eyes was 625.07±89.64/mm2, significantly higher than that of no or PBS treatment (P<0.05). While RGCs was even less in the retina with intravitreal injection of BIM (354.07+39.77) and GIM (326.67+33.37) than that without treatment (P<0.05). BMSCs injection improved the internal BDNF expression in retinas. CONCLUSION Optic nerve crush caused rust loss of RGCs and intravitreally transplanted BMSCs at some extent protected RGCs from death. The effect of BMSCs and level of BDNF in retinas are both related to BDNF and GDNF expression in BMSCs.
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Affiliation(s)
- Zong-Li Hu
- Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Ni Li
- Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Xin Wei
- Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Li Tang
- Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Ting-Hua Wang
- Institute of Neurological Disease, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Xiao-Ming Chen
- Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
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Mead B, Tomarev S. Bone Marrow-Derived Mesenchymal Stem Cells-Derived Exosomes Promote Survival of Retinal Ganglion Cells Through miRNA-Dependent Mechanisms. Stem Cells Transl Med 2017. [DOI: 10.1002/sctm.12056] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Affiliation(s)
- Ben Mead
- Section of Retinal Ganglion Cell Biology, Laboratory of Retinal Cell and Molecular Biology; National Eye Institute, National Institutes of Health; Bethesda Maryland USA
| | - Stanislav Tomarev
- Section of Retinal Ganglion Cell Biology, Laboratory of Retinal Cell and Molecular Biology; National Eye Institute, National Institutes of Health; Bethesda Maryland USA
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Overview of retinal differentiation potential of mesenchymal stem cells: A promising approach for retinal cell therapy. Ann Anat 2016; 210:52-63. [PMID: 27986614 DOI: 10.1016/j.aanat.2016.11.010] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2016] [Revised: 10/10/2016] [Accepted: 11/11/2016] [Indexed: 12/15/2022]
Abstract
Retinal disease caused by retinal cell apoptosis leads to irreversible vision loss. Stem cell investigation efforts have been made to solve and cure retinal disorders. There are several sources of stem cells which have been used in these experiments. Numerous studies demonstrated that transplanted stem cells can migrate into and integrate in different layers of retina. Among these, mesenchymal stem cells (MSCs) were considered a promising source for cell therapy. Here, we review the literature assessing the potential of MSCs to differentiate into retinal cells in vivo and in vitro as well as their clinical application. However, more investigation is required to define the protocols that optimize stem cell differentiation and their functional integration in the retina.
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Lopez Sanchez M, Crowston J, Mackey D, Trounce I. Emerging Mitochondrial Therapeutic Targets in Optic Neuropathies. Pharmacol Ther 2016; 165:132-52. [DOI: 10.1016/j.pharmthera.2016.06.004] [Citation(s) in RCA: 66] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2015] [Indexed: 12/14/2022]
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Vellasamy S, Tong CK, Azhar NA, Kodiappan R, Chan SC, Veerakumarasivam A, Ramasamy R. Human mesenchymal stromal cells modulate T-cell immune response via transcriptomic regulation. Cytotherapy 2016; 18:1270-83. [PMID: 27543068 DOI: 10.1016/j.jcyt.2016.06.017] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2016] [Revised: 06/29/2016] [Accepted: 06/30/2016] [Indexed: 02/08/2023]
Abstract
BACKGROUND AIMS Mesenchymal stromal cells (MSCs) have been identified as pan-immunosuppressant in various in vitro and in vivo inflammatory models. Although the immunosuppressive activity of MSCs has been explored in various contexts, the precise molecular signaling pathways that govern inhibitory functions remain poorly elucidated. METHODS By using a microarray-based global gene expression profiling system, this study aimed to decipher the underlying molecular pathways that may mediate the immunosuppressive activity of umbilical cord-derived MSCs (UC-MSCs) on activated T cells. RESULTS In the presence of UC-MSCs, the proliferation of activated T cells was suppressed in a dose-depended manner by cell-to-cell contact mode via an active cell-cycle arrest at the G0/G1 phase of the cell cycle. The microarray analysis revealed that particularly, IFNG, CXCL9, IL2, IL2RA and CCND3 genes were down-regulated, whereas IL11, VSIG4, GFA1, TIMP3 and BBC3 genes were up-regulated by UC-MSCs. The dysregulated gene clusters associated with immune-response-related ontologies, namely, lymphocyte proliferation or activation, apoptosis and cell cycle, were further analyzed. CONCLUSIONS Among the nine canonical pathways identified, three pathways (namely T-helper cell differentiation, cyclins and cell cycle regulation, and gap/tight junction signalling pathways) were highly enriched with these dysregulated genes. The pathways represent putative molecular pathways through which UC-MSCs elicit immunosuppressive activity toward activated T cells. This study provides a global snapshot of gene networks and pathways that contribute to the ability of UC-MSCs to suppress activated T cells.
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Affiliation(s)
- Shalini Vellasamy
- Department of Biomedical Science, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia; Immunology Laboratory, Department of Pathology, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, Selangor, Malaysia
| | - Chih Kong Tong
- Immunology Laboratory, Department of Pathology, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, Selangor, Malaysia
| | - Nur Atiqah Azhar
- Centre for Bioinformatics, School of Data Sciences, Perdana University, Jalan MAEPS Perdana, Serdang, Selangor Darul Ehsan, Malaysia
| | - Radha Kodiappan
- Perdana University-Royal College of Surgeons in Ireland, Perdana University, Jalan MAEPS Perdana, Serdang, Selangor Darul Ehsan, Malaysia; Medical Genetics Laboratory, Genetics & Regenerative Medicine Research Centre, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, Selangor Darul Ehsan, Malaysia
| | - Soon Choy Chan
- Perdana University Graduate School of Medicine, Perdana University, Jalan MAEPS Perdana, Serdang, Selangor Darul Ehsan, Malaysia
| | - Abhi Veerakumarasivam
- Perdana University Graduate School of Medicine, Perdana University, Jalan MAEPS Perdana, Serdang, Selangor Darul Ehsan, Malaysia; Medical Genetics Laboratory, Genetics & Regenerative Medicine Research Centre, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, Selangor Darul Ehsan, Malaysia
| | - Rajesh Ramasamy
- Immunology Laboratory, Department of Pathology, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, Selangor, Malaysia; Stem Cell Research Laboratory, Genetics & Regenerative Medicine Research Centre, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, Selangor Darul Ehsan, Malaysia.
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Yuan J, Yu JX. Gender difference in the neuroprotective effect of rat bone marrow mesenchymal cells against hypoxia-induced apoptosis of retinal ganglion cells. Neural Regen Res 2016; 11:846-53. [PMID: 27335573 PMCID: PMC4904480 DOI: 10.4103/1673-5374.182764] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Bone marrow mesenchymal stem cells can reduce retinal ganglion cell death and effectively prevent vision loss. Previously, we found that during differentiation, female rhesus monkey bone marrow mesenchymal stem cells acquire a higher neurogenic potential compared with male rhesus monkey bone marrow mesenchymal stem cells. This suggests that female bone marrow mesenchymal stem cells have a stronger neuroprotective effect than male bone marrow mesenchymal stem cells. Here, we first isolated and cultured bone marrow mesenchymal stem cells from female and male rats by density gradient centrifugation. Retinal tissue from newborn rats was prepared by enzymatic digestion to obtain primary retinal ganglion cells. Using the transwell system, retinal ganglion cells were co-cultured with bone marrow mesenchymal stem cells under hypoxia. Cell apoptosis was detected by flow cytometry and caspase-3 activity assay. We found a marked increase in apoptotic rate and caspase-3 activity of retinal ganglion cells after 24 hours of hypoxia compared with normoxia. Moreover, apoptotic rate and caspase-3 activity of retinal ganglion cells significantly decreased with both female and male bone marrow mesenchymal stem cell co-culture under hypoxia compared with culture alone, with more significant effects from female bone marrow mesenchymal stem cells. Our results indicate that bone marrow mesenchymal stem cells exert a neuroprotective effect against hypoxia-induced apoptosis of retinal ganglion cells, and also that female cells have greater neuroprotective ability compared with male cells.
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Affiliation(s)
- Jing Yuan
- Eye Center, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, China
| | - Jian-Xiong Yu
- Department of Gastrointestinal Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, China
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Stem Cell Therapy for Treatment of Ocular Disorders. Stem Cells Int 2016; 2016:8304879. [PMID: 27293447 PMCID: PMC4884591 DOI: 10.1155/2016/8304879] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2016] [Accepted: 04/10/2016] [Indexed: 12/30/2022] Open
Abstract
Sustenance of visual function is the ultimate focus of ophthalmologists. Failure of complete recovery of visual function and complications that follow conventional treatments have shifted search to a new form of therapy using stem cells. Stem cell progenitors play a major role in replenishing degenerated cells despite being present in low quantity and quiescence in our body. Unlike other tissues and cells, regeneration of new optic cells responsible for visual function is rarely observed. Understanding the transcription factors and genes responsible for optic cells development will assist scientists in formulating a strategy to activate and direct stem cells renewal and differentiation. We review the processes of human eye development and address the strategies that have been exploited in an effort to regain visual function in the preclinical and clinical state. The update of clinical findings of patients receiving stem cell treatment is also presented.
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41
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Zarbakhsh S, Goudarzi N, Shirmohammadi M, Safari M. Histological Study of Bone Marrow and Umbilical Cord Stromal Cell Transplantation in Regenerating Rat Peripheral Nerve. CELL JOURNAL 2016; 17:668-77. [PMID: 26862526 PMCID: PMC4746417 DOI: 10.22074/cellj.2016.3839] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/25/2014] [Accepted: 02/05/2015] [Indexed: 12/15/2022]
Abstract
Objective Bone marrow and umbilical cord stromal cells are multipotential stem cells
that have the ability to produce growth factors that play an important role in survival and
generation of axons. The goal of this study was to evaluate the effects of the two different
mesenchymal stem cells on peripheral nerve regeneration.
Materials and Methods In this experimental study, a 10 mm segment of the left sciatic
nerve of male Wistar rats (250-300 g) was removed with a silicone tube interposed into
this nerve gap. Bone marrow stromal cells (BMSCs) and human umbilical cord stromal
cells (HUCSCs) were respectively obtained from rat and human. The cells were sepa-
rately cultured and transplanted into the nerve gap. The sciatic nerve regeneration was
evaluated by immunohistochemistry, and light and electron microscopy. Moreover, histo-
morphology of the gastrocnemius muscle was observed.
Results The nerve regeneration in the BMSCs and HUCSCs groups that had received
the stem cells was significantly more favorable than the control group. In addition, the BM-
SCs group was significantly more favorable than the HUCSCs group (P<0.05).
Conclusion The results of this study suggest that both homograft BMSCs and het-
erograft HUCSCs may have the potential to regenerate peripheral nerve injury and
transplantation of BMSCs may be more effective than HUCSCs in rat.
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Affiliation(s)
- Sam Zarbakhsh
- Research Center of Nervous System Stem Cells, Department of Anatomy, Faculty of Medicine, Semnan University of Medical Sciences, Semnan, Iran
| | - Nasim Goudarzi
- Department of Anatomy, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Maryam Shirmohammadi
- Department of Anatomy, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Manouchehr Safari
- Research Center of Nervous System Stem Cells, Department of Anatomy, Faculty of Medicine, Semnan University of Medical Sciences, Semnan, Iran
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Stem Cell Imaging: Tools to Improve Cell Delivery and Viability. Stem Cells Int 2016; 2016:9240652. [PMID: 26880997 PMCID: PMC4736428 DOI: 10.1155/2016/9240652] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2015] [Revised: 10/06/2015] [Accepted: 10/15/2015] [Indexed: 01/01/2023] Open
Abstract
Stem cell therapy (SCT) has shown very promising preclinical results in a variety of regenerative medicine applications. Nevertheless, the complete utility of this technology remains unrealized. Imaging is a potent tool used in multiple stages of SCT and this review describes the role that imaging plays in cell harvest, cell purification, and cell implantation, as well as a discussion of how imaging can be used to assess outcome in SCT. We close with some perspective on potential growth in the field.
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Roubeix C, Godefroy D, Mias C, Sapienza A, Riancho L, Degardin J, Fradot V, Ivkovic I, Picaud S, Sennlaub F, Denoyer A, Rostene W, Sahel JA, Parsadaniantz SM, Brignole-Baudouin F, Baudouin C. Intraocular pressure reduction and neuroprotection conferred by bone marrow-derived mesenchymal stem cells in an animal model of glaucoma. Stem Cell Res Ther 2015; 6:177. [PMID: 26377305 PMCID: PMC4574127 DOI: 10.1186/s13287-015-0168-0] [Citation(s) in RCA: 67] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2015] [Revised: 01/28/2015] [Accepted: 08/21/2015] [Indexed: 12/13/2022] Open
Abstract
INTRODUCTION Glaucoma is a sight-threatening retinal neuropathy associated with elevated intraocular pressure (IOP) due to degeneration and fibrosis of the trabecular meshwork (TM). Glaucoma medications aim to reduce IOP without targeting the specific TM pathology, Bone-marrow mesenchymal stem cells (MSCs) are used today in various clinical studies. Here, we investigated the potential of MSCs therapy in an glaucoma-like ocular hypertension (OHT) model and decipher in vitro the effects of MSCs on primary human trabecular meshwork cells. METHODS Ocular hypertension model was performed by cauterization of 3 episcleral veins (EVC) of Long-Evans male rat eyes. MSCs were isolated from rat bone marrow, amplified in vitro and tagged with quantum dot nanocrystals. Animals were distributed as 1) MSCs group receiving 5.10(5)cells/6μl Minimum Essential Medium and 2) MEM group receiving 6μl MEM (n = 10 each). Injections were performed into the anterior chamber of 20 days-hypertensive eyes and IOP was monitored twice a week for 4 weeks. At the end of experiment, cell distribution in the anterior segment was examined in confocal microscopy on flat mounted corneas. Moreover, we tested in vitro effects of MSCs conditioned medium (MSC-CM) on primary human trabecular meshwork cells (hTM cells) using Akt activation, myosin phosphorylation and TGF-β2-dependent profibrotic phenotype in hTM cells. RESULTS We demonstrated a rapid and long-lasting in vivo effect of MSCs transplantation that significantly reduced IOP in hypertensive eyes induced by EVC. MSCs were located to the ciliary processes and the TM. Enumeration of RGCs on whole flat-mounted retina highlighted a protective effect of MSCs on RGCs death. In vitro, MSC-CM promotes: (i) hTM cells survival by activating the antiapoptotic pathway, Akt, (ii) hTM cells relaxation as analyzed by the decrease in myosin phosphorylation and (iii) inhibition of TGF-β2-dependent profibrotic phenotype acquisition in hTM cells. CONCLUSIONS MSCs injection in the ocular anterior chamber in a rat model of OHT provides neuroprotective effect in the glaucoma pathophysiology via TM protection. These results demonstrate that MSCs constitute promising tool for treating ocular hypertension and retinal cell degeneration.
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Affiliation(s)
- Christophe Roubeix
- INSERM, U968, Paris, F-75012, France.
- UPMC Université Paris 06, UMR_S 968, Institut de la Vision, Paris, F-75012, France.
- CNRS, UMR_7210, Paris, F-75012, France.
| | - David Godefroy
- INSERM, U968, Paris, F-75012, France.
- UPMC Université Paris 06, UMR_S 968, Institut de la Vision, Paris, F-75012, France.
- CNRS, UMR_7210, Paris, F-75012, France.
| | - Céline Mias
- Institut des Maladies Métaboliques et Cardiovasculaires, INSERM UMR 1048, 31432 Toulouse cedex 4, France, Toulouse, France.
| | - Anaïs Sapienza
- INSERM, U968, Paris, F-75012, France.
- UPMC Université Paris 06, UMR_S 968, Institut de la Vision, Paris, F-75012, France.
- CNRS, UMR_7210, Paris, F-75012, France.
| | - Luisa Riancho
- INSERM, U968, Paris, F-75012, France.
- UPMC Université Paris 06, UMR_S 968, Institut de la Vision, Paris, F-75012, France.
- CNRS, UMR_7210, Paris, F-75012, France.
| | - Julie Degardin
- INSERM, U968, Paris, F-75012, France.
- UPMC Université Paris 06, UMR_S 968, Institut de la Vision, Paris, F-75012, France.
- CNRS, UMR_7210, Paris, F-75012, France.
| | - Valérie Fradot
- INSERM, U968, Paris, F-75012, France.
- UPMC Université Paris 06, UMR_S 968, Institut de la Vision, Paris, F-75012, France.
- CNRS, UMR_7210, Paris, F-75012, France.
| | - Ivana Ivkovic
- INSERM, U968, Paris, F-75012, France.
- UPMC Université Paris 06, UMR_S 968, Institut de la Vision, Paris, F-75012, France.
- CNRS, UMR_7210, Paris, F-75012, France.
| | - Serge Picaud
- INSERM, U968, Paris, F-75012, France.
- UPMC Université Paris 06, UMR_S 968, Institut de la Vision, Paris, F-75012, France.
- CNRS, UMR_7210, Paris, F-75012, France.
| | - Florian Sennlaub
- INSERM, U968, Paris, F-75012, France.
- UPMC Université Paris 06, UMR_S 968, Institut de la Vision, Paris, F-75012, France.
- CNRS, UMR_7210, Paris, F-75012, France.
| | - Alexandre Denoyer
- INSERM, U968, Paris, F-75012, France.
- UPMC Université Paris 06, UMR_S 968, Institut de la Vision, Paris, F-75012, France.
- CNRS, UMR_7210, Paris, F-75012, France.
- Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts, INSERM-DHOS CIC 503, Paris, F-75012, France.
| | - William Rostene
- INSERM, U968, Paris, F-75012, France.
- UPMC Université Paris 06, UMR_S 968, Institut de la Vision, Paris, F-75012, France.
- CNRS, UMR_7210, Paris, F-75012, France.
| | - José Alain Sahel
- INSERM, U968, Paris, F-75012, France.
- UPMC Université Paris 06, UMR_S 968, Institut de la Vision, Paris, F-75012, France.
- CNRS, UMR_7210, Paris, F-75012, France.
- Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts, INSERM-DHOS CIC 503, Paris, F-75012, France.
| | - Stéphane Melik Parsadaniantz
- INSERM, U968, Paris, F-75012, France.
- UPMC Université Paris 06, UMR_S 968, Institut de la Vision, Paris, F-75012, France.
- CNRS, UMR_7210, Paris, F-75012, France.
| | - Françoise Brignole-Baudouin
- INSERM, U968, Paris, F-75012, France.
- UPMC Université Paris 06, UMR_S 968, Institut de la Vision, Paris, F-75012, France.
- CNRS, UMR_7210, Paris, F-75012, France.
- Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts, INSERM-DHOS CIC 503, Paris, F-75012, France.
- University Paris Descartes, Sorbonne Paris Cité, Paris, F-75006, France.
- Faculté de Pharmacie de Paris, University Paris Descartes, Sorbonne Paris Cité, Paris, F-75006, France.
| | - Christophe Baudouin
- INSERM, U968, Paris, F-75012, France.
- UPMC Université Paris 06, UMR_S 968, Institut de la Vision, Paris, F-75012, France.
- CNRS, UMR_7210, Paris, F-75012, France.
- Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts, INSERM-DHOS CIC 503, Paris, F-75012, France.
- Department of Ophthalmology, Hôpital Ambroise Pare, AP HP, Boulogne, F-92100, France.
- University Versailles St Quentin en Yvelines, Montigny-Le-Bretonneux, F-78180, France.
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Subbot AM, Kasparova EA, Subbot AM, Kasparova EA. [Review of approaches to cell therapy in ophthalmology]. Vestn Oftalmol 2015; 131:74-81. [PMID: 26845876 DOI: 10.17116/oftalma2015131574-81] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/05/2023]
Abstract
The review covers global trends in cell therapy research and clinical trials aimed at the treatment of ophthalmic diseases. Some definitions are provided and mechanisms of action of cell products studied to date are listed.
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Affiliation(s)
- A M Subbot
- Research Institute of Eye Diseases, 11 A, B, Rossolimo St., Moscow, Russian Federation, 119021
| | - Evg A Kasparova
- Research Institute of Eye Diseases, 11 A, B, Rossolimo St., Moscow, Russian Federation, 119021
| | - A M Subbot
- Research Institute of Eye Diseases, 11 A, B, Rossolimo St., Moscow, Russian Federation, 119021
| | - Evg A Kasparova
- Research Institute of Eye Diseases, 11 A, B, Rossolimo St., Moscow, Russian Federation, 119021
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45
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Roubeix C, Denoyer A, Brignole-Baudouin F, Baudouin C. [Mesenchymal stem cell therapy, a new hope for eye disease]. J Fr Ophtalmol 2015. [PMID: 26215486 DOI: 10.1016/j.jfo.2015.05.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
Mesenchymal stem cells (MSC) are adult stem cells, first identified in skeletal tissues and then found in the entire body. MSC are able to not only differentiate into specialized cells within skeletal tissue - chondrocytes, osteocytes, adipocytes and fibroblasts - but also secrete a large range of soluble mediators defining their secretome and allowing their interaction with a number of cell protagonists. Thus, in a general sense, MSC are involved in tissue homeostasis through their secretome and are specifically responsible for cell turn-over in skeletal tissues. For a decade and a half, safety and efficiency of MSC has led to the development of many clinical trials in various fields. However, results were often disappointing, probably because of difficulties in methods and evaluation. At a time when the first clinical trials using MSC are emerging in ophthalmology, the goal of this literature review is to gather and put into perspective preclinical and clinical results in order to better predict the future of this innovative therapeutic pathway.
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Affiliation(s)
- C Roubeix
- Inserm, U968, 75012 Paris, France; UMR_S 968, institut de la vision, UPMC université Paris 06, 17, rue Moreau, 75012 Paris, France; CNRS, UMR_7210, 75012 Paris, France.
| | - A Denoyer
- Inserm, U968, 75012 Paris, France; UMR_S 968, institut de la vision, UPMC université Paris 06, 17, rue Moreau, 75012 Paris, France; CNRS, UMR_7210, 75012 Paris, France; Inserm-DHOS CIC 503, centre hospitalier national d'ophtalmologie des Quinze-Vingts, 75012 Paris, France
| | - F Brignole-Baudouin
- Inserm, U968, 75012 Paris, France; UMR_S 968, institut de la vision, UPMC université Paris 06, 17, rue Moreau, 75012 Paris, France; CNRS, UMR_7210, 75012 Paris, France; Inserm-DHOS CIC 503, centre hospitalier national d'ophtalmologie des Quinze-Vingts, 75012 Paris, France; Faculté de pharmacie de Paris, université Paris Descartes, Sorbonne Paris-Cité, 75006 Paris, France
| | - C Baudouin
- Inserm, U968, 75012 Paris, France; UMR_S 968, institut de la vision, UPMC université Paris 06, 17, rue Moreau, 75012 Paris, France; CNRS, UMR_7210, 75012 Paris, France; Inserm-DHOS CIC 503, centre hospitalier national d'ophtalmologie des Quinze-Vingts, 75012 Paris, France; Service d'ophtalmologie, hôpital Ambroise-Paré, AP-HP, 92100 Boulogne, France; Université Versailles-Saint-Quentin-en-Yvelines, 78180 Montigny-le-Bretonneux, France
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M K. Present and New Treatment Strategies in the Management of Glaucoma. Open Ophthalmol J 2015; 9:89-100. [PMID: 26069521 PMCID: PMC4460216 DOI: 10.2174/1874364101509010089] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2015] [Revised: 03/30/2015] [Accepted: 03/30/2015] [Indexed: 12/17/2022] Open
Abstract
Glaucoma is a neurodegenerative disease characterized by retinal ganglion cell (RGC) death and axonal loss. It remains a major cause of blindness worldwide. All current modalities of treatment are focused on lowering intraocular pressure (IOP), and it is evident that increased IOP is an important risk factor for progression of the disease. However, it is clear that a significant number of glaucoma patients show disease progression despite of pressure lowering treatments. Much attention has been given to the development of neuroprotective treatment strategies, but the identification of such has been hampered by lack of understanding of the etiology of glaucoma. Hence, in spite of many attempts no neuroprotective drug has yet been clinically approved. Even though neuroprotection is without doubt an important treatment strategy, many glaucoma subjects are diagnosed after substantial loss of RGCs. In this matter, recent approaches aim to rescue RGCs and regenerate axons in order to restore visual function in glaucoma. The present review seeks to provide an overview of the present and new treatment strategies in the management of glaucoma. The treatment strategies are divided into current available glaucoma medications, new pressure lowering targets, prospective neuroprotective interventions, and finally possible neuroregenrative strategies.
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Affiliation(s)
- Kolko M
- Department of Neuroscience and Pharmacology, the Panum Institute, University of Copenhagen, Denmark ; Department of Ophthalmology, Roskilde University Hospital, Copenhagen, Denmark ; Center of Healthy Aging, Department of Cellular and Molecular Medicine, the Panum Institute, University of Copenhagen, Denmark
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47
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Mead B, Berry M, Logan A, Scott RAH, Leadbeater W, Scheven BA. Stem cell treatment of degenerative eye disease. Stem Cell Res 2015; 14:243-57. [PMID: 25752437 PMCID: PMC4434205 DOI: 10.1016/j.scr.2015.02.003] [Citation(s) in RCA: 156] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2014] [Revised: 02/12/2015] [Accepted: 02/14/2015] [Indexed: 12/16/2022] Open
Abstract
Stem cell therapies are being explored extensively as treatments for degenerative eye disease, either for replacing lost neurons, restoring neural circuits or, based on more recent evidence, as paracrine-mediated therapies in which stem cell-derived trophic factors protect compromised endogenous retinal neurons from death and induce the growth of new connections. Retinal progenitor phenotypes induced from embryonic stem cells/induced pluripotent stem cells (ESCs/iPSCs) and endogenous retinal stem cells may replace lost photoreceptors and retinal pigment epithelial (RPE) cells and restore vision in the diseased eye, whereas treatment of injured retinal ganglion cells (RGCs) has so far been reliant on mesenchymal stem cells (MSC). Here, we review the properties of non-retinal-derived adult stem cells, in particular neural stem cells (NSCs), MSC derived from bone marrow (BMSC), adipose tissues (ADSC) and dental pulp (DPSC), together with ESC/iPSC and discuss and compare their potential advantages as therapies designed to provide trophic support, repair and replacement of retinal neurons, RPE and glia in degenerative retinal diseases. We conclude that ESCs/iPSCs have the potential to replace lost retinal cells, whereas MSC may be a useful source of paracrine factors that protect RGC and stimulate regeneration of their axons in the optic nerve in degenerate eye disease. NSC may have potential as both a source of replacement cells and also as mediators of paracrine treatment.
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Affiliation(s)
- Ben Mead
- Neurotrauma Research Group, Neurobiology Section, School of Clinical and Experimental Medicine, University of Birmingham, B15 2TT, UK; School of Dentistry, University of Birmingham, B4 6NN, UK.
| | - Martin Berry
- Neurotrauma Research Group, Neurobiology Section, School of Clinical and Experimental Medicine, University of Birmingham, B15 2TT, UK
| | - Ann Logan
- Neurotrauma Research Group, Neurobiology Section, School of Clinical and Experimental Medicine, University of Birmingham, B15 2TT, UK
| | - Robert A H Scott
- Neurotrauma Research Group, Neurobiology Section, School of Clinical and Experimental Medicine, University of Birmingham, B15 2TT, UK
| | - Wendy Leadbeater
- Neurotrauma Research Group, Neurobiology Section, School of Clinical and Experimental Medicine, University of Birmingham, B15 2TT, UK
| | - Ben A Scheven
- School of Dentistry, University of Birmingham, B4 6NN, UK
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Dental pulp stem cells differentiation into retinal ganglion-like cells in a three dimensional network. Biochem Biophys Res Commun 2014; 457:154-60. [PMID: 25543058 DOI: 10.1016/j.bbrc.2014.12.069] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2014] [Accepted: 12/14/2014] [Indexed: 12/16/2022]
Abstract
The loss of retinal ganglion cells (RGCs) in majority of retinal degenerative diseases is the first seen pathological event. A lot of studies aim to discover suitable cell sources to replace lost and damaged RGCs. Among them dental pulp stem cells (DPSCs) have a great potential of differentiating into neuronal lineages as well as RGCs. Moreover, three-dimensional (3D) networks and its distribution for growing and differentiation of stem cells as much as possible mimic to native tissue holds great potential in retinal tissue engineering. In this study, we isolate DPSCs from rat incisors and validate them with flow cytometry. Briefly, we differentiated cells using DMEM/F12 containing FGF2, Shh and 0.5% FBS into retinal ganglion-like cells (RGLCs) in two conditions; 3D state in biocompatible fibrin hydrogel and two-dimensional (2D) or conventional culture in polystyrene plates. Immuncytochemical and gene expression analysis revealed the expression of Pax6, Atoh7 and BRN3B increased in 3D fibrin culture compared to 2D conventional culture. In combination, these data demonstrate that using 3D networks can resemble near natural tissue properties for effective generating RGCs which used to treat neurodegenerative diseases such as glaucoma.
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Peng Y, Zhang Y, Huang B, Luo Y, Zhang M, Li K, Li W, Wen W, Tang S. Survival and migration of pre-induced adult human peripheral blood mononuclear cells in retinal degeneration slow (rds) mice three months after subretinal transplantation. Curr Stem Cell Res Ther 2014; 9:124-33. [PMID: 24350910 PMCID: PMC4101734 DOI: 10.2174/1574888x09666131219115125] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2013] [Revised: 12/07/2013] [Accepted: 12/10/2013] [Indexed: 12/18/2022]
Abstract
Introduction: Retinitis pigmentosa (RP), an inherited disease characterized by progressive loss of photoreceptors and retinal pigment epithelium, is a leading genetic cause of blindness. Cell transplantation to replace lost photoreceptors is a potential therapeutic strategy, but technical limitations have prevented clinical application. Adult human peripheral blood mononuclear cells (hPBMCs) may be an ideal cell source for such therapies. This study examined the survival and migration of pre-induced hPBMCs three months after subretinal transplantation in the retinal degeneration slow (rds) mouse model of RP. Materials and Methods: Freshly isolated adult hPBMCs were pre-induced by co-culture with neonatal Sprague-Dawley (SD) rat retinal tissue for 4 days in neural stem cell medium. Pre-induced cells were labeled with CM-DiI for tracing and injected into the right subretinal space of rds mice by the trans-scleral approach. After two and three months, right eyes were harvested and transplanted cell survival and migration examined in frozen sections and whole mountretinas. Immunofluorescence in whole-mount retinas was used to detect the expression of human neuronal and photorece ptorsprotein markers by transplanted cells. Results: Pre-induced adult hPBMCs could survive in vivo and migrate to various parts of the retina. After two and three months, transplanted cells were observed in the ciliary body, retinal outer nuclear layer, inner nuclear layer, ganglion cell layer, optic papilla, and within the optic nerve. The neuronal and photoreceptor markers CD90/Thy1, MAP-2, nestin, and rhodopsin were expressed by subpopulations of CM-DiI-positive cells three months after subretinal transplantation. Conclusion: Pre-induced adult hPBMCs survived for at least three months after subretinal transplantation, migrated throughout the retina, and expressed human protein markers. These results suggest that hPBMCs could be used for cell replacement therapy to treat retinal degenerative diseases.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Shibo Tang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, GuangZhou 510060, China.
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Cuenca N, Fernández-Sánchez L, Campello L, Maneu V, De la Villa P, Lax P, Pinilla I. Cellular responses following retinal injuries and therapeutic approaches for neurodegenerative diseases. Prog Retin Eye Res 2014; 43:17-75. [PMID: 25038518 DOI: 10.1016/j.preteyeres.2014.07.001] [Citation(s) in RCA: 316] [Impact Index Per Article: 28.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2014] [Revised: 07/03/2014] [Accepted: 07/07/2014] [Indexed: 01/17/2023]
Abstract
Retinal neurodegenerative diseases like age-related macular degeneration, glaucoma, diabetic retinopathy and retinitis pigmentosa each have a different etiology and pathogenesis. However, at the cellular and molecular level, the response to retinal injury is similar in all of them, and results in morphological and functional impairment of retinal cells. This retinal degeneration may be triggered by gene defects, increased intraocular pressure, high levels of blood glucose, other types of stress or aging, but they all frequently induce a set of cell signals that lead to well-established and similar morphological and functional changes, including controlled cell death and retinal remodeling. Interestingly, an inflammatory response, oxidative stress and activation of apoptotic pathways are common features in all these diseases. Furthermore, it is important to note the relevant role of glial cells, including astrocytes, Müller cells and microglia, because their response to injury is decisive for maintaining the health of the retina or its degeneration. Several therapeutic approaches have been developed to preserve retinal function or restore eyesight in pathological conditions. In this context, neuroprotective compounds, gene therapy, cell transplantation or artificial devices should be applied at the appropriate stage of retinal degeneration to obtain successful results. This review provides an overview of the common and distinctive features of retinal neurodegenerative diseases, including the molecular, anatomical and functional changes caused by the cellular response to damage, in order to establish appropriate treatments for these pathologies.
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Affiliation(s)
- Nicolás Cuenca
- Department of Physiology, Genetics and Microbiology, University of Alicante, Alicante, Spain; Multidisciplinary Institute for Environmental Studies "Ramon Margalef", University of Alicante, Alicante, Spain.
| | - Laura Fernández-Sánchez
- Department of Physiology, Genetics and Microbiology, University of Alicante, Alicante, Spain
| | - Laura Campello
- Department of Physiology, Genetics and Microbiology, University of Alicante, Alicante, Spain
| | - Victoria Maneu
- Department of Optics, Pharmacology and Anatomy, University of Alicante, Alicante, Spain
| | - Pedro De la Villa
- Department of Systems Biology, University of Alcalá, Alcalá de Henares, Spain
| | - Pedro Lax
- Department of Physiology, Genetics and Microbiology, University of Alicante, Alicante, Spain
| | - Isabel Pinilla
- Department of Ophthalmology, Lozano Blesa University Hospital, Aragon Institute of Health Sciences, Zaragoza, Spain
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