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Sutthiwanjampa C, Kang SH, Kim MK, Hwa Choi J, Kim HK, Woo SH, Bae TH, Kim WJ, Kang SH, Park H. Tumor necrosis factor-α-treated human adipose-derived stem cells enhance inherent radiation tolerance and alleviate in vivo radiation-induced capsular contracture. J Adv Res 2025; 72:433-449. [PMID: 39019109 DOI: 10.1016/j.jare.2024.07.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2024] [Revised: 07/10/2024] [Accepted: 07/13/2024] [Indexed: 07/19/2024] Open
Abstract
INTRODUCTION Post-mastectomy radiotherapy plays a crucial role in breast cancer treatment but can lead to an inflammatory response causing soft tissue damage, particularly radiation-induced capsular contracture (RICC), impacting breast reconstruction outcomes. Adipose-derived stem cells (ADSCs), known for their regenerative potential via paracrine capacity, exhibit inherent radiotolerance. The influence of tumor necrosis factor-alpha (TNF-α) on ADSCs has been reported to enhance the paracrine effect of ADSCs, promoting wound healing by modulating inflammatory responses. OBJECTIVE This study investigates the potential of TNF-α-treated human ADSCs (T-hASCs) on silicone implants to alleviate RICC, hypothesizing to enhance suppressive effects on RICC by modulating inflammatory responses in a radiation-exposed environment. METHODS In vitro, T-hASCs were cultured on various surfaces to assess viability after exposure to radiation up to 20 Gy. In vivo, T-hASC and non-TNF-α-treated hASC (C-hASCs)-coated membranes were implanted in mice before radiation exposure, and an evaluation of the RICC mitigation took place 4 and 8 weeks after implantation. In addition, the growth factors released from T-hASCs were assessed. RESULTS In vitro, hASCs displayed significant radiotolerance, maintaining consistent viability after exposure to 10 Gy. TNF-α treatment further enhanced radiation tolerance, as evidenced by significantly higher viability than C-hASCs at 20 Gy. In vivo, T-hASC-coated implants effectively suppressed RICC, reducing capsule thickness. T-hASCs exhibited remarkable modulation of the inflammatory response, suppressing M1 macrophage polarization while enhancing M2 polarization. The elevated secretion of vascular endothelial growth factor from T-hASCs is believed to induce macrophage polarization, potentially reducing RICC. CONCLUSION This study establishes T-hASCs as a promising strategy for ameliorating the adverse effects experienced by breast reconstruction patients after mastectomy and radiation therapy. The observed radiotolerance, anti-fibrotic effects, and immune modulation suggest the possibility of enhancing patient outcomes and quality of life. Further research and clinical trials are warranted for broader clinical uses.
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Affiliation(s)
- Chanutchamon Sutthiwanjampa
- School of Integrative Engineering, Chung-Ang University, 84 Heukseok-ro, Heukseok-dong, Dongjak-gu, Seoul 06974, Republic of Korea; College of Medicine, Chung-Ang University, 84 Heukseok-ro, Heukseok-dong, Dongjak-gu, Seoul 06974, Republic of Korea
| | - Seung Hyun Kang
- College of Medicine, Chung-Ang University, 84 Heukseok-ro, Heukseok-dong, Dongjak-gu, Seoul 06974, Republic of Korea; Department of Plastic and Reconstructive Surgery, Chung-Ang University Hospital, Chung-Ang University College of Medicine, 102 Heukseok-ro, Heukseok-dong, Dongjak-gu, Seoul 06973, Republic of Korea
| | - Mi Kyung Kim
- College of Medicine, Chung-Ang University, 84 Heukseok-ro, Heukseok-dong, Dongjak-gu, Seoul 06974, Republic of Korea; Departments of Pathology, Chung-Ang University Hospital, Chung-Ang University College of Medicine, 102 Heukseok-ro, Heukseok-dong, Dongjak-gu, Seoul 06973, Republic of Korea
| | - Jin Hwa Choi
- College of Medicine, Chung-Ang University, 84 Heukseok-ro, Heukseok-dong, Dongjak-gu, Seoul 06974, Republic of Korea; Department of Radiation Oncology, Chung-Ang University Hospital, Chung-Ang University College of Medicine, 102 Heukseok-ro, Heukseok-dong, Dongjak-gu, Seoul 06973, Republic of Korea
| | - Han Koo Kim
- Department of Plastic and Reconstructive Surgery, Chung-Ang University Hospital, Chung-Ang University College of Medicine, 102 Heukseok-ro, Heukseok-dong, Dongjak-gu, Seoul 06973, Republic of Korea
| | - Soo Hyun Woo
- Department of Plastic and Reconstructive Surgery, Chung-Ang University Hospital, Chung-Ang University College of Medicine, 102 Heukseok-ro, Heukseok-dong, Dongjak-gu, Seoul 06973, Republic of Korea
| | - Tae Hui Bae
- Department of Plastic and Reconstructive Surgery, Chung-Ang University Hospital, Chung-Ang University College of Medicine, 102 Heukseok-ro, Heukseok-dong, Dongjak-gu, Seoul 06973, Republic of Korea
| | - Woo Joo Kim
- Department of Plastic Surgery, Chung-Ang University Gwangmyeong Hospital, Chung-Ang University College of Medicine, Gwangmyeong-si, Gyeonggi-do 14353, Republic of Korea
| | - Shin Hyuk Kang
- College of Medicine, Chung-Ang University, 84 Heukseok-ro, Heukseok-dong, Dongjak-gu, Seoul 06974, Republic of Korea; Department of Plastic and Reconstructive Surgery, Chung-Ang University Hospital, Chung-Ang University College of Medicine, 102 Heukseok-ro, Heukseok-dong, Dongjak-gu, Seoul 06973, Republic of Korea.
| | - Hansoo Park
- School of Integrative Engineering, Chung-Ang University, 84 Heukseok-ro, Heukseok-dong, Dongjak-gu, Seoul 06974, Republic of Korea.
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Hossain MS, Rasiah PK, Seetharaman ATM, Alvarado D, Luo M, Wohlschlegel JA, Pentecost M, Gangaraju R. TNF-Stimulated Gene-6, Part of Extracellular Vesicles in Adipose Tissue-Derived Mesenchymal Stem Cell Concentrated Conditioned Medium, Affects Microglial Activity. J Neuroimmune Pharmacol 2025; 20:60. [PMID: 40439794 PMCID: PMC12122589 DOI: 10.1007/s11481-025-10216-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2024] [Accepted: 04/30/2025] [Indexed: 06/02/2025]
Abstract
Identifying the specific bioactive molecules produced by mesenchymal stem cells (MSCs) and the signaling pathways and cell types upon which they act is critical to developing MSC-based therapeutics for inflammatory diseases with high unmet needs. Our study aimed to investigate the impact of extracellular vesicle (EV)-derived TNF-Stimulated Gene-6 (TSG-6, from adipose tissue-derived mesenchymal stem cell concentrated conditioned medium, ASC-CCM or TSG-6 overexpression in ASC using ORF expression-ready clone) on microglia and its potential anti-inflammatory effects. EV but not non-vesicular secretome prepared by ultracentrifugation confirmed the expression of TSG-6 exclusively in the small EV (sEV) fraction. sEV ranged from 50-150 nm as determined by Zetasizer, demonstrated bilipid membrane evidenced by transmission electron microscopy, expressed positive exosomal (e.g. CD63) markers, and were endocytosed by BV2 cells confirmed by DiI fluorescently labeled exosomes. BV2 microglia cultured under serum-free conditions stimulated with TLR4 agonists (LPS and IFNγ) for 12 h in the presence of p-ASC-EV (sEV derived from ASC after cytokine stimulation) and TSG-6-ORF-EV significantly reduced nitrite release (p < 0.001), phagocytic activity (p < 0.001) and reduced CD44 expression (p < 0.05). CD44 knockdown in BV2 cells ablated TSG-6-ORF-EV mediated nitrite release, IL1β downregulation, and phagocytosis with TLR4 agonists. Our results revealed that under cytokine stimulation, the EV portion of ASC-CCM becomes enriched with TSG-6. Overexpressing TSG-6 in ASC leads to an increased concentration of TSG-6 in sEVs. This enriched EV fraction, containing TSG-6, regulates microglial dynamics through a feedback loop with CD44. EV-associated TSG-6 can influence immune cell behavior and signaling, mitigating excessive inflammation or immune dysfunction.
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Affiliation(s)
| | - Pratheepa Kumari Rasiah
- Biomedical Engineering, Vanderbilt University, Vanderbilt Biophotonics Center, Nashville, TN, USA
| | - Amritha T M Seetharaman
- Department of Ophthalmology, University of Tennessee Health Science Center, Memphis, TN, USA
| | | | - Megan Luo
- Department of Biological Chemistry, University of California Los Angeles, Los Angeles, CA, USA
| | - James A Wohlschlegel
- Department of Biological Chemistry, University of California Los Angeles, Los Angeles, CA, USA
| | | | - Rajashekhar Gangaraju
- Department of Ophthalmology, Anatomy and Neurobiology, University of Tennessee Health Science Center, Memphis, TN, USA.
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Wu KY, Dave A, Nirwal GK, Giunta M, Nguyen VDH, Tran SD. Exosome Innovations in Ophthalmology and Sjögren's Syndrome. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2025. [PMID: 40360847 DOI: 10.1007/5584_2025_865] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/15/2025]
Abstract
Exosomes, a subset of extracellular vesicles, have emerged as potential therapeutic agents in ophthalmology due to their ability to modulate immune responses, facilitate cellular communication, and promote tissue repair. This chapter explores the potential applications of exosome-based therapies in corneal and anterior segment disorders, retinal diseases, glaucoma, and Sjögren's syndrome. In corneal disorders, mesenchymal stem cell (MSC)-derived secretomes have shown promise in accelerating wound healing, reducing fibrosis, and modulating inflammation, with hydrogel encapsulation strategies potentially enhancing their efficacy. In retinal diseases, exosomes may provide neuroprotective effects in age-related macular degeneration, diabetic retinopathy, and retinitis pigmentosa by modulating oxidative stress and inflammation. In glaucoma, secretome-based therapies could support retinal ganglion cell survival and optic nerve regeneration, though their impact on intraocular pressure via the trabecular meshwork remains uncertain. Additionally, exosomal biomarkers in aqueous humor are being investigated as potential diagnostic tools. In Sjögren's syndrome, exosomal biomarkers may facilitate earlier detection, while stem cell-derived exosomes hold promise in modulating immune responses and restoring glandular function. Despite encouraging preclinical and early clinical findings, standardization, scalability, and long-term safety must be addressed before clinical translation. Future research will focus on optimizing exosome-based therapies and exploring their feasibility for ophthalmic applications.
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Affiliation(s)
- Kevin Y Wu
- Department of Surgery, Division of Ophthalmology, University of Sherbrooke, Sherbrooke, QC, Canada.
| | - Archan Dave
- Department of Medicine, University of British Columbia, Vancouver, BC, Canada
| | - Gurleen K Nirwal
- Department of Zoology, University of British Columbia, Vancouver, BC, Canada
| | - Michel Giunta
- Department of Surgery, Division of Ophthalmology, University of Sherbrooke, Sherbrooke, QC, Canada
| | | | - Simon D Tran
- Faculty of Dental Medicine and Oral Health Sciences, McGill University, Montreal, QC, Canada
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Kąpa M, Koryciarz I, Kustosik N, Jurowski P, Pniakowska Z. Future Directions in Diabetic Retinopathy Treatment: Stem Cell Therapy, Nanotechnology, and PPARα Modulation. J Clin Med 2025; 14:683. [PMID: 39941353 PMCID: PMC11818668 DOI: 10.3390/jcm14030683] [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: 11/06/2024] [Revised: 01/15/2025] [Accepted: 01/17/2025] [Indexed: 02/16/2025] Open
Abstract
This narrative review focuses on innovative treatment approaches to diabetic retinopathy to meet the urgent demand for advancements in managing both the early and late stages of the disease. Recent studies highlight the potential of adipose stem cells and their secreted factors in mitigating the retinal complications of diabetes, with promising results in improving visual acuity and reducing inflammation and angiogenesis in diabetic retinopathy. However, caution is warranted regarding the safety and long-term therapeutic effects of adipose stem cells transplantation. Bone marrow mesenchymal stem cells can also mitigate retinal damage in diabetic retinopathy. Studies demonstrate that bone marrow mesenchymal stem cells-derived exosomes can suppress the Wnt/β-catenin pathway, reducing oxidative stress, inflammation, and angiogenesis in the diabetic retina, offering promise for future diabetic retinopathy treatments. Nanotechnology has the ability to precisely target the retina and minimize systemic side effects. Nanoparticles and nanocarriers offer improved bioavailability, sustained release of therapeutics, and potential for synergistic effects. They can be a new way of effective treatment and prevention of diabetic retinopathy. Activation and modulation of PPARα as a means for diabetic retinopathy treatment has been widely investigated in recent years and demonstrated promising effects in clinical trials. PPARα activation turned out to be a promising therapeutic method for treating dyslipidemia, inflammation, and insulin sensitivity. The combination of PPARα modulators with small molecules offers an interesting perspective for retinal diseases' therapy.
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Affiliation(s)
- Maria Kąpa
- Department of Ophthalmology and Vision Rehabilitation, Medical University of Lodz, 90-549 Lodz, Poland; (M.K.); (N.K.); (P.J.); (Z.P.)
| | - Iga Koryciarz
- Department of Ophthalmology and Vision Rehabilitation, Medical University of Lodz, 90-549 Lodz, Poland; (M.K.); (N.K.); (P.J.); (Z.P.)
| | - Natalia Kustosik
- Department of Ophthalmology and Vision Rehabilitation, Medical University of Lodz, 90-549 Lodz, Poland; (M.K.); (N.K.); (P.J.); (Z.P.)
| | - Piotr Jurowski
- Department of Ophthalmology and Vision Rehabilitation, Medical University of Lodz, 90-549 Lodz, Poland; (M.K.); (N.K.); (P.J.); (Z.P.)
| | - Zofia Pniakowska
- Department of Ophthalmology and Vision Rehabilitation, Medical University of Lodz, 90-549 Lodz, Poland; (M.K.); (N.K.); (P.J.); (Z.P.)
- Optegra Eye Clinic, 90-127 Lodz, Poland
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Anvarinia Y, Del Mar NA, Awad AM, Hossain S, Seetharaman AT, Ravindran S, Roth S, Gangaraju R. MicroRNA-based engineered mesenchymal stem cell extracellular vesicles to treat visual deficits after blast-induced trauma. Exp Eye Res 2024; 247:110031. [PMID: 39128668 PMCID: PMC11392619 DOI: 10.1016/j.exer.2024.110031] [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: 04/29/2024] [Revised: 07/19/2024] [Accepted: 08/07/2024] [Indexed: 08/13/2024]
Abstract
Our previous studies have shown the benefit of intravitreal injection of a mesenchymal stem cell (MSC)- derived secretome to treat visual deficits in a mild traumatic brain injury (mTBI) mouse model. In this study, we have addressed whether MSC-derived extracellular vesicles (EV) overexpressing miR424, which particularly targets neuroinflammation, show similar benefits in the mTBI model. Adult C57BL/6 mice were subjected to a 50-psi air pulse on the left side, overlying the forebrain, resulting in mTBI. Sham-blast mice were controls. Within an hour of blast injury, 3 μl (∼7.5 × 108 particles) of miR424-EVs, native-EVs, or saline was delivered intravitreally. One month later, retinal morphology was observed through optical coherence tomography (OCT); visual function was assessed using optokinetic nystagmus (OKN) and electroretinogram (ERG), followed by immunohistological analysis. A separate study in adult mice tested the dose-response of EVs for safety. Blast injury mice with saline showed decreased visual acuity compared with the sham group (0.30 ± 0.03 vs. 0.39 ± 0.01 c/d, p < 0.02), improved with miR424-EVs (0.39 ± 0.02 c/d, p < 0.01) but not native-EVs (0.33 ± 0.04 c/d, p > 0.05). Contrast sensitivity thresholds of blast mice receiving saline increased compared with the sham group (85.3 ± 5.9 vs. 19.9 ± 4.8, %, p < 0.001), rescued by miR424-EVs (23.6 ± 7.3 %, p < 0.001) and native-EVs (45.6 ± 10.7 %, p < 0.01). Blast injury decreased "b" wave amplitude compared to sham mice (94.6 ± 24.0 vs. 279.2 ± 25.3 μV, p < 0.001), improved with miR424-EVs (173.0 ± 27.2 μV, p < 0.03) and native-EVs (230.2 ± 37.2 μV, p < 0.01) with a similar decrease in a-wave amplitude in blast mice improved with both miR424-EVs and native-EVs. Immunohistology showed increased GFAP and IBA1 in blast mice with saline compared with sham (GFAP: 11.9 ± 1.49 vs. 9.1 ± 0.8, mean intensity/100,000 μm2 area, p < 0.03; IBA1: 36.08 ± 4.3 vs. 24.0 ± 1.54, mean intensity/100,000 μm2 area, p < 0.01), with no changes with native-EVs (GFAP: 12.6 ± 0.79, p > 0.05; IBA1: 32.8 ± 2.9, p > 0.05), and miR424-EV (GFAP: 13.14 ± 0.76, p > 0.05; IBA1: 31.4 ± 2.7, p > 0.05). Both native-EVs and miR424-EVs exhibited vitreous aggregation, as evidenced by particulates in the vitreous by OCT, and increased vascular structures, as evidenced by αSMA and CD31 immunostainings. The number of capillary lumens in the ganglion cell layer increased with increased particles in the eye, with native EVs showing the worst effects. In conclusion, our study highlights the promise of EV-based therapies for treating visual dysfunction caused by mTBI, with miR424-EVs showing particularly strong neuroprotective benefits. Both miR424-EVs and native-EVs provided similar protection, but issues with EV aggregation and astrogliosis or microglial/macrophage activation at the current dosage call for improved delivery methods and dosage adjustments. Future research should investigate the mechanisms behind EVs' effects and optimize miR424 delivery strategies to enhance therapeutic outcomes and reduce complications.
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Affiliation(s)
- Yasaman Anvarinia
- Department of Ophthalmology, University of Tennessee Health Science Center, 930 Madison Ave, Suite 769, Memphis, TN, 38163, USA.
| | - Nobel A Del Mar
- Department of Ophthalmology, University of Tennessee Health Science Center, 930 Madison Ave, Suite 769, Memphis, TN, 38163, USA.
| | - Ahmed M Awad
- Department of Ophthalmology, University of Tennessee Health Science Center, 930 Madison Ave, Suite 769, Memphis, TN, 38163, USA; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura National University, Gamasa, 7731168, Mansoura, Egypt; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, 35516, Mansoura, Egypt.
| | - Shahadat Hossain
- Department of Ophthalmology, University of Tennessee Health Science Center, 930 Madison Ave, Suite 769, Memphis, TN, 38163, USA.
| | - Amritha Tm Seetharaman
- Department of Ophthalmology, University of Tennessee Health Science Center, 930 Madison Ave, Suite 769, Memphis, TN, 38163, USA.
| | - Sriram Ravindran
- Department of Oral Biology, College of Dentistry, University of Illinois-Chicago, USA.
| | - Steven Roth
- Department of Anesthesiology, College of Medicine, University of Illinois-Chicago, USA.
| | - Rajashekhar Gangaraju
- Department of Ophthalmology, Anatomy & Neurobiology, Neuroscience Institute, University of Tennessee Health Science Center, 930 Madison Ave, Suite 768, Memphis, TN, 38163, USA.
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Reddy SK, Devi V, Seetharaman ATM, Shailaja S, Bhat KMR, Gangaraju R, Upadhya D. Cell and molecular targeted therapies for diabetic retinopathy. Front Endocrinol (Lausanne) 2024; 15:1416668. [PMID: 38948520 PMCID: PMC11211264 DOI: 10.3389/fendo.2024.1416668] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2024] [Accepted: 05/27/2024] [Indexed: 07/02/2024] Open
Abstract
Diabetic retinopathy (DR) stands as a prevalent complication in the eye resulting from diabetes mellitus, predominantly associated with high blood sugar levels and hypertension as individuals age. DR is a severe microvascular complication of both type I and type II diabetes mellitus and the leading cause of vision impairment. The critical approach to combatting and halting the advancement of DR lies in effectively managing blood glucose and blood pressure levels in diabetic patients; however, this is seldom achieved. Both human and animal studies have revealed the intricate nature of this condition involving various cell types and molecules. Aside from photocoagulation, the sole therapy targeting VEGF molecules in the retina to prevent abnormal blood vessel growth is intravitreal anti-VEGF therapy. However, a substantial portion of cases, approximately 30-40%, do not respond to this treatment. This review explores distinctive pathophysiological phenomena of DR and identifiable cell types and molecules that could be targeted to mitigate the chronic changes occurring in the retina due to diabetes mellitus. Addressing the significant research gap in this domain is imperative to broaden the treatment options available for managing DR effectively.
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Affiliation(s)
- Shivakumar K. Reddy
- Centre for Molecular Neurosciences, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India
| | - Vasudha Devi
- Department of Pharmacology, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India
| | - Amritha T. M. Seetharaman
- Department of Ophthalmology, The University of Tennessee Health Science Center, Memphis, TN, United States
| | - S. Shailaja
- Department of Ophthalmology, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India
| | - Kumar M. R. Bhat
- Department of Anatomy, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India
| | - Rajashekhar Gangaraju
- Department of Ophthalmology, The University of Tennessee Health Science Center, Memphis, TN, United States
- Department of Anatomy & Neurobiology, The University of Tennessee Health Science Center, Memphis, TN, United States
| | - Dinesh Upadhya
- Centre for Molecular Neurosciences, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India
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Guo S, Wang D. Novel insights into the potential applications of stem cells in pulmonary hypertension therapy. Respir Res 2024; 25:237. [PMID: 38849894 PMCID: PMC11162078 DOI: 10.1186/s12931-024-02865-4] [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: 10/07/2023] [Accepted: 06/04/2024] [Indexed: 06/09/2024] Open
Abstract
Pulmonary hypertension (PH) refers to a group of deadly lung diseases characterized by vascular lesions in the microvasculature and a progressive increase in pulmonary vascular resistance. The prevalence of PH has increased over time. Currently, the treatment options available for PH patients have limited efficacy, and none of them can fundamentally reverse pulmonary vascular remodeling. Stem cells represent an ideal seed with proven efficacy in clinical studies focusing on liver, cardiovascular, and nerve diseases. Since the potential therapeutic effect of mesenchymal stem cells (MSCs) on PH was first reported in 2006, many studies have demonstrated the efficacy of stem cells in PH animal models and suggested that stem cells can help slow the deterioration of lung tissue. Existing PH treatment studies basically focus on the paracrine action of stem cells, including protein regulation, exosome pathway, and cell signaling; however, the specific mechanisms have not yet been clarified. Apoptotic and afunctional pulmonary microvascular endothelial cells (PMVECs) and alveolar epithelial cells (AECs) are two fundamental promoters of PH although they have not been extensively studied by researchers. This review mainly focuses on the supportive communication and interaction between PMVECs and AECs as well as the potential restorative effect of stem cells on their injury. In the future, more studies are needed to prove these effects and explore more radical cures for PH.
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Affiliation(s)
- Sijia Guo
- Stem Cell Laboratory, Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China.
| | - Dachun Wang
- Stem Cell Laboratory, Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China
- The Brown Foundation Institute of Molecular Medicine for the prevention of Human Diseases, University of Texas Medical School at Houston, Houston, TX, USA
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Finocchio L, Zeppieri M, Gabai A, Spadea L, Salati C. Recent Advances of Adipose-Tissue-Derived Mesenchymal Stem Cell-Based Therapy for Retinal Diseases. J Clin Med 2023; 12:7015. [PMID: 38002628 PMCID: PMC10672618 DOI: 10.3390/jcm12227015] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2023] [Revised: 10/29/2023] [Accepted: 11/06/2023] [Indexed: 11/26/2023] Open
Abstract
With the rapid development of stem cell research in modern times, stem cell-based therapy has opened a new era of tissue regeneration, becoming one of the most promising strategies for currently untreatable retinal diseases. Among the various sources of stem cells, adipose tissue-derived mesenchymal stem cells (ADSCs) have emerged as a promising therapeutic modality due to their characteristics and multiple functions, which include immunoregulation, anti-apoptosis of neurons, cytokine and growth factor secretion, and antioxidative activities. Studies have shown that ADSCs can facilitate the replacement of dying cells, promote tissue remodeling and regeneration, and support the survival and growth of retinal cells. Recent studies in this field have provided numerous experiments using different preclinical models. The aim of our review is to provide an overview of the therapeutic strategies, modern-day clinical trials, experimental models, and potential clinical use of this fascinating class of cells in addressing retinal disorders and diseases.
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Affiliation(s)
- Lucia Finocchio
- Department of Ophthalmology, University Hospital of Udine, 33100 Udine, Italy; (L.F.)
| | - Marco Zeppieri
- Department of Ophthalmology, University Hospital of Udine, 33100 Udine, Italy; (L.F.)
| | - Andrea Gabai
- Department of Ophthalmology, University Hospital of Udine, 33100 Udine, Italy; (L.F.)
| | - Leopoldo Spadea
- Eye Clinic, Policlinico Umberto I, La Sapienza University of Rome, 00142 Rome, Italy
| | - Carlo Salati
- Department of Ophthalmology, University Hospital of Udine, 33100 Udine, Italy; (L.F.)
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Bouche Djatche WH, Zhu H, Ma W, Li Y, Li Z, Zhao H, Liu Z, Qiao H. Potential of mesenchymal stem cell-derived conditioned medium/secretome as a therapeutic option for ocular diseases. Regen Med 2023; 18:795-807. [PMID: 37702008 DOI: 10.2217/rme-2023-0089] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/14/2023] Open
Abstract
Research has shown that the therapeutic effect of mesenchymal stem cells (MSCs) is partially due to its secreted factors as opposed to the implantation of the cells into the treated tissue or tissue replacement. MSC secretome, especially in the form of conditioned medium (MSC-CM) is now being explored as an alternative to MSCs transplantation. Despite the observed benefits of MSC-CM, only a few clinical trials have evaluated it and other secretome components in the treatment of eye diseases. This review provides insight into the potential therapeutic use of MSC-CM in eye conditions, such as corneal diseases, dry eye, glaucoma, retinal diseases and uveitis. We discuss the current evidence, some limitations, and the progress that remains to be achieved before clinical translation becomes possible.
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Affiliation(s)
| | - Huimin Zhu
- School of Basic Medicine, Shanxi Medical University, Taiyuan, 030001, China
| | - Wenlei Ma
- School of Basic Medicine, Shanxi Medical University, Taiyuan, 030001, China
| | - Yue Li
- School of Basic Medicine, Shanxi Medical University, Taiyuan, 030001, China
| | - Ziang Li
- School of Basic Medicine, Shanxi Medical University, Taiyuan, 030001, China
| | - Hong Zhao
- School of Basic Medicine, Shanxi Medical University, Taiyuan, 030001, China
| | - Zhizhen Liu
- School of Basic Medicine, Shanxi Medical University, Taiyuan, 030001, China
| | - Hua Qiao
- School of Basic Medicine, Shanxi Medical University, Taiyuan, 030001, China
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Nouralishahi A, Fazlinejad N, Pecho RDC, Zaidan HK, Kheradjoo H, Amin AH, Mohammadzadehsaliani S. Pathological role of inflammation in ocular disease progress and its targeting by mesenchymal stem cells (MSCs) and their exosome; current status and prospect. Pathol Res Pract 2023; 248:154619. [PMID: 37406377 DOI: 10.1016/j.prp.2023.154619] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2023] [Revised: 06/11/2023] [Accepted: 06/12/2023] [Indexed: 07/07/2023]
Abstract
Because of their unique capacity for differentiation to a diversity of cell lineages and immunosuppressive properties, mesenchymal stem cells (MSC) are being looked at as a potential new treatment option in ophthalmology. The MSCs derived from all tissue sources possess immunomodulatory attributes through cell-to-cell contact and releasing a myriad of immunomodulatory factors (IL-10, TGF-β, growth-related oncogene (GRO), indoleamine 2,3 dioxygenase (IDO), nitric oxide (NO), interleukin 1 receptor antagonist (IL-1Ra), prostaglandin E2 (PGE2)). Such mediators, in turn, alter both the phenotype and action of all immune cells that serve a pathogenic role in the progression of inflammation in eye diseases. Exosomes from MSCs, as natural nano-particles, contain the majority of the bioactive components of parental MSCs and can easily by-pass all biological barriers to reach the target epithelial and immune cells in the eye without interfering with nearby parenchymal cells, thus having no serious side effects. We outlined the most recent research on the molecular mechanisms underlying the therapeutic benefits of MSC and MSC-exosome in the treatment of inflammatory eye diseases in the current article.
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Affiliation(s)
- Alireza Nouralishahi
- Isfahan Eye Research Center, Isfahan University of Medical Sciences, Isfahan, Iran; KIMS Hospital, Oman
| | | | | | - Haider Kamil Zaidan
- Department of Medical Laboratories Techniques, Al-Mustaqbal University College, Hillah, Babylon, Iraq
| | | | - Ali H Amin
- Zoology Department, Faculty of Science, Mansoura University, Mansoura 35516, Egypt
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Zhang C, Xiao J, Fa L, Jiang F, Jiang H, Zhou L, Xu Z. Advances in the applications of mesenchymal stem cell-conditioned medium in ocular diseases. Exp Eye Res 2023:109560. [PMID: 37385531 DOI: 10.1016/j.exer.2023.109560] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Revised: 05/06/2023] [Accepted: 06/26/2023] [Indexed: 07/01/2023]
Abstract
Mesenchymal stem cell-conditioned medium (MSC-CM), also known as secretome, is secreted by MSC and contains a variety of bioactive factors with anti-inflammatory, anti-apoptotic, neuroprotection, and proliferation effects. Increasing evidence proved that MSC-CM plays an important role in various diseases, including skin, bone, muscle, and dental diseases. However, the role of MSC-CM in ocular diseases is not quite clear, Therefore, this article reviewed the composition, biological functions, preparation, and characterization of MSC-CM and summarized current research advances in different sources of MSC-CM in corneal and retinal diseases, including dry eye, corneal epithelial damage, chemical corneal injury, retinitis pigmentosa (RP), anterior ischemic optic neuropathy (AION), diabetic retinopathy (DR), and other retinal degenerative changes. For these diseases, MSC-CM can promote cell proliferation, reduce inflammation and vascular leakage, inhibit retinal cell degeneration and apoptosis, protect corneal and retinal structures, and further improves visual function. Hence, we summarize the production, composition and biological functions of MSC-CM and focus on describing its mechanisms in the treatment of ocular diseases. Furthermore, we look at the unexplored mechanisms and further research directions for MSC-CM based therapy in ocular diseases.
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Affiliation(s)
- Chun Zhang
- Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Jing Xiao
- Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Luzhong Fa
- Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Fanwen Jiang
- Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Hui Jiang
- Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Lin Zhou
- Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Zhuping Xu
- Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
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12
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Saha B, Roy A, Beltramo E, Sahoo OS. Stem cells and diabetic retinopathy: From models to treatment. Mol Biol Rep 2023; 50:4517-4526. [PMID: 36842153 DOI: 10.1007/s11033-023-08337-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2022] [Accepted: 02/15/2023] [Indexed: 02/27/2023]
Abstract
Diabetic retinopathy is a common yet complex microvascular disease, caused as a complication of diabetes mellitus. Associated with hyperglycemia and subsequent metabolic abnormalities, advanced stages of the disease lead to fibrosis, subsequent visual impairment and blindness. Though clinical postmortems, animal and cell models provide information about the progression and prognosis of diabetic retinopathy, its underlying pathophysiology still needs a better understanding. In addition to it, the loss of pericytes, immature retinal angiogenesis and neuronal apoptosis portray the disease treatment to be challenging. Indulged with cell loss of both vascular and neuronal type cells, novel therapies like cell replacement strategies by various types of stem cells have been sightseen as a possible treatment of the disease. This review provides insight into the pathophysiology of diabetic retinopathy, current models used in modelling the disease, as well as the varied aspects of stem cells in generating three-dimensional retinal models. Further outlook on stem cell therapy and the future directions of stem cell treatment in diabetic retinopathy have also been contemplated.
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Affiliation(s)
- Bihan Saha
- National Institute of Technology Durgapur, Durgapur, 713209, West Bengal, India
| | - Akshita Roy
- Autonomous State Medical College, Fatehpur, 212601, Uttar Pradesh, India
| | - Elena Beltramo
- Department of Medical Sciences, University of Turin, 10124, Turin, Italy
| | - Om Saswat Sahoo
- National Institute of Technology Durgapur, Durgapur, 713209, West Bengal, India.
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Protective Effects of Human Pericyte-like Adipose-Derived Mesenchymal Stem Cells on Human Retinal Endothelial Cells in an In Vitro Model of Diabetic Retinopathy: Evidence for Autologous Cell Therapy. Int J Mol Sci 2023; 24:ijms24020913. [PMID: 36674425 PMCID: PMC9860961 DOI: 10.3390/ijms24020913] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Revised: 12/23/2022] [Accepted: 12/31/2022] [Indexed: 01/06/2023] Open
Abstract
Diabetic retinopathy (DR) is characterized by morphologic and metabolic alterations in endothelial cells (ECs) and pericytes (PCs) of the blood-retinal barrier (BRB). The loss of interendothelial junctions, increased vascular permeability, microaneurysms, and finally, EC detachment are the main features of DR. In this scenario, a pivotal role is played by the extensive loss of PCs. Based on previous results, the aim of this study was to assess possible beneficial effects exerted by adipose mesenchymal stem cells (ASCs) and their pericyte-like differentiated phenotype (P-ASCs) on human retinal endothelial cells (HRECs) in high glucose conditions (25 mM glucose, HG). P-ASCs were more able to preserve BRB integrity than ASCs in terms of (a) increased transendothelial electrical resistance (TEER); (b) increased expression of adherens junction and tight junction proteins (VE-cadherin and ZO-1); (c) reduction in mRNA levels of inflammatory cytokines TNF-α, IL-1β, and MMP-9; (d) reduction in the angiogenic factor VEGF and in fibrotic TGF-β1. Moreover, P-ASCs counteracted the HG-induced activation of the pro-inflammatory phospho-ERK1/2/phospho-cPLA2/COX-2 pathway. Finally, crosstalk between HRECs and ASCs or P-ASCs based on the PDGF-B/PDGFR-β axis at the mRNA level is described herein. Thus, P-ASCs might be considered valuable candidates for therapeutic approaches aimed at countering BRB disruption in DR.
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Adelipour M, Lubman DM, Kim J. Potential applications of mesenchymal stem cells and their derived exosomes in regenerative medicine. Expert Opin Biol Ther 2023; 23:491-507. [PMID: 37147781 PMCID: PMC10330313 DOI: 10.1080/14712598.2023.2211203] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Accepted: 05/03/2023] [Indexed: 05/07/2023]
Abstract
INTRODUCTION Regenerative medicine involves the replacement of damaged cells, tissues, or organs to restore normal function. Mesenchymal stem cells (MSCs) and exosomes secreted by MSCs have unique advantages that make them a suitable candidate in the field of regenerative medicine. AREAS COVERED This article provides a comprehensive overview of regenerative medicine, focusing on the use of MSCs and their exosomes as potential therapies for replacing damaged cells, tissues, or organs. This article discusses the distinct advantages of both MSCs and their secreted exosomes, including their immunomodulatory effects, lack of immunogenicity, and recruitment to damaged areas. While both MSCs and exosomes have these advantages, MSCs also have the unique ability to self-renew and differentiate. This article also assesses the current challenges associated with the application of MSCs and their secreted exosomes in therapy. We have reviewed proposed solutions for improving MSC or exosome therapy, including ex-vivo preconditioning strategies, genetic modification, and encapsulation. Literature search was conducted using Google Scholar and PubMed databases. EXPERT OPINION Providing insight into the future development of MSC and exosome-based therapies and to encourage the scientific community to focus on the identified gaps, develop appropriate guidelines, and enhance the clinical application of these therapies.
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Affiliation(s)
- Maryam Adelipour
- Department of Chemistry, Chungnam National University, Daejeon, Republic of Korea
- Department of Biochemistry, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - David M. Lubman
- Department of Surgery, University of Michigan Medical Center, Ann Arbor, MI, USA
| | - Jeongkwon Kim
- Department of Chemistry, Chungnam National University, Daejeon, Republic of Korea
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Zhu L, Wang S, Qu J, Hui Z, Kan C, Hou N, Sun X. The Therapeutic Potential of Mesenchymal Stem Cells in the Treatment of Diabetes Mellitus. Cell Reprogram 2022; 24:329-342. [PMID: 35877064 DOI: 10.1089/cell.2022.0039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023] Open
Abstract
Mesenchymal stem cells (MSCs) exist in many tissues and can differentiate into cells of multiple lineages, such as adipocytes, osteoblasts, or chondrocytes. MSC administration has demonstrated therapeutic potential in various degenerative and inflammatory diseases (e.g., graft-vs.-host disease, multiple sclerosis, Crohn's disease, organ fibrosis, and diabetes mellitus [DM]). The mechanisms involved in the therapeutic effects of MSCs are multifaceted. Generally, implanted MSCs can migrate to sites of injury, where they establish an anti-inflammatory and regenerative microenvironment in damaged tissues. In addition, MSCs can modulate innate and adaptive immune responses through immunosuppressive mechanisms that involve immune cells, inflammatory cytokines, chemokines, and immunomodulatory factors. DM has a high prevalence worldwide; it also contributes to a high rate of mortality worldwide. MSCs offer a promising therapeutic agent to prevent or repair damage from DM and diabetic complications through properties such as multilineage differentiation, homing, promotion of angiogenesis, and immunomodulation (e.g., prevention of oxidative stress, fibrosis, and cell death). In this study, we review current findings regarding the immunomodulatory and regenerative mechanisms of MSCs, as well as their therapeutic applications in DM and DM-related complications.
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Affiliation(s)
- Liang Zhu
- Department of Endocrinology and Metabolism, Affiliated Hospital of Weifang Medical University, Weifang, China
- Clinical Research Center, Affiliated Hospital of Weifang Medical University, Weifang, China
| | - Sheng Wang
- Department of Spinal Surgery, Affiliated Hospital of Weifang Medical University, Weifang, China
| | - JunSheng Qu
- Department of Endocrinology and Metabolism, Affiliated Hospital of Weifang Medical University, Weifang, China
- Clinical Research Center, Affiliated Hospital of Weifang Medical University, Weifang, China
| | - Zongguang Hui
- Department of Endocrinology and Metabolism, Affiliated Hospital of Weifang Medical University, Weifang, China
- Clinical Research Center, Affiliated Hospital of Weifang Medical University, Weifang, China
| | - Chengxia Kan
- Department of Endocrinology and Metabolism, Affiliated Hospital of Weifang Medical University, Weifang, China
- Clinical Research Center, Affiliated Hospital of Weifang Medical University, Weifang, China
| | - Ningning Hou
- Department of Endocrinology and Metabolism, Affiliated Hospital of Weifang Medical University, Weifang, China
- Clinical Research Center, Affiliated Hospital of Weifang Medical University, Weifang, China
| | - Xiaodong Sun
- Department of Endocrinology and Metabolism, Affiliated Hospital of Weifang Medical University, Weifang, China
- Clinical Research Center, Affiliated Hospital of Weifang Medical University, Weifang, China
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Chen X, Jiang Y, Duan Y, Zhang X, Li X. Mesenchymal-Stem-Cell-Based Strategies for Retinal Diseases. Genes (Basel) 2022; 13:genes13101901. [PMID: 36292786 PMCID: PMC9602395 DOI: 10.3390/genes13101901] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2022] [Revised: 10/08/2022] [Accepted: 10/11/2022] [Indexed: 12/04/2022] Open
Abstract
Retinal diseases are major causes of irreversible vision loss and blindness. Despite extensive research into their pathophysiology and etiology, pharmacotherapy effectiveness and surgical outcomes remain poor. Based largely on numerous preclinical studies, administration of mesenchymal stem cells (MSCs) as a therapeutic strategy for retinal diseases holds great promise, and various approaches have been applied to the therapies. However, hindered by the retinal barriers, the initial vision for the stem cell replacement strategy fails to achieve the anticipated effect and has now been questioned. Accumulating evidence now suggests that the paracrine effect may play a dominant role in MSC-based treatment, and MSC-derived extracellular vesicles emerge as a novel compelling alternative for cell-free therapy. This review summarizes the therapeutic potential and current strategies of this fascinating class of cells in retinal degeneration and other retinal dysfunctions.
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Rasiah PK, Jha KA, Gentry J, Del Mar NA, Townsend T, Torgbe KE, Reiner A, Gangaraju R. A Long-Term Safety and Efficacy Report on Intravitreal Delivery of Adipose Stem Cells and Secretome on Visual Deficits After Traumatic Brain Injury. Transl Vis Sci Technol 2022; 11:1. [PMID: 36180031 PMCID: PMC9547363 DOI: 10.1167/tvst.11.10.1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Accepted: 08/30/2022] [Indexed: 11/24/2022] Open
Abstract
Purpose We compared intravitreal injection of human adipose stem cell concentrated conditioned media (ASC-CCM) to injection of live ASCs for their long-term safety and effectiveness against the visual deficits of mild traumatic brain injury (mTBI). Methods We first tested different intravitreal ASC doses for safety. Other C57BL/6 mice then received focal cranial blast mTBI and were injected with the safe ASC dose (1000 cells/eye), ASC-CCM (∼200 ng protein/eye), or saline solution. At five and 10 months after blast injury, visual, molecular, and histological assessments evaluated treatment efficacy. Histological evaluation of eyes and other organs at 10 months after blast injury assessed safety. Results Human ASCs at 1000 cells/eye were found to be safe, with >10,000 cells causing retinal damage. Blast-injured mice showed significant vision deficits compared to sham blast mice up to 10 months. Blast mice receiving ASC or ASC-CCM showed improved vision at five months but marginal effects at 10 months, correlated with changes in glial fibrillary acidic protein and proinflammatory gene expression in retina. Immunostaining for human IgG failed to detect ASCs in retina. Peripheral organs examined histologically at 10 months after blast injury were normal. Conclusions Intravitreal injection of ASCs or ASC-CCM is safe and effective against the visual deficits of mTBI. Considering the unimproved glial response and the risk of retinal damage with live cells, our studies suggest that ASC-CCM has better safety and effectiveness than live cells for the treatment of visual dysfunction in mTBI. Translational Relevance This study demonstrates the safety and efficacy of mesenchymal stem cell-based therapeutics, supporting them for phase 1 clinical studies.
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Affiliation(s)
- Pratheepa Kumari Rasiah
- Department of Ophthalmology, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Kumar Abhiram Jha
- Department of Ophthalmology, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Jordy Gentry
- Department of Ophthalmology, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Nobel A. Del Mar
- Department of Anatomy & Neurobiology, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Tanisha Townsend
- Department of Pathology, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Kwame E. Torgbe
- Department of Pathology, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Anton Reiner
- Department of Anatomy & Neurobiology, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Rajashekhar Gangaraju
- Department of Ophthalmology, University of Tennessee Health Science Center, Memphis, TN, USA
- Department of Anatomy & Neurobiology, University of Tennessee Health Science Center, Memphis, TN, USA
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Ma J, Lei P, Chen H, Wang L, Fang Y, Yan X, Yang Q, Peng B, Jin L, Sun D. Advances in lncRNAs from stem cell-derived exosome for the treatment of cardiovascular diseases. Front Pharmacol 2022; 13:986683. [PMID: 36147326 PMCID: PMC9486024 DOI: 10.3389/fphar.2022.986683] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Accepted: 08/12/2022] [Indexed: 11/21/2022] Open
Abstract
Cardiovascular diseases (CVDs) are the leading cause of mortality globally. Benefiting from the advantages of early diagnosis and precision medicine, stem cell-based therapies have emerged as promising treatment options for CVDs. However, autologous or allogeneic stem cell transplantation imposes a potential risk of immunological rejection, infusion toxicity, and oncogenesis. Fortunately, exosome can override these limitations. Increasing evidence has demonstrated that long non-coding RNAs (lncRNAs) in exosome from stem cell paracrine factors play critical roles in stem cell therapy and participate in numerous regulatory processes, including transcriptional silencing, transcriptional activation, chromosome modification, and intranuclear transport. Accordingly, lncRNAs can treat CVDs by directly acting on specific signaling pathways. This mini review systematically summarizes the key regulatory actions of lncRNAs from different stem cells on myocardial aging and apoptosis, ischemia-reperfusion injury, retinopathy, atherosclerosis, and hypertension. In addition, the current challenges and future prospects of lncRNAs treatment for CVDs are discussed.
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Affiliation(s)
- Jiahui Ma
- Institute of Life Sciences & Biomedical Collaborative Innovation Center of Zhejiang Province, Wenzhou University, Wenzhou, China
| | - Pengyu Lei
- Institute of Life Sciences & Biomedical Collaborative Innovation Center of Zhejiang Province, Wenzhou University, Wenzhou, China
| | - Haojie Chen
- Institute of Life Sciences & Biomedical Collaborative Innovation Center of Zhejiang Province, Wenzhou University, Wenzhou, China
| | - Lei Wang
- Institute of Life Sciences & Biomedical Collaborative Innovation Center of Zhejiang Province, Wenzhou University, Wenzhou, China
| | - Yimeng Fang
- Institute of Life Sciences & Biomedical Collaborative Innovation Center of Zhejiang Province, Wenzhou University, Wenzhou, China
| | - Xiaoqing Yan
- Department of Pharmacy, Chinese-American Research Institute for Diabetic Complications, Wenzhou Medical University, Wenzhou, China
| | - Qinsi Yang
- Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, China
| | - Bo Peng
- Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, China
| | - Libo Jin
- Institute of Life Sciences & Biomedical Collaborative Innovation Center of Zhejiang Province, Wenzhou University, Wenzhou, China
- *Correspondence: Da Sun, ; Libo Jin,
| | - Da Sun
- Institute of Life Sciences & Biomedical Collaborative Innovation Center of Zhejiang Province, Wenzhou University, Wenzhou, China
- *Correspondence: Da Sun, ; Libo Jin,
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Liu S, Ju Y, Gu P. Experiment-Based Interventions to Diabetic Retinopathy: Present and Advances. Int J Mol Sci 2022; 23:ijms23137005. [PMID: 35806008 PMCID: PMC9267063 DOI: 10.3390/ijms23137005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Revised: 06/21/2022] [Accepted: 06/22/2022] [Indexed: 02/04/2023] Open
Abstract
Diabetic retinopathy is the major blinding disease among working-age populations, which is becoming more significant due to the growth of diabetes. The metabolic-induced oxidative and inflammatory stress leads to the insult of neovascular unit, resulting in the core pathophysiology of diabetic retinopathy. Existing therapies focus on the inflammation, oxidation, and angiogenesis phenomena of diabetic retinopathy, without effect to radically cure the disease. This review also summarizes novel therapeutic attempts for diabetic retinopathy along with their advantages and disadvantages, mainly focusing on those using cellular and genetic techniques to achieve remission on a fundamental level of disease.
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Affiliation(s)
- Siwei Liu
- Department of Ophthalmology, Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China; (S.L.); (Y.J.)
- Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai 200011, China
| | - Yahan Ju
- Department of Ophthalmology, Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China; (S.L.); (Y.J.)
- Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai 200011, China
| | - Ping Gu
- Department of Ophthalmology, Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China; (S.L.); (Y.J.)
- Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai 200011, China
- Correspondence:
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Mannino G, Cristaldi M, Giurdanella G, Perrotta RE, Lo Furno D, Giuffrida R, Rusciano D. ARPE-19 conditioned medium promotes neural differentiation of adipose-derived mesenchymal stem cells. World J Stem Cells 2021; 13:1783-1796. [PMID: 34909123 PMCID: PMC8641022 DOI: 10.4252/wjsc.v13.i11.1783] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Revised: 06/25/2021] [Accepted: 10/15/2021] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Adipose-derived stem cells (ASCs) have been increasingly explored for cell-based medicine because of their numerous advantages in terms of easy availability, high proliferation rate, multipotent differentiation ability and low immunogenicity. In this respect, they have been widely investigated in the last two decades to develop therapeutic strategies for a variety of human pathologies including eye disease. In ocular diseases involving the retina, various cell types may be affected, such as Müller cells, astrocytes, photoreceptors and retinal pigment epithelium (RPE), which plays a fundamental role in the homeostasis of retinal tissue, by secreting a variety of growth factors that support retinal cells. AIM To test ASC neural differentiation using conditioned medium (CM) from an RPE cell line (ARPE-19). METHODS ASCs were isolated from adipose tissue, harvested from the subcutaneous region of healthy donors undergoing liposuction procedures. Four ASC culture conditions were investigated: ASCs cultured in basal Dulbecco's Modified Eagle Medium (DMEM); ASCs cultured in serum-free DMEM; ASCs cultured in serum-free DMEM/F12; and ASCs cultured in a CM from ARPE-19, a spontaneously arising cell line with a normal karyotype derived from a human RPE. Cell proliferation rate and viability were assessed by crystal violet and MTT assays at 1, 4 and 8 d of culture. At the same time points, ASC neural differentiation was evaluated by immunocytochemistry and western blot analysis for typical neuronal and glial markers: Nestin, neuronal specific enolase (NSE), protein gene product (PGP) 9.5, and glial fibrillary acidic protein (GFAP). RESULTS Depending on the culture medium, ASC proliferation rate and viability showed some significant differences. Overall, less dense populations were observed in serum-free cultures, except for ASCs cultured in ARPE-19 serum-free CM. Moreover, a different cell morphology was seen in these cultures after 8 d of treatment, with more elongated cells, often showing cytoplasmic ramifications. Immunofluorescence results and western blot analysis were indicative of ASC neural differentiation. In fact, basal levels of neural markers detected under control conditions significantly increased when cells were cultured in ARPE-19 CM. Specifically, neural marker overexpression was more marked at 8 d. The most evident increase was observed for NSE and GFAP, a modest increase was observed for nestin, and less relevant changes were observed for PGP9.5. CONCLUSION The presence of growth factors produced by ARPE-19 cells in tissue culture induces ASCs to express neural differentiation markers typical of the neuronal and glial cells of the retina.
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Affiliation(s)
- Giuliana Mannino
- Department of Biomedical and Biotechnological Sciences, University of Catania, Catania 95123, CT, Italy
| | | | - Giovanni Giurdanella
- Department of Biomedical and Biotechnological Sciences, University of Catania, Catania 95123, CT, Italy
| | - Rosario Emanuele Perrotta
- Department of General Surgery and Medical-Surgery Specialties, University of Catania, Catania 95100, CT, Italy
| | - Debora Lo Furno
- Department of Biomedical and Biotechnological Sciences, University of Catania, Catania 95123, CT, Italy
| | - Rosario Giuffrida
- Department of Biomedical and Biotechnological Sciences, University of Catania, Catania 95123, CT, Italy
| | - Dario Rusciano
- Research Center, SOOFT-Italia S.p.A., Catania 95123, CT, Italy
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Agrawal M, Rasiah PK, Bajwa A, Rajasingh J, Gangaraju R. Mesenchymal Stem Cell Induced Foxp3(+) Tregs Suppress Effector T Cells and Protect against Retinal Ischemic Injury. Cells 2021; 10:3006. [PMID: 34831229 PMCID: PMC8616393 DOI: 10.3390/cells10113006] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Revised: 10/22/2021] [Accepted: 10/29/2021] [Indexed: 12/02/2022] Open
Abstract
Mesenchymal stem/stromal cells (MSC) are well known for immunomodulation; however, the mechanisms involved in their benefits in the ischemic retina are unknown. This study tested the hypothesis that MSC induces upregulation of transcription factor forkhead box protein P3 (Foxp3) in T cells to elicit immune modulation, and thus, protect against retinal damage. Induced MSCs (iMSCs) were generated by differentiating the induced pluripotent stem cells (iPSC) derived from urinary epithelial cells through a noninsertional reprogramming approach. In in-vitro cultures, iMSC transferred mitochondria to immune cells via F-actin nanotubes significantly increased oxygen consumption rate (OCR) for basal respiration and ATP production, suppressed effector T cells, and promoted differentiation of CD4+CD25+ T regulatory cells (Tregs) in coculture with mouse splenocytes. In in-vivo studies, iMSCs transplanted in ischemia-reperfusion (I/R) injured eye significantly increased Foxp3+ Tregs in the retina compared to that of saline-injected I/R eyes. Furthermore, iMSC injected I/R eyes significantly decreased retinal inflammation as evidenced by reduced gene expression of IL1β, VCAM1, LAMA5, and CCL2 and improved b-wave amplitudes compared to that of saline-injected I/R eyes. Our study demonstrates that iMSCs can transfer mitochondria to immune cells to suppress the effector T cell population. Additionally, our current data indicate that iMSC can enhance differentiation of T cells into Foxp3 Tregs in vitro and therapeutically improve the retina's immune function by upregulation of Tregs to decrease inflammation and reduce I/R injury-induced retinal degeneration in vivo.
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Affiliation(s)
- Mona Agrawal
- Department of Ophthalmology, University of Tennessee Health Science Center, Memphis, TN 38163, USA; (M.A.); (P.K.R.)
| | - Pratheepa Kumari Rasiah
- Department of Ophthalmology, University of Tennessee Health Science Center, Memphis, TN 38163, USA; (M.A.); (P.K.R.)
| | - Amandeep Bajwa
- James D. Eason Transplant Institute, Department of Surgery, University of Tennessee Health Science Center, Memphis, TN 38163, USA;
- Department of Genetics, Genomics, and Informatics, University of Tennessee Health Science Center, Memphis, TN 38163, USA
- Department of Microbiology, Immunology, and Biochemistry, University of Tennessee Health Science Center, Memphis, TN 38163, USA;
| | - Johnson Rajasingh
- Department of Microbiology, Immunology, and Biochemistry, University of Tennessee Health Science Center, Memphis, TN 38163, USA;
- Department of Bioscience Research, University of Tennessee Health Science Center, Memphis, TN 38163, USA
| | - Rajashekhar Gangaraju
- Department of Ophthalmology, University of Tennessee Health Science Center, Memphis, TN 38163, USA; (M.A.); (P.K.R.)
- Department of Anatomy & Neurobiology, University of Tennessee Health Science Center, Memphis, TN 38163, USA
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22
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Al-Sowayan BS, Al-Shareeda AT. Stem cells and the pursuit of youth, a tale of limitless possibilities and commercial fraud. World J Biol Chem 2021; 12:52-56. [PMID: 34354805 PMCID: PMC8316836 DOI: 10.4331/wjbc.v12.i4.52] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2021] [Revised: 05/17/2021] [Accepted: 07/07/2021] [Indexed: 02/06/2023] Open
Abstract
This article examines the hype generated around the term “stem cell”, and the capitalization of the stem cell craze by the cosmetic industry. It started by introducing product lines containing active ingredients derived from plant stem cells. Then, evolved to using own cells for skin regeneration and hair loss treatment, and allogenic cells for the manufacturing of stem cell-derived products. This article also discusses the missing links for safe and reliable stem cell applications in cosmetics, and why local regulatory bodies, members of the industry and consumers must all work together to stop the illegitimate use of the “stem cell” good name in unsafe or fraudulent commercial practices.
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Affiliation(s)
- Batla S Al-Sowayan
- Department of Cell Therapy and Cancer Research, King Abdullah International Medical Research Center, King Saud Bin Abdulaziz University for Health Sciences, Ministry of National Guard Health Affairs, Riyadh 11632, Saudi Arabia
| | - Alaa T Al-Shareeda
- Department of Cell Therapy and Cancer Research and Departmebt of the Saudi Biobank, King Abdullah International Medical Research Center, King Saud Bin Abdulaziz University for Health Sciences, Ministry of National Guard Health Affairs, Riyadh 11481, Saudi Arabia
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23
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Sharma A, Jaganathan BG. Stem Cell Therapy for Retinal Degeneration: The Evidence to Date. Biologics 2021; 15:299-306. [PMID: 34349498 PMCID: PMC8327474 DOI: 10.2147/btt.s290331] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2021] [Accepted: 07/16/2021] [Indexed: 12/28/2022]
Abstract
There is a rise in the number of people who have vision loss due to retinal diseases, and conventional therapies for treating retinal degeneration fail to repair and regenerate the damaged retina. Several studies in animal models and human trials have explored the use of stem cells to repair the retinal tissue to improve visual acuity. In addition to the treatment of age-related macular degeneration (AMD) and diabetic retinopathy (DR), stem cell therapies were used to treat genetic diseases such as retinitis pigmentosa (RP) and Stargardt’s disease, characterized by gradual loss of photoreceptor cells in the retina. Transplantation of retinal pigment epithelial (RPE) cells derived from embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) have shown promising results in improving retinal function in various preclinical models of retinal degeneration and clinical studies without any severe side effects. Mesenchymal stem cells (MSCs) were utilized to treat optic neuropathy, RP, DR, and glaucoma with positive clinical outcomes. This review summarizes the preclinical and clinical evidence of stem cell therapy and current limitations in utilizing stem cells for retinal degeneration.
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Affiliation(s)
- Amit Sharma
- Stem Cells and Cancer Biology Research Group, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam, 781039, India
| | - Bithiah Grace Jaganathan
- Stem Cells and Cancer Biology Research Group, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam, 781039, India
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24
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Mannino G, Russo C, Longo A, Anfuso CD, Lupo G, Lo Furno D, Giuffrida R, Giurdanella G. Potential therapeutic applications of mesenchymal stem cells for the treatment of eye diseases. World J Stem Cells 2021; 13:632-644. [PMID: 34249232 PMCID: PMC8246249 DOI: 10.4252/wjsc.v13.i6.632] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2021] [Revised: 05/07/2021] [Accepted: 06/04/2021] [Indexed: 02/06/2023] Open
Abstract
Stem cell-based treatments have been extensively explored in the last few decades to develop therapeutic strategies aimed at providing effective alternatives for those human pathologies in which surgical or pharmacological therapies produce limited effects. Among stem cells of different sources, mesenchymal stem cells (MSCs) offer several advantages, such as the absence of ethical concerns, easy harvesting, low immunogenicity and reduced tumorigenesis risks. Other than a multipotent differentiation ability, MSCs can release extracellular vesicles conveying proteins, mRNA and microRNA. Thanks to these properties, new therapeutic approaches have been designed for the treatment of various pathologies, including ocular diseases. In this review, the use of different MSCs and different administration strategies are described for the treatment of diabetic retinopathy, glaucoma, and retinitis pigmentosa. In a large number of investigations, positive results have been obtained by in vitro experiments and by MSC administration in animal models. Most authors agree that beneficial effects are likely related to MSC paracrine activity. Based on these considerations, many clinical trials have already been carried out. Overall, although some adverse effects have been described, promising outcomes are reported. It can be assumed that in the near future, safer and more effective protocols will be developed for more numerous clinical applications to improve the quality of life of patients affected by eye diseases.
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Affiliation(s)
- Giuliana Mannino
- Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, Catania 95123, Italy
| | - Cristina Russo
- Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, Catania 95123, Italy
| | - Anna Longo
- Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, Catania 95123, Italy
| | - Carmelina Daniela Anfuso
- Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, Catania 95123, Italy
| | - Gabriella Lupo
- Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, Catania 95123, Italy
| | - Debora Lo Furno
- Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, Catania 95123, Italy.
| | - Rosario Giuffrida
- Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, Catania 95123, Italy
| | - Giovanni Giurdanella
- Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, Catania 95123, Italy
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25
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Effects of High Glucose Concentration on Pericyte-Like Differentiated Human Adipose-Derived Mesenchymal Stem Cells. Int J Mol Sci 2021; 22:ijms22094604. [PMID: 33925714 PMCID: PMC8125146 DOI: 10.3390/ijms22094604] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Revised: 04/19/2021] [Accepted: 04/24/2021] [Indexed: 02/07/2023] Open
Abstract
A pericyte-like differentiation of human adipose-derived mesenchymal stem cells (ASCs) was tested in in vitro experiments for possible therapeutic applications in cases of diabetic retinopathy (DR) to replace irreversibly lost pericytes. For this purpose, pericyte-like ASCs were obtained after their growth in a specific pericyte medium. They were then cultured in high glucose conditions to mimic the altered microenvironment of a diabetic eye. Several parameters were monitored, especially those particularly affected by disease progression: cell proliferation, viability and migration ability; reactive oxygen species (ROS) production; inflammation-related cytokines and angiogenic factors. Overall, encouraging results were obtained. In fact, even after glucose addition, ASCs pre-cultured in the pericyte medium (pmASCs) showed high proliferation rate, viability and migration ability. A considerable increase in mRNA expression levels of the anti-inflammatory cytokines transforming growth factor-β1 (TGF-β1) and interleukin-10 (IL-10) was observed, associated with reduction in ROS production, and mRNA expression of pro-inflammatory cytokines interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α), and angiogenic factors. Finally, a pmASC-induced better organization of tube-like formation by retinal endothelial cells was observed in three-dimensional co-culture. The pericyte-like ASCs obtained in these experiments represent a valuable tool for the treatment of retinal damages occurring in diabetic patients.
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Extracellular Vesicles from Human Adipose-Derived Mesenchymal Stem Cells: A Review of Common Cargos. Stem Cell Rev Rep 2021; 18:854-901. [PMID: 33904115 PMCID: PMC8942954 DOI: 10.1007/s12015-021-10155-5] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/14/2021] [Indexed: 12/14/2022]
Abstract
In recent years, the interest in adipose tissue mesenchymal cell–derived extracellular vesicles (AT-MSC-EVs) has increasingly grown. Numerous articles support the potential of human AT-MSC-EVs as a new therapeutic option for treatment of diverse diseases in the musculoskeletal and cardiovascular systems, kidney, skin, and immune system, among others. This approach makes use of the molecules transported inside of EVs, which play an important role in cell communication and in transmission of macromolecules. However, to our knowledge, there is no database where essential information about AT-MSC-EVs cargo molecules is gathered for easy reference. The aim of this study is to describe the different molecules reported so far in AT-MSC- EVs, their main molecular functions, and biological processes in which they are involved. Recently, the presence of 591 proteins and 604 microRNAs (miRNAs) has been described in human AT-MSC-EVs. The main molecular function enabled by both proteins and miRNAs present in human AT-MSC-EVs is the binding function. Signal transduction and gene silencing are the biological processes in which a greater number of proteins and miRNAs from human AT-MSC-EVs are involved, respectively. In this review we highlight the therapeutics effects of AT-MSC-EVs related with their participation in relevant biological processes including inflammation, angiogenesis, cell proliferation, apoptosis and migration, among others.
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27
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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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28
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Wen YT, Ho YC, Lee YC, Ding DC, Liu PK, Tsai RK. The Benefits and Hazards of Intravitreal Mesenchymal Stem Cell (MSC) Based-Therapies in the Experimental Ischemic Optic Neuropathy. Int J Mol Sci 2021; 22:ijms22042117. [PMID: 33672743 PMCID: PMC7924624 DOI: 10.3390/ijms22042117] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Revised: 02/05/2021] [Accepted: 02/14/2021] [Indexed: 02/07/2023] Open
Abstract
Mesenchymal stem cell (MSC) therapy has been investigated intensively for many years. However, there is a potential risk related to MSC applications in various cell niches. Methods: The safety of intravitreal MSC application and the efficacy of MSC-derived conditioned medium (MDCM) were evaluated in the normal eye and the diseased eye, respectively. For safety evaluation, the fundus morphology, visual function, retinal function, and histological changes of the retina were examined. For efficacy evaluation, the MDCM was intravitreally administrated in a rodent model of anterior ischemic optic neuropathy (rAION). The visual function, retinal ganglion cell (RGC) density, and neuroinflammation were evaluated at day 28 post-optic nerve (ON) infarct. Results: The fundus imaging showed that MSC transplantation induced retinal distortion and venous congestion. The visual function, retinal function, and RGC density were significantly decreased in MSC-treated eyes. MSC transplantation induced astrogliosis, microgliosis, and macrophage infiltration in the retina due to an increase in the HLA-DR-positive MSC proportion in vitreous. Treatment with the MDCM preserved the visual function and RGC density in rAION via inhibition of macrophage infiltration and RGC apoptosis. Conclusions: The vitreous induced the HLA-DR expression in the MSCs to cause retinal inflammation and retina injury. However, the MDCM provided the neuroprotective effects in rAION.
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Affiliation(s)
- Yao-Tseng Wen
- Institute of Eye Research, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien 970, Taiwan; (Y.-T.W.); (Y.-C.H.); (Y.-C.L.)
| | - Yu-Chieh Ho
- Institute of Eye Research, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien 970, Taiwan; (Y.-T.W.); (Y.-C.H.); (Y.-C.L.)
| | - Yueh-Chang Lee
- Institute of Eye Research, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien 970, Taiwan; (Y.-T.W.); (Y.-C.H.); (Y.-C.L.)
| | - Dah-Ching Ding
- Department of Obstetrics and Gynecology, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien 970, Taiwan;
- Institute of Medical Sciences, Tzu Chi University, Hualien 970, Taiwan
| | - Pei-Kang Liu
- Department of Ophthalmology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan;
- School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan
| | - Rong-Kung Tsai
- Institute of Eye Research, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien 970, Taiwan; (Y.-T.W.); (Y.-C.H.); (Y.-C.L.)
- Institute of Medical Sciences, Tzu Chi University, Hualien 970, Taiwan
- Doctoral Degree Program in Translational Medicine, Tzu Chi University and Academia Sinica, Hualien 970, Taiwan
- Correspondence: ; Tel.: +886-3-8561-825 (ext. 2112)
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29
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Lin Y, Ren X, Chen Y, Chen D. Interaction Between Mesenchymal Stem Cells and Retinal Degenerative Microenvironment. Front Neurosci 2021; 14:617377. [PMID: 33551729 PMCID: PMC7859517 DOI: 10.3389/fnins.2020.617377] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Accepted: 12/17/2020] [Indexed: 02/06/2023] Open
Abstract
Retinal degenerative diseases (RDDs) are a group of diseases contributing to irreversible vision loss with yet limited therapies. Stem cell-based therapy is a promising novel therapeutic approach in RDD treatment. Mesenchymal stromal/stem cells (MSCs) have emerged as a leading cell source due to their neurotrophic and immunomodulatory capabilities, limited ethical concerns, and low risk of tumor formation. Several pre-clinical studies have shown that MSCs have the potential to delay retinal degeneration, and recent clinical trials have demonstrated promising safety profiles for the application of MSCs in retinal disease. However, some of the clinical-stage MSC therapies have been unable to meet primary efficacy end points, and severe side effects were reported in some retinal “stem cell” clinics. In this review, we provide an update of the interaction between MSCs and the RDD microenvironment and discuss how to balance the therapeutic potential and safety concerns of MSCs' ocular application.
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Affiliation(s)
- Yu Lin
- The Research Laboratory of Ophthalmology and Vision Sciences, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.,The Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, China
| | - Xiang Ren
- The Research Laboratory of Ophthalmology and Vision Sciences, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.,The Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, China
| | - Yongjiang Chen
- The School of Optometry and Vision Science, University of Waterloo, Waterloo, ON, Canada
| | - Danian Chen
- The Research Laboratory of Ophthalmology and Vision Sciences, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.,The Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, China
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30
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Elshaer SL, Park HS, Pearson L, Hill WD, Longo FM, El-Remessy AB. Modulation of p75 NTR on Mesenchymal Stem Cells Increases Their Vascular Protection in Retinal Ischemia-Reperfusion Mouse Model. Int J Mol Sci 2021; 22:E829. [PMID: 33467640 PMCID: PMC7830385 DOI: 10.3390/ijms22020829] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Revised: 01/10/2021] [Accepted: 01/11/2021] [Indexed: 12/17/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are a promising therapy to improve vascular repair, yet their role in ischemic retinopathy is not fully understood. The aim of this study is to investigate the impact of modulating the neurotrophin receptor; p75NTR on the vascular protection of MSCs in an acute model of retinal ischemia/reperfusion (I/R). Wild type (WT) and p75NTR-/- mice were subjected to I/R injury by increasing intra-ocular pressure to 120 mmHg for 45 min, followed by perfusion. Murine GFP-labeled MSCs (100,000 cells/eye) were injected intravitreally 2 days post-I/R and vascular homing was assessed 1 week later. Acellular capillaries were counted using trypsin digest 10-days post-I/R. In vitro, MSC-p75NTR was modulated either genetically using siRNA or pharmacologically using the p75NTR modulator; LM11A-31, and conditioned media were co-cultured with human retinal endothelial cells (HREs) to examine the angiogenic response. Finally, visual function in mice undergoing retinal I/R and receiving LM11A-31 was assessed by visual-clue water-maze test. I/R significantly increased the number of acellular capillaries (3.2-Fold) in WT retinas, which was partially ameliorated in p75NTR-/- retinas. GFP-MSCs were successfully incorporated and engrafted into retinal vasculature 1 week post injection and normalized the number of acellular capillaries in p75NTR-/- retinas, yet ischemic WT retinas maintained a 2-Fold increase. Silencing p75NTR on GFP-MSCs coincided with a higher number of cells homing to the ischemic WT retinal vasculature and normalized the number of acellular capillaries when compared to ischemic WT retinas receiving scrambled-GFP-MSCs. In vitro, silencing p75NTR-MSCs enhanced their secretome, as evidenced by significant increases in SDF-1, VEGF and NGF release in MSCs conditioned medium; improved paracrine angiogenic response in HREs, where HREs showed enhanced migration (1.4-Fold) and tube formation (2-Fold) compared to controls. In parallel, modulating MSCs-p75NTR using LM11A-31 resulted in a similar improvement in MSCs secretome and the enhanced paracrine angiogenic potential of HREs. Further, intervention with LM11A-31 significantly mitigated the decline in visual acuity post retinal I/R injury. In conclusion, p75NTR modulation can potentiate the therapeutic potential of MSCs to harness vascular repair in ischemic retinopathy diseases.
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Affiliation(s)
- Sally L. Elshaer
- Augusta Biomedical Research Corporation, Charlie Norwood VA Medical Center, Augusta, GA 30901, USA; (S.L.E.); (L.P.); (W.D.H.)
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt
| | - Hang-soo Park
- Department of Surgery, University of Illinois at Chicago, Chicago, IL 60612, USA;
- Department of Obstetrics and Gynecology, University of Chicago, Chicago, IL 60637, USA
| | - Laura Pearson
- Augusta Biomedical Research Corporation, Charlie Norwood VA Medical Center, Augusta, GA 30901, USA; (S.L.E.); (L.P.); (W.D.H.)
| | - William D. Hill
- Augusta Biomedical Research Corporation, Charlie Norwood VA Medical Center, Augusta, GA 30901, USA; (S.L.E.); (L.P.); (W.D.H.)
- Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC 29403, USA
- Ralph H. Johnson Veterans Affairs Medical Center, Charleston, SC 29403, USA
| | - Frank M. Longo
- Department of Neurology and Neurological Sciences, Stanford University, Palo Alto, CA 94304, USA;
| | - Azza B. El-Remessy
- Augusta Biomedical Research Corporation, Charlie Norwood VA Medical Center, Augusta, GA 30901, USA; (S.L.E.); (L.P.); (W.D.H.)
- Department of Surgery, University of Illinois at Chicago, Chicago, IL 60612, USA;
- Department of the Pharmacy, Doctors Hospital of Augusta, Augusta, GA 30909, USA
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31
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Li XJ, Li CY, Bai D, Leng Y. Insights into stem cell therapy for diabetic retinopathy: a bibliometric and visual analysis. Neural Regen Res 2021; 16:172-178. [PMID: 32788473 PMCID: PMC7818871 DOI: 10.4103/1673-5374.286974] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Stem cells have been confirmed to be involved in the occurrence and development of diabetic retinopathy; however, the underlying mechanisms remain unclear. In this study, we used Citespace software to visually analyze 552 articles exploring the stem cell-based treatment of diabetic retinopathy over the past 20 years, which were included in the Web of Science Core Collection. We found the following: (1) a co-citation analysis of the references cited by all 552 articles indicated 15 clusters. In cluster #0, representing the stem cell field, some highly cited landmark studies emerged between 2009–2013. For example, endothelial progenitor cells and diabetic retinopathy gradually received the full attention of scholars, in terms of their relationship and therapeutic prospects. Some researchers also verified the potential of adipose-derived stem cells to differentiate into stable retinal perivascular cells, using a variety of animal models of retinal vascular disease. All of these achievements provided references for the subsequent stem cell research. (2) An analysis of popular keywords among the 552 articles revealed that, during the past 20 years, a relative increase in basic research articles examining stem cells and endothelial progenitor cells for the treatment of diabetic retinopathy was observed. The contents of these articles primarily involved the expression of vascular endothelial growth factor, vascular regeneration, oxidative stress, and inflammatory response. (3) A burst analysis of keywords used in the 552 articles indicated that genetic and cytological research regarding the promotion of angiogenesis was an issue of concern from 2001 to 2012, including several studies addressing the expression of various growth factor genes; from 2014 to 2020, mouse models of diabetic retinopathy were recognized as mature animal models, and the most recent research has focused on macular degeneration, macular edema, neurodegeneration, and inflammatory changes in diabetic animal models. (4) Globally, the current authoritative studies have focused on basic research towards the stem cell treatment of diabetic retinopathy. Existing clinical studies are of low quality and have insufficient evidence levels, and their findings have not yet been widely accepted in clinical practice. Major challenges during stem cell transplantation remain, including stem cell heterogeneity, cell delivery, and the effective homing of stem cells to damaged tissue. However, clinical trials examining potential stem cell-based treatments of diabetic retinopathy, including the use of pluripotent stem cells, retinal pigment epithelial cells, bone marrow mesenchymal stem cells, and endothelial progenitor cells, are currently ongoing, and high-quality clinical evidence is likely to appear in the future, to promote clinical transformation.
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Affiliation(s)
- Xiang-Jun Li
- Department of Ophthalmology, Affiliated Hospital of Beihua University, Jilin, Jilin Province, China
| | - Chun-Yan Li
- Department of Endocrinology, Affiliated Hospital of Beihua University, Jilin, Jilin Province, China
| | - Dan Bai
- Department of Ophthalmology, Affiliated Hospital of Beihua University, Jilin, Jilin Province, China
| | - Ying Leng
- Department of Ophthalmology, Affiliated Hospital of Beihua University, Jilin, Jilin Province, China
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32
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Goenka V, Borkar T, Desai A, Das RK. Therapeutic potential of mesenchymal stem cells in treating both types of diabetes mellitus and associated diseases. J Diabetes Metab Disord 2020; 19:1979-1993. [PMID: 33520872 PMCID: PMC7843693 DOI: 10.1007/s40200-020-00647-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2020] [Accepted: 09/24/2020] [Indexed: 10/23/2022]
Abstract
Diabetes mellitus is a common lifestyle disease which can be classified into type 1 diabetes mellitus and type 2 diabetes mellitus. While both result in hyperglycemia due to lack of insulin action and further associated chronic ailments, there is a marked distinction in the cause for each type due to which both require a different prophylaxis. As observed, type 1 diabetes is caused due to the autoimmune action of the body resulting in the destruction of pancreatic islet cells. On the other hand, type 2 diabetes is caused either due to insulin resistance of target cells or lack of insulin production as per physiological requirements. Attempts to cure the disease have been made by bringing drastic changes in the patients' lifestyle; parenteral administration of insulin; prescription of drugs such as biguanides, meglitinides, and amylin; pancreatic transplantation; and immunotherapy. While these attempts cause a certain degree of relief to the patient, none of these can cure diabetes mellitus. However, a new treatment strategy led by the discovery of mesenchymal stem cells and their unique immunomodulatory and multipotent properties has inspired therapies to treat diabetes by essentially reversing the conditions causing the disease. The current review aims to enumerate the role of various mesenchymal stem cells and the different approaches to treat both types of diabetes and its associated diseases as well.
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Affiliation(s)
- Vidul Goenka
- School of Biosciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu India
| | - Tanhai Borkar
- School of Biosciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu India
| | - Aska Desai
- School of Biosciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu India
| | - Raunak Kumar Das
- Centre for Biomaterials, Cellular and Molecular Theranostics, Vellore Institute of Technology, Vellore, Tamil Nadu India
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Long noncoding RNA UCA1 from hypoxia-conditioned hMSC-derived exosomes: a novel molecular target for cardioprotection through miR-873-5p/XIAP axis. Cell Death Dis 2020; 11:696. [PMID: 32826854 PMCID: PMC7442657 DOI: 10.1038/s41419-020-02783-5] [Citation(s) in RCA: 88] [Impact Index Per Article: 17.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2020] [Revised: 06/29/2020] [Accepted: 07/09/2020] [Indexed: 12/28/2022]
Abstract
Exosomes (Exo) secreted from mesenchymal stem cells (hMSCs) are protective against myocardial injury. The purpose of the study was to investigate the role and mechanisms by which exosomes promote cardiomyocyte survival and function following myocardial infarction (MI). hMSCs were cultured under hypoxic and normoxic conditions. Hypoxia-conditioned hMSC-derived exosomes (Hypo-Exo) and normoxic-conditioned hMSC-derived exosomes (Nor-Exo) were collected and intramyocardially injected into rats with MI. The therapeutic effects of Hypo-Exo and Nor-Exo were evaluated after 4 weeks. Quantitative real-time PCR (qRT-PCR) was used to detect the expression of candidate long noncoding RNA urothelial carcinoma associated 1 (lncRNA-UCA1) in Nor-Exo and Hypo-Exo. Intramyocardial injection of lncRNA-UCA1-knockdown-Hypo-Exo in a rat model of MI was then performed and the cardiac function was characterized. The target and downstream of the molecular mechanism lncRNA-UCA1 was disclosed by luciferase reporter assays and western blot. Circulating exosomal lncRNA-UCA1 level in AMI patients and healthy volunteers was assessed. We found that (1) hMSC exosomal (from hypoxic and normoxic conditions) cardioprotection in vitro and in vivo correlated with the presence of encapsulated lncRNA-UCA1 in exosomes; (2) lncRNA-UCA1 targeted miR-873 via sponging, reducing the latter’s suppressive effects on its target XIAP, and this translated into AMPK phosphorylation and increased level of the antiapoptotic protein BCL2; and (3) plasma derived from patients with AMI contained exosomes enriched with the lncRNA-UCA1, unlike that from normal subjects. This study demonstrates that Hypo-Exo lncRNA-UCA1 plays a cardioprotective role via the miR-873-5p/XIAP axis and circulating exosomal lncRNA-UCA1 may be a promising novel biomarker for the diagnosis of AMI.
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Mesenchymal Stem Cell Secretome Enhancement by Nicotinamide and Vasoactive Intestinal Peptide: A New Therapeutic Approach for Retinal Degenerative Diseases. Stem Cells Int 2020; 2020:9463548. [PMID: 32676122 PMCID: PMC7336242 DOI: 10.1155/2020/9463548] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2019] [Revised: 04/16/2020] [Accepted: 06/04/2020] [Indexed: 12/24/2022] Open
Abstract
Mesenchymal stem cells (MSC) secrete neuroprotective molecules that may be useful as an alternative to cell transplantation itself. Our purpose was to develop different pharmaceutical compositions based on conditioned medium (CM) of adipose MSC (aMSC) stimulated by and/or combined with nicotinamide (NIC), vasoactive intestinal peptide (VIP), or both factors; and to evaluate in vitro their proliferative and neuroprotective potential. Nine pharmaceutical compositions were developed from 3 experimental approaches: (1) unstimulated aMSC-CM collected and combined with NIC, VIP, or both factors (NIC+VIP), referred to as the aMSC-CM combined composition; (2) aMSC-CM collected just after stimulation with the mentioned factors and containing them, referred to as the aMSC-CM stimulated-combined composition; and (3) aMSC-CM previously stimulated with the factors, referred to as the aMSC stimulated composition. The potential of the pharmaceutical compositions to increase cell proliferation under oxidative stress and neuroprotection were evaluated in vitro by using a subacute oxidative stress model of retinal pigment epithelium cells (line ARPE-19) and spontaneous degenerative neuroretina model. Results showed that oxidatively stressed ARPE-19 cells exposed to aMSC-CM stimulated and stimulated-combined with NIC or NIC+VIP tended to have better recovery from the oxidative stress status. Neuroretinal explants cultured with aMSC-CM stimulated-combined with NIC+VIP had better preservation of the neuroretinal morphology, mainly photoreceptors, and a lower degree of glial cell activation. In conclusion, aMSC-CM stimulated-combined with NIC+VIP contributed to improving the proliferative and neuroprotective properties of the aMSC secretome. Further studies are necessary to evaluate higher concentrations of the drugs and to characterize specifically the aMSC-secreted factors related to neuroprotection. However, this study supports the possibility of improving the potential of new effective pharmaceutical compositions based on the secretome of MSC plus exogenous factors or drugs without the need to inject cells into the eye, which can be very useful in retinal pathologies.
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Recent developments in regenerative ophthalmology. SCIENCE CHINA-LIFE SCIENCES 2020; 63:1450-1490. [PMID: 32621058 DOI: 10.1007/s11427-019-1684-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/09/2020] [Accepted: 03/21/2020] [Indexed: 12/13/2022]
Abstract
Regenerative medicine (RM) is one of the most promising disciplines for advancements in modern medicine, and regenerative ophthalmology (RO) is one of the most active fields of regenerative medicine. This review aims to provide an overview of regenerative ophthalmology, including the range of tools and materials being used, and to describe its application in ophthalmologic subspecialties, with the exception of surgical implantation of artificial tissues or organs (e.g., contact lens, artificial cornea, intraocular lens, artificial retina, and bionic eyes) due to space limitations. In addition, current challenges and limitations of regenerative ophthalmology are discussed and future directions are highlighted.
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Yang H, Wu L, Deng H, Chen Y, Zhou H, Liu M, Wang S, Zheng L, Zhu L, Lv X. Anti-inflammatory protein TSG-6 secreted by bone marrow mesenchymal stem cells attenuates neuropathic pain by inhibiting the TLR2/MyD88/NF-κB signaling pathway in spinal microglia. J Neuroinflammation 2020; 17:154. [PMID: 32393298 PMCID: PMC7216552 DOI: 10.1186/s12974-020-1731-x] [Citation(s) in RCA: 98] [Impact Index Per Article: 19.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2019] [Accepted: 01/30/2020] [Indexed: 12/11/2022] Open
Abstract
Background Neuroinflammation plays a vital role in the development and maintenance of neuropathic pain. Recent evidence has proved that bone marrow mesenchymal stem cells (BMSCs) can inhibit neuropathic pain and possess potent immunomodulatory and immunosuppressive properties via secreting a variety of bioactive molecules, such as TNF-α-stimulated gene 6 protein (TSG-6). However, it is unknown whether BMSCs exert their analgesic effect against neuropathic pain by secreting TSG-6. Therefore, the present study aimed to evaluate the analgesic effects of TSG-6 released from BMSCs on neuropathic pain induced by chronic constriction injury (CCI) in rats and explored the possible underlying mechanisms in vitro and in vivo. Methods BMSCs were isolated from rat bone marrow and characterized by flow cytometry and functional differentiation. One day after CCI surgery, about 5 × 106 BMSCs were intrathecally injected into spinal cerebrospinal fluid. Behavioral tests, including mechanical allodynia, thermal hyperalgesia, and motor function, were carried out at 1, 3, 5, 7, 14 days after CCI surgery. Spinal cords were processed for immunohistochemical analysis of the microglial marker Iba-1. The mRNA and protein levels of pro-inflammatory cytokines (IL-1β, TNFα, IL-6) were detected by real-time RT-PCR and ELISA. The activation of the TLR2/MyD88/NF-κB signaling pathway was evaluated by Western blot and immunofluorescence staining. The analgesic effect of exogenous recombinant TSG-6 on CCI-induced mechanical allodynia and heat hyperalgesia was observed by behavioral tests. In the in vitro experiments, primary cultured microglia were stimulated with the TLR2 agonist Pam3CSK4, and then co-cultured with BMSCs or recombinant TSG-6. The protein expression of TLR2, MyD88, p-p65 was evaluated by Western blot. The mRNA and protein levels of IL-1β, TNFα, IL-6 were detected by real-time RT-PCR and ELISA. BMSCs were transfected with the TSG-6-specific shRNA and then intrathecally injected into spinal cerebrospinal fluid in vivo or co-cultured with Pam3CSK4-treated primary microglia in vitro to investigate whether TSG-6 participated in the therapeutic effect of BMSCs on CCI-induced neuropathic pain and neuroinflammation. Results We found that CCI-induced mechanical allodynia and heat hyperalgesia were ameliorated by intrathecal injection of BMSCs. Moreover, intrathecal administration of BMSCs inhibited CCI-induced neuroinflammation in spinal cord tissues. The analgesic effect and anti-inflammatory property of BMSCs were attenuated when TSG-6 expression was silenced. We also found that BMSCs inhibited the activation of the TLR2/MyD88/NF-κB pathway in the ipsilateral spinal cord dorsal horn by secreting TSG-6. Meanwhile, we proved that intrathecal injection of exogenous recombinant TSG-6 effectively attenuated CCI-induced neuropathic pain. Furthermore, in vitro experiments showed that BMSCs and TSG-6 downregulated the TLR2/MyD88/NF-κB signaling and reduced the production of pro-inflammatory cytokines, such as IL-1β, IL-6, and TNF-α, in primary microglia treated with the specific TLR2 agonist Pam3CSK4. Conclusions The present study demonstrated a paracrine mechanism by which intrathecal injection of BMSCs targets the TLR2/MyD88/NF-κB pathway in spinal cord dorsal horn microglia to elicit neuroprotection and sustained neuropathic pain relief via TSG-6 secretion.
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Affiliation(s)
- Hao Yang
- Department of Anesthesiology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, 507 Zhengmin Rd, Shanghai, 200433, China
| | - Lingmin Wu
- Department of Anesthesiology, The first Hospital of Anhui Medical University, 218 Jixi Rd, Hefei, 230022, China
| | - Huimin Deng
- Department of Anesthesiology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, 507 Zhengmin Rd, Shanghai, 200433, China
| | - Yuanli Chen
- Department of Anesthesiology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, 507 Zhengmin Rd, Shanghai, 200433, China
| | - Huanping Zhou
- Department of Anesthesiology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, 507 Zhengmin Rd, Shanghai, 200433, China
| | - Meiyun Liu
- Department of Anesthesiology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, 507 Zhengmin Rd, Shanghai, 200433, China
| | - Shaochen Wang
- Department of Anesthesiology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, 507 Zhengmin Rd, Shanghai, 200433, China
| | - Li Zheng
- Department of Anesthesiology, Fuyang Hospital of Anhui Medical University, 99 Huangshan Rd, Fuyang, 236000, China
| | - Lina Zhu
- Department of Anesthesiology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, 507 Zhengmin Rd, Shanghai, 200433, China.
| | - Xin Lv
- Department of Anesthesiology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, 507 Zhengmin Rd, Shanghai, 200433, China. .,Department of Anesthesiology, The first Hospital of Anhui Medical University, 218 Jixi Rd, Hefei, 230022, China.
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Huang H, Kolibabka M, Eshwaran R, Chatterjee A, Schlotterer A, Willer H, Bieback K, Hammes HP, Feng Y. Intravitreal injection of mesenchymal stem cells evokes retinal vascular damage in rats. FASEB J 2019; 33:14668-14679. [DOI: 10.1096/fj.201901500r] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Affiliation(s)
- Hongpeng Huang
- Experimental Pharmacology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Matthias Kolibabka
- Fifth Medical Clinic, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Rachana Eshwaran
- Experimental Pharmacology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Anupriya Chatterjee
- Experimental Pharmacology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Andrea Schlotterer
- Fifth Medical Clinic, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Hélène Willer
- Institute of Transfusion Medicine and Immunology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Karen Bieback
- Institute of Transfusion Medicine and Immunology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Hans-Peter Hammes
- Fifth Medical Clinic, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Yuxi Feng
- Experimental Pharmacology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
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Jha KA, Pentecost M, Lenin R, Gentry J, Klaic L, Del Mar N, Reiner A, Yang CH, Pfeffer LM, Sohl N, Gangaraju R. TSG-6 in conditioned media from adipose mesenchymal stem cells protects against visual deficits in mild traumatic brain injury model through neurovascular modulation. Stem Cell Res Ther 2019; 10:318. [PMID: 31690344 PMCID: PMC6833275 DOI: 10.1186/s13287-019-1436-1] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2019] [Revised: 09/21/2019] [Accepted: 09/30/2019] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Retinal inflammation affecting the neurovascular unit may play a role in the development of visual deficits following mild traumatic brain injury (mTBI). We have shown that concentrated conditioned media from adipose tissue-derived mesenchymal stem cells (ASC-CCM) can limit retinal damage from blast injury and improve visual function. In this study, we addressed the hypothesis that TNFα-stimulated gene-6 (TSG-6), an anti-inflammatory protein released by mesenchymal cells, mediates the observed therapeutic potential of ASCs via neurovascular modulation. METHODS About 12-week-old C57Bl/6 mice were subjected to 50-psi air pulse on the left side of the head overlying the forebrain resulting in an mTBI. Age-matched sham blast mice served as control. About 1 μl of ASC-CCM (siControl-ASC-CCM) or TSG-6 knockdown ASC-CCM (siTSG-6-ASC-CCM) was delivered intravitreally into both eyes. One month following injection, the ocular function was assessed followed by molecular and immunohistological analysis. In vitro, mouse microglial cells were used to evaluate the anti-inflammatory effect of ASC-CCM. Efficacy of ASC-CCM in normalizing retinal vascular permeability was assessed using trans-endothelial resistance (TER) and VE-cadherin expression in the presence of TNFα (1 ng/ml). RESULTS We show that intravitreal injection of ASC-CCM (siControl-ASC-CCM) but not the TSG-6 knockdown ASC-CCM (siTSG-6-ASC-CCM) mitigates the loss of visual acuity and contrast sensitivity, retinal expression of genes associated with microglial and endothelial activation, and retinal GFAP immunoreactivity at 4 weeks after blast injury. In vitro, siControl-ASC-CCM but not the siTSG-6-ASC-CCM not only suppressed microglial activation and STAT3 phosphorylation but also protected against TNFα-induced endothelial permeability as measured by transendothelial electrical resistance and decreased STAT3 phosphorylation. CONCLUSIONS Our findings suggest that ASCs respond to an inflammatory milieu by secreting higher levels of TSG-6 that mediates the resolution of the inflammatory cascade on multiple cell types and correlates with the therapeutic potency of the ASC-CCM. These results expand our understanding of innate mesenchymal cell function and confirm the importance of considering methods to increase the production of key analytes such as TSG-6 if mesenchymal stem cell secretome-derived biologics are to be developed as a treatment solution against the traumatic effects of blast injuries and other neurovascular inflammatory conditions of the retina.
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Affiliation(s)
- Kumar Abhiram Jha
- Department of Ophthalmology, University of Tennessee Health Science Center, College of Medicine, 930 Madison Ave, Suite#768, Memphis, TN, 38163, USA
| | - Mickey Pentecost
- Cell Care Therapeutics, Inc., Los Angeles, CA, USA.,Present Address: Pathways to Stem Cell Science, Monrovia, CA, USA
| | - Raji Lenin
- Department of Ophthalmology, University of Tennessee Health Science Center, College of Medicine, 930 Madison Ave, Suite#768, Memphis, TN, 38163, USA
| | - Jordy Gentry
- Department of Ophthalmology, University of Tennessee Health Science Center, College of Medicine, 930 Madison Ave, Suite#768, Memphis, TN, 38163, USA
| | - Lada Klaic
- Cell Care Therapeutics, Inc., Los Angeles, CA, USA
| | - Nobel Del Mar
- Department of Anatomy and Neurobiology, University of Tennessee Health Science Center, College of Medicine, 855 Monroe Avenue, Suite#515, Memphis, TN, 38163, USA
| | - Anton Reiner
- Department of Anatomy and Neurobiology, University of Tennessee Health Science Center, College of Medicine, 855 Monroe Avenue, Suite#515, Memphis, TN, 38163, USA
| | - Chuan He Yang
- Department of Pathology, University of Tennessee Health Science Center, College of Medicine, 19 South Manassas Street, Suite#214, Memphis, TN, 38163, USA
| | - Lawrence M Pfeffer
- Department of Pathology, University of Tennessee Health Science Center, College of Medicine, 19 South Manassas Street, Suite#214, Memphis, TN, 38163, USA
| | - Nicolas Sohl
- Cell Care Therapeutics, Inc., Los Angeles, CA, USA
| | - Rajashekhar Gangaraju
- Department of Ophthalmology, University of Tennessee Health Science Center, College of Medicine, 930 Madison Ave, Suite#768, Memphis, TN, 38163, USA. .,Department of Anatomy and Neurobiology, University of Tennessee Health Science Center, College of Medicine, 855 Monroe Avenue, Suite#515, Memphis, TN, 38163, USA.
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Gaddam S, Periasamy R, Gangaraju R. Adult Stem Cell Therapeutics in Diabetic Retinopathy. Int J Mol Sci 2019; 20:ijms20194876. [PMID: 31575089 PMCID: PMC6801872 DOI: 10.3390/ijms20194876] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2019] [Revised: 09/27/2019] [Accepted: 09/29/2019] [Indexed: 12/17/2022] Open
Abstract
Diabetic retinopathy (DR), a complication of diabetes, is one of the leading causes of blindness in working-age adults. The pathology of the disease prevents the endogenous stem cells from participating in the natural repair of the diseased retina. Current treatments, specifically stem cell therapeutics, have shown variable efficacy in preclinical models due to the multi-faceted nature of the disease. Among the various adult stem cells, mesenchymal stem cells, especially those derived from adipose tissue and bone marrow, have been explored as a possible treatment for DR. This review summarizes the current literature around the various adult stem cell treatments for the disease and outlines the benefits and limitations of the therapeutics that are being explored in the field. The paracrine nature of adipose stem cells, in particular, has been highlighted as a potential solution to the lack of a homing and conducive environment that poses a challenge to the implantation of exogenous stem cells in the target tissue. Various methods of mesenchymal stem cell priming to adapt to a hostile retinal microenvironment have been discussed. Current clinical trials and potential safety concerns have been examined, and the future directions of stem cell therapeutics in DR have also been contemplated.
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Affiliation(s)
- Sriprachodaya Gaddam
- Department of Ophthalmology, University of Tennessee Health Science Center, College of Medicine, Memphis, TN 38163, USA.
| | - Ramesh Periasamy
- Department of Ophthalmology, University of Tennessee Health Science Center, College of Medicine, Memphis, TN 38163, USA.
| | - Rajashekhar Gangaraju
- Department of Ophthalmology, University of Tennessee Health Science Center, College of Medicine, Memphis, TN 38163, USA.
- Department of Anatomy & Neurobiology, University of Tennessee Health Science Center, College of Medicine, Memphis, TN 38163, USA.
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Solis MA, Moreno Velásquez I, Correa R, Huang LLH. Stem cells as a potential therapy for diabetes mellitus: a call-to-action in Latin America. Diabetol Metab Syndr 2019; 11:20. [PMID: 30820250 PMCID: PMC6380040 DOI: 10.1186/s13098-019-0415-0] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2018] [Accepted: 02/13/2019] [Indexed: 02/06/2023] Open
Abstract
Latin America is a fast-growing region that currently faces unique challenges in the treatment of all forms of diabetes mellitus. The burden of this disease will be even greater in the coming years due, in part, to the large proportion of young adults living in urban areas and engaging in unhealthy lifestyles. Unfortunately, the national health systems in Latin-American countries are unprepared and urgently need to reorganize their health care services to achieve diabetic therapeutic goals. Stem cell research is attracting increasing attention as a promising and fast-growing field in Latin America. As future healthcare systems will include the development of regenerative medicine through stem cell research, Latin America is urged to issue a call-to-action on stem cell research. Increased efforts are required in studies focused on stem cells for the treatment of diabetes. In this review, we aim to inform physicians, researchers, patients and funding sources about the advances in stem cell research for possible future applications in diabetes mellitus. Emerging studies are demonstrating the potential of stem cells for β cell differentiation and pancreatic regeneration. The major economic burden implicated in patients with diabetes complications suggests that stem cell research may relieve diabetic complications. Closer attention should be paid to stem cell research in the future as an alternative treatment for diabetes mellitus.
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Affiliation(s)
| | | | - Ricardo Correa
- Department of Medicine, Warren Alpert School of Medicine, Brown University, Rhode Island, USA
- Department of Medicine, University of Arizona College of Medicine, Phoenix, AZ USA
| | - Lynn L. H. Huang
- Department of Biotechnology and Bioindustry Sciences, National Cheng Kung University, Tainan, Taiwan
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- Research Center of Excellence in Regenerative Medicine, National Cheng Kung University, Tainan, Taiwan
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