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Park JY, Jung SY, Yoo D, Lee S, Go D, Bui VD, Jung WK, You DG, Park JH, Um W. Stem Cell-Derived Extracellular Vesicles in Skin Antiaging Treatments. ACS NANO 2025. [PMID: 40527735 DOI: 10.1021/acsnano.4c17406] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/19/2025]
Abstract
As the median age of the global population rises and the demand for aesthetic enhancement increases, interest in antiaging skin technologies has been growing significantly. This review first addresses the molecular mechanisms underlying skin aging, followed by an overview of traditional antiaging approaches and their benefits and limitations. Furthermore, it emphasizes the potential of mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) as promising alternatives to address the shortcomings of conventional strategies. This article highlights the antiaging effects and therapeutic mechanisms of MSC-EVs in the skin microenvironment and identifies promising targets for skin antiaging interventions based on the functional properties of MSC-EVs. Finally, this review introduces the recent advances and future directions for MSC-EV-based antiaging strategies.
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Affiliation(s)
- Ji Yeong Park
- Department of Biotechnology, College of Fisheries Science, Pukyong National University, Busan 48513, Republic of Korea
| | - Se Young Jung
- Department of Biotechnology, College of Fisheries Science, Pukyong National University, Busan 48513, Republic of Korea
| | - Donghyeon Yoo
- Department of Biotechnology, College of Fisheries Science, Pukyong National University, Busan 48513, Republic of Korea
| | - Sihun Lee
- Department of Biotechnology, College of Fisheries Science, Pukyong National University, Busan 48513, Republic of Korea
| | - Dabin Go
- Department of Biotechnology, College of Fisheries Science, Pukyong National University, Busan 48513, Republic of Korea
| | - Van Dat Bui
- School of Chemical Engineering, College of Engineering, Sungkyunkwan University (SKKU), Suwon 16419, Republic of Korea
- Vinmec Research Institute of Stem Cell and Gene Technology, College of Health Sciences, VinUniversity, Vinhomes Ocean Park, Gia Lam District, Hanoi 1310, Vietnam
| | - Won-Kyo Jung
- Marine Integrated Biomedical Technology Center, The National Key Research Institutes in Universities, Pukyong National University, Busan 48513, Republic of Korea
| | - Dong Gil You
- Department of Chemical Engineering and Biotechnology, Tech University of Korea, Siheung 15073, Republic of Korea
| | - Jae Hyung Park
- School of Chemical Engineering, College of Engineering, Sungkyunkwan University (SKKU), Suwon 16419, Republic of Korea
| | - Wooram Um
- Department of Biotechnology, College of Fisheries Science, Pukyong National University, Busan 48513, Republic of Korea
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Chandran NS, Bhupendrabhai MN, Tan TT, Zhang B, Lim SK, Choo ABH, Lai RC. A phase 1, open-label study to determine safety and tolerability of the topical application of mesenchymal stem/stromal cell (MSC) exosome ointment to treat psoriasis in healthy volunteers. Cytotherapy 2025; 27:633-641. [PMID: 39918488 DOI: 10.1016/j.jcyt.2025.01.007] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2024] [Revised: 12/15/2024] [Accepted: 01/15/2025] [Indexed: 05/24/2025]
Abstract
BACKGROUND Topical application of mesenchymal stem/stromal cell (MSC) exosomes have yielded encouraging results in the treatment of psoriasis in pre-clinical studies. The safety of topical applications of MSC exosome in ointment has not yet been determined in human subjects. OBJECTIVE To assess the safety and tolerability of an MSC exosome ointment, PTD2021P, for topical application in healthy adult volunteers. METHODS Ten healthy adult volunteers were enrolled. All subjects received topical treatment with PTD2021P immediately followed by Vesiderm liposome cream ter in die (TID) (thrice a day) on the forearm with a gap of 4 hours between doses for 20 days and underwent another round of screening procedure at end of study (Day 21 + 3 days). Screening procedures included vital signs, blood examinations, photographs and visual assessment of the area of application. All through the treatment period, the subjects completed the daily Subject Diary to capture adverse events, concomitant medications, and time of study product application. RESULTS One subject was reported with 1 treatment-emergent adverse event (TEAE) of COVID-19 infection during the study. The TEAE was moderate in severity and unlikely related to the study drug. This TEAE was resolved and the subject recovered fully. No subject was reported with clinically significant abnormality for laboratory parameters. As per the visual assessment of the area of application, no subject had dryness, itch, oozing/crusting, redness, scratch marks, skin thickening, sleeplessness, or swelling at the area of application of skin. CONCLUSIONS PTD 2021P was well tolerated for topical application. There were no serious adverse events (SAEs) or TEAEs related to the treatment, and no subject discontinued the study. No clinically significant abnormality was reported for laboratory parameters and vital signs. No abnormality was reported for visual assessment of the area of application of exosome ointment. This ointment could be an alternative therapeutic option for patients who are refractory to current first line therapy.
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Affiliation(s)
- Nisha Suyien Chandran
- Division of Dermatology, National University Hospital, Singapore, Republic of Singapore
| | | | - Thong Teck Tan
- Paracrine Therapeutics Pt. Ltd., Singapore, Republic of Singapore
| | - Bin Zhang
- Paracrine Therapeutics Pt. Ltd., Singapore, Republic of Singapore
| | - Sai Kiang Lim
- Paracrine Therapeutics Pt. Ltd., Singapore, Republic of Singapore; Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore C/O NUHS Tower Block, Singapore, Republic of Singapore.
| | - Andre Boon Hwa Choo
- Bioprocessing Technology Institute, Singapore, Republic of Singapore; Department of Biomedical Engineering, Faculty of Engineering, National University of Singapore (NUS), Singapore, Republic of Singapore
| | - Ruenn Chai Lai
- Paracrine Therapeutics Pt. Ltd., Singapore, Republic of Singapore
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Sadeghi M, Moghaddam A, Amiri AM, Charoghdoozi K, Mohammadi M, Dehnavi S, Orazizadeh M. Improving the Wound Healing Process: Pivotal role of Mesenchymal stromal/stem Cells and Immune Cells. Stem Cell Rev Rep 2025; 21:680-697. [PMID: 39921839 DOI: 10.1007/s12015-025-10849-0] [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] [Accepted: 01/31/2025] [Indexed: 02/10/2025]
Abstract
Wound healing, a physiological process, involves several different types of cells, from immune cells to non-immune cells, including mesenchymal stromal/stem cells (MSC), and their interactions. Immune cells including macrophages, neutrophils, dendritic cells (DC), innate lymphoid cells (ILC), natural killer (NK) cells, and B and T lymphocytes participate in wound healing by secreting various mediators and interacting with other cells. MSCs, as self-renewing, fast proliferating, and multipotent stromal/stem cells, are found in a wide variety of tissues and critically involved in different phases of wound healing by secreting various molecules that help to improve tissue healing and regeneration. In this review, first, we described the four main phases of wound healing, second, we reviewed the function of MSCs, MSC secretome and immune cells in improving the progress of wound repair (mainly focusing on skin wound healing), third, we explained the immune cells/MSCs interactions in the process of wound healing and regeneration, and finally, we introduce clinical applications of MSCs to improve the process of wound healing.
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Affiliation(s)
- Mahvash Sadeghi
- Allergy Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Asma Moghaddam
- Cellular and Molecular Research Center, Medical Basic Sciences Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
- Department of Anatomical Sciences, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Amir Mohammad Amiri
- Department of Immunology, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
- Student Research Committee, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Kianush Charoghdoozi
- Student Research Committee, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Immunology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mojgan Mohammadi
- Pharmacological Research Center of Medicinal Plants, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Sajad Dehnavi
- Allergy Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
- Department of Immunology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
- Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
| | - Mahmoud Orazizadeh
- Cellular and Molecular Research Center, Medical Basic Sciences Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
- Department of Anatomical Sciences, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
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Chen G, Lin T, Wu M, Cai G, Wu C, Ding Q, Xu J, Chen H, Li W, Xu G, Lan Y. Causal Association of Cytokines and Growth Factors with Stroke and Its Subtypes: a Mendelian Randomization Study. Mol Neurobiol 2024; 61:3212-3222. [PMID: 37979035 DOI: 10.1007/s12035-023-03752-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2023] [Accepted: 10/28/2023] [Indexed: 11/19/2023]
Abstract
Cytokines and growth factors contribute to nerve growth and angiogenesis and are associated with the development of vascular disease. This Mendelian randomization (MR) study was designed to examine the causal relationship between factors associated with stem cell paracrine mechanisms and with stroke and its subtypes. We used pooled statistics on cytokine levels from three studies (INTERIAL, Olink Proseek CVD array, and KORA) encompassing 7795 participants in Europe. Data for stroke and its subtypes were pooled from these European populations (40,585 cases and 406,111 controls) in a multiprogenitor genome-wide association study (GWAS). MR was performed using established analytical methods, including inverse variance weighting (IVW), weighted median (WM), and MR-Egger. Genetically determined high IGF-1 levels were found to associate negatively with risk of stroke, ischemic stroke (large-artery atherosclerosis), and ischemic stroke (cardiogenic embolism). Meanwhile, high IL-13 levels had a positive causal relationship with ischemic stroke (large-artery atherosclerosis). An additional 27 cytokines were found to have a causal association with stroke or its subtypes. However, these results should be interpreted with caution given that the power efficacy was <80%. This MR study supports the concept of a causal relationship of 29 cytokines with stroke or its subtypes. Our genetic analysis provides new insights into stroke prevention and treatment by demonstrating an association of stem cell paracrine-related cytokines with stroke risk.
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Affiliation(s)
- Gengbin Chen
- Department of Rehabilitation Medicine, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, China
- Postgraduate Research Institute, Guangzhou Sport University, Guangzhou, China
| | - Tuo Lin
- Department of Rehabilitation Medicine, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, China
| | - Manfeng Wu
- Department of Rehabilitation Medicine, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, China
| | - Guiyuan Cai
- Department of Rehabilitation Medicine, the Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou, China
| | - Cheng Wu
- Department of Rehabilitation Medicine, the Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou, China
- Department of Rehabilitation Medicine, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, No. 106 Zhongshan Road II, Guangzhou, 510080, China
| | - Qian Ding
- Department of Rehabilitation Medicine, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, No. 106 Zhongshan Road II, Guangzhou, 510080, China
| | - Jiayue Xu
- Department of Rehabilitation Medicine, the Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou, China
| | - Hongying Chen
- Department of Rehabilitation Medicine, the Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou, China
| | - Wanqi Li
- Department of Rehabilitation Medicine, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, China
| | - Guangqing Xu
- Department of Rehabilitation Medicine, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, No. 106 Zhongshan Road II, Guangzhou, 510080, China.
| | - Yue Lan
- Department of Rehabilitation Medicine, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, China.
- Guangzhou Key Laboratory of Aging Frailty and Neurorehabilitation, Guangzhou, China.
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Zhang B, Lai RC, Sim WK, Tan TT, Lim SK. An Assessment of Administration Route on MSC-sEV Therapeutic Efficacy. Biomolecules 2024; 14:622. [PMID: 38927026 PMCID: PMC11202284 DOI: 10.3390/biom14060622] [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: 04/09/2024] [Revised: 05/15/2024] [Accepted: 05/22/2024] [Indexed: 06/28/2024] Open
Abstract
Mesenchymal stem/stromal cell-derived small extracellular vesicles (MSC-sEVs) are promising therapeutic agents. In this study, we investigated how the administration route of MSC-sEVs affects their therapeutic efficacy in a mouse model of bleomycin (BLM)-induced skin scleroderma (SSc). We evaluated the impact of topical (TOP), subcutaneous (SC), and intraperitoneal (IP) administration of MSC-sEVs on dermal fibrosis, collagen density, and thickness. All three routes of administration significantly reduced BLM-induced fibrosis in the skin, as determined by Masson's Trichrome staining. However, only TOP administration reduced BLM-induced dermal collagen density, with no effect on dermal thickness observed for all administration routes. Moreover, SC, but not TOP or IP administration, increased anti-inflammatory profibrotic CD163+ M2 macrophages. These findings indicate that the administration route influences the therapeutic efficacy of MSC-sEVs in alleviating dermal fibrosis, with TOP administration being the most effective, and this efficacy is not mediated by M2 macrophages. Since both TOP and SC administration target the skin, the difference in their efficacy likely stems from variations in MSC-sEV delivery in the skin. Fluorescence-labelled TOP, but not SC MSC-sEVs when applied to skin explant cultures, localized in the stratum corneum. Hence, the superior efficacy of TOP over SC MSC-sEVs could be attributed to this localization. A comparison of the proteomes of stratum corneum and MSC-sEVs revealed the presence of >100 common proteins. Most of these proteins, such as filaggrin, were known to be crucial for maintaining skin barrier function against irritants and toxins, thereby mitigating inflammation-induced fibrosis. Therefore, the superior efficacy of TOP MSC-sEVs over SC and IP MSC-sEVs against SSc is mediated by the delivery of proteins to the stratum corneum to reinforce the skin barrier.
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Affiliation(s)
- Bin Zhang
- Paracrine Therapeutics Pte. Ltd., 1 Tai Seng Ave, #02-04 Tai Seng Exchange, Singapore 536464, Singapore; (B.Z.); (R.C.L.); (W.K.S.); (T.T.T.)
| | - Ruenn Chai Lai
- Paracrine Therapeutics Pte. Ltd., 1 Tai Seng Ave, #02-04 Tai Seng Exchange, Singapore 536464, Singapore; (B.Z.); (R.C.L.); (W.K.S.); (T.T.T.)
| | - Wei Kian Sim
- Paracrine Therapeutics Pte. Ltd., 1 Tai Seng Ave, #02-04 Tai Seng Exchange, Singapore 536464, Singapore; (B.Z.); (R.C.L.); (W.K.S.); (T.T.T.)
| | - Thong Teck Tan
- Paracrine Therapeutics Pte. Ltd., 1 Tai Seng Ave, #02-04 Tai Seng Exchange, Singapore 536464, Singapore; (B.Z.); (R.C.L.); (W.K.S.); (T.T.T.)
| | - Sai Kiang Lim
- Paracrine Therapeutics Pte. Ltd., 1 Tai Seng Ave, #02-04 Tai Seng Exchange, Singapore 536464, Singapore; (B.Z.); (R.C.L.); (W.K.S.); (T.T.T.)
- Department of Surgery, YLL School of Medicine, National University Singapore (NUS), 5 Lower Kent Ridge Road, Singapore 119074, Singapore
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Wang Y, Liu X, Wang B, Sun H, Ren Y, Zhang H. Compounding engineered mesenchymal stem cell-derived exosomes: A potential rescue strategy for retinal degeneration. Biomed Pharmacother 2024; 173:116424. [PMID: 38471273 DOI: 10.1016/j.biopha.2024.116424] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2024] [Revised: 02/28/2024] [Accepted: 03/08/2024] [Indexed: 03/14/2024] Open
Abstract
The prevalence of retinal degenerative diseases, including age-related macular degeneration and retinitis pigmentosa, has been increasing globally and is linked to the aging population and improved life expectancy. These diseases are characterized by chronic, progressive neuronal damage or depletion of the photoreceptor cells in the retina, and limited effective treatment options are currently available. Mesenchymal stem cell-derived exosomes (MSC-EXOs) containing cytokines, growth factors, lipids, mRNA, and miRNA, which act as mediators of intercellular communication transferring bioactive molecules to recipient cells, offer an appealing, non-cellular nanotherapeutic approach for retinal degenerative diseases. However, treatment specificity is compromised due to their high heterogeneity in size, content, functional effects, and parental cellular source. To improve this, engineered MSC-EXOs with increased drug-loading capacity, targeting ability, and resistance to bodily degradation and elimination have been developed. This review summarizes the recent advances in miRNAs of MSC-EXOs as a treatment for retinal degeneration, discussing the strategies and methods for engineering therapeutic MSC-EXOs. Notably, to address the single functional role of engineered MSC-EXOs, we propose a novel concept called "Compound Engineered MSC-EXOs (Co-E-MSC-EXOs)" along with its derived potential therapeutic approaches. The advantages and challenges of employing Co-E-MSC-EXOs for retinal degeneration in clinical applications, as well as the strategies and issues related to them, are also highlighted.
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Affiliation(s)
- Yao Wang
- Shaanxi Provincial Clinical Research Center for Ophthalmology Diseases, the First Affiliated Hospital of Northwest University, Xi'an No.1 hospital, Xi'an, Shaanxi, China; Shaanxi Key Laboratory of Ophthalmology, Shaanxi Institute of Ophthalmology, Xi'an, Shaanxi 710002, China.
| | - Xianning Liu
- Shaanxi Provincial Clinical Research Center for Ophthalmology Diseases, the First Affiliated Hospital of Northwest University, Xi'an No.1 hospital, Xi'an, Shaanxi, China; Shaanxi Key Laboratory of Ophthalmology, Shaanxi Institute of Ophthalmology, Xi'an, Shaanxi 710002, China
| | - Bei Wang
- The College of Life Sciences, Northwest University, Xi'an, Shaanxi 710069, China
| | - Hanhan Sun
- The College of Life Sciences, Northwest University, Xi'an, Shaanxi 710069, China
| | - Yiqian Ren
- Shaanxi Provincial Clinical Research Center for Ophthalmology Diseases, the First Affiliated Hospital of Northwest University, Xi'an No.1 hospital, Xi'an, Shaanxi, China; Shaanxi Key Laboratory of Ophthalmology, Shaanxi Institute of Ophthalmology, Xi'an, Shaanxi 710002, China
| | - Hongbing Zhang
- Shaanxi Provincial Clinical Research Center for Ophthalmology Diseases, the First Affiliated Hospital of Northwest University, Xi'an No.1 hospital, Xi'an, Shaanxi, China; Shaanxi Key Laboratory of Ophthalmology, Shaanxi Institute of Ophthalmology, Xi'an, Shaanxi 710002, China.
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Padinharayil H, Varghese J, Wilson C, George A. Mesenchymal stem cell-derived exosomes: Characteristics and applications in disease pathology and management. Life Sci 2024; 342:122542. [PMID: 38428567 DOI: 10.1016/j.lfs.2024.122542] [Citation(s) in RCA: 20] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Revised: 02/25/2024] [Accepted: 02/27/2024] [Indexed: 03/03/2024]
Abstract
Mesenchymal stem cells (MSCs) possess a role in tissue regeneration and homeostasis because of inherent immunomodulatory capacity and the production of factors that encourage healing. There is substantial evidence that MSCs' therapeutic efficacy is primarily determined by their paracrine function including in cancers. Extracellular vesicles (EVs) are basic paracrine effectors of MSCs that reside in numerous bodily fluids and cell homogenates and play an important role in bidirectional communication. MSC-derived EVs (MSC-EVs) offer a wide range of potential therapeutic uses that exceed cell treatment, while maintaining protocell function and having less immunogenicity. We describe characteristics and isolation methods of MSC-EVs, and focus on their therapeutic potential describing its roles in tissue repair, anti-fibrosis, and cancer with an emphasis on the molecular mechanism and immune modulation and clinical trials. We also explain current understanding and challenges in the clinical applications of MSC-EVs as a cell free therapy.
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Affiliation(s)
- Hafiza Padinharayil
- Jubilee Centre for Medical Research, Jubilee Mission Medical College and Research Institute, Thrissur 05, Kerala, India; PG & Research Department of Zoology, St. Thomas College, Kozhencherry, Pathanamthitta, Kerala 689641, India
| | - Jinsu Varghese
- PG & Research Department of Zoology, St. Thomas College, Kozhencherry, Pathanamthitta, Kerala 689641, India
| | - Cornelia Wilson
- Canterbury Christ Church University, Natural Applied Sciences, Life Science Industry Liaison Lab, Discovery Park, Sandwich CT139FF, United Kingdom.
| | - Alex George
- Jubilee Centre for Medical Research, Jubilee Mission Medical College and Research Institute, Thrissur 05, Kerala, India.
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Makarczyk MJ. Cell Therapy Approaches for Articular Cartilage Regeneration. Organogenesis 2023; 19:2278235. [PMID: 37963189 PMCID: PMC10898818 DOI: 10.1080/15476278.2023.2278235] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Accepted: 10/27/2023] [Indexed: 11/16/2023] Open
Abstract
Articular cartilage is a common cartilage type found in a multitude of joints throughout the human body. However, cartilage is limited in its regenerative capacity. A range of methods have been employed to aid adults under the age of 45 with cartilage defects, but other cartilage pathologies such as osteoarthritis are limited to non-steroidal anti-inflammatory drugs and total joint arthroplasty. Cell therapies and synthetic biology can be utilized to assist not only cartilage defects but have the potential as a therapeutic approach for osteoarthritis as well. In this review, we will cover current cell therapy approaches for cartilage defect regeneration with a focus on autologous chondrocyte implantation and matrix autologous chondrocyte implantation. We will then discuss the potential of stem cells for cartilage repair in osteoarthritis and the use of synthetic biology to genetically engineer cells to promote cartilage regeneration and potentially reverse osteoarthritis.
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Affiliation(s)
- Meagan J Makarczyk
- Department of Bioengineering, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
- Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
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da Silva AV, Serrenho I, Araújo B, Carvalho AM, Baltazar G. Secretome as a Tool to Treat Neurological Conditions: Are We Ready? Int J Mol Sci 2023; 24:16544. [PMID: 38003733 PMCID: PMC10671352 DOI: 10.3390/ijms242216544] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2023] [Revised: 11/04/2023] [Accepted: 11/17/2023] [Indexed: 11/26/2023] Open
Abstract
Due to their characteristics, mesenchymal stem cells (MSCs) are considered a potential therapy for brain tissue injury or degeneration. Nevertheless, despite the promising results observed, there has been a growing interest in the use of cell-free therapies in regenerative medicine, such as the use of stem cell secretome. This review provides an in-depth compilation of data regarding the secretome composition, protocols used for its preparation, as well as existing information on the impact of secretome administration on various brain conditions, pointing out gaps and highlighting relevant findings. Moreover, due to the ability of MSCs to respond differently depending on their microenvironment, preconditioning of MSCs has been used to modulate their composition and, consequently, their therapeutic potential. The different strategies used to modulate the MSC secretome were also reviewed. Although secretome administration was effective in improving functional impairments, regeneration, neuroprotection, and reducing inflammation in brain tissue, a high variability in secretome preparation and administration was identified, compromising the transposition of preclinical data to clinical studies. Indeed, there are no reports of the use of secretome in clinical trials. Despite the existing limitations and lack of clinical data, secretome administration is a potential tool for the treatment of various diseases that impact the CNS.
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Affiliation(s)
- Andreia Valente da Silva
- Health Sciences Research Center (CICS-UBI), University of Beira Interior, 6201-506 Covilhã, Portugal
| | - Inês Serrenho
- Health Sciences Research Center (CICS-UBI), University of Beira Interior, 6201-506 Covilhã, Portugal
- Center for Neuroscience and Cell Biology (CNC-UC), University of Coimbra, 3004-504 Coimbra, Portugal
| | - Beatriz Araújo
- Health Sciences Research Center (CICS-UBI), University of Beira Interior, 6201-506 Covilhã, Portugal
| | | | - Graça Baltazar
- Health Sciences Research Center (CICS-UBI), University of Beira Interior, 6201-506 Covilhã, Portugal
- Faculty of Health Sciences, University of Beira Interior, 6201-506 Covilhã, Portugal
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Székiová E, Michalová Z, Blaško J, Mucha R, Slovinská L, Kello M, Vanický I. Characterisation of mesenchymal stem cells conditioned media obtained at different conditioning times: their effect on glial cells in in vitro scratch model. Growth Factors 2023; 41:57-70. [PMID: 36825505 DOI: 10.1080/08977194.2023.2182145] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Accepted: 02/07/2023] [Indexed: 02/25/2023]
Abstract
In this study, the bone marrow mesenchymal stem cells conditioned media (BMMSC-CM) obtained by conditioning for 24(CM24), 48(CM48) and 72(CM72) hours was characterised. In vitro, the impact of BMMSC-CM on the astrocyte migratory response and oligodendrocyte density was evaluated using the scratch model. The proteomic profiles of individual secretomes were analysed by mass spectrometry and the concentrations of four selected neurotrophins (BDNF, NGF, GDNF and VEGF) were determined by ELISA. Our results revealed an increased number of proteins at CM72, many of which are involved in neuroregenerative processes. ELISA documented a gradual increase in the concentration of two neurotrophins (NGF, VEGF), peaking at CM72. In vitro, the different effect of individual BMMSC-CM on astrocyte migration response and oligodendrocyte density was observed, most pronounced with CM72. The outcomes demonstrate that the prolonged conditioning results in increased release of detectable proteins, neurotrophic factors concentration and stronger effect on reparative processes in neural cell cultures.
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Affiliation(s)
- Eva Székiová
- Department of Regenerative Medicine and Cell Therapy, Institute of Neurobiology Biomedical Research Center, Slovak Academy of Sciences, Košice, Slovakia
| | - Zuzana Michalová
- Department of Regenerative Medicine and Cell Therapy, Institute of Neurobiology Biomedical Research Center, Slovak Academy of Sciences, Košice, Slovakia
| | - Juraj Blaško
- Department of Regenerative Medicine and Cell Therapy, Institute of Neurobiology Biomedical Research Center, Slovak Academy of Sciences, Košice, Slovakia
| | - Rastislav Mucha
- Department of Regenerative Medicine and Cell Therapy, Institute of Neurobiology Biomedical Research Center, Slovak Academy of Sciences, Košice, Slovakia
| | - Lucia Slovinská
- Department of Regenerative Medicine and Cell Therapy, Institute of Neurobiology Biomedical Research Center, Slovak Academy of Sciences, Košice, Slovakia
- Associated Tissue Bank, P. J. Šafárik University and L. Pasteur University Hospital, Košice, Slovakia
| | - Martin Kello
- Department of Pharmacology, P. J. Šafárik University, Košice, Slovakia
| | - Ivo Vanický
- Department of Regenerative Medicine and Cell Therapy, Institute of Neurobiology Biomedical Research Center, Slovak Academy of Sciences, Košice, Slovakia
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Ortiz GGR, Zaidi NH, Saini RS, Ramirez Coronel AA, Alsandook T, Hadi Lafta M, Arias-Gonzáles JL, Amin AH, Maaliw Iii RR. The developing role of extracellular vesicles in autoimmune diseases: special attention to mesenchymal stem cell-derived extracellular vesicles. Int Immunopharmacol 2023; 122:110531. [PMID: 37437434 DOI: 10.1016/j.intimp.2023.110531] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Revised: 06/10/2023] [Accepted: 06/16/2023] [Indexed: 07/14/2023]
Abstract
Autoimmune diseases are complex, chronic inflammatory conditions initiated by the loss of immunological tolerance to self-antigens. Nowadays, there is no effective and useful therapy for autoimmune diseases, and the existing medications have some limitations due to their nonspecific targets and side effects. During the last few decades, it has been established that mesenchymal stem cells (MSCs) have immunomodulatory functions. It is proposed that MSCs can exert an important therapeutic effect on autoimmune disorders. In parallel with these findings, several investigations have shown that MSCs alleviate autoimmune diseases. Intriguingly, the results of studies have demonstrated that the effective roles of MSCs in autoimmune diseases do not depend on direct intercellular communication but on their ability to release a wide spectrum of paracrine mediators such as growth factors, cytokines and extracellular vehicles (EVs). EVs that range from 50 to 5,000 nm were produced by almost any cell type, and these nanoparticles participate in homeostasis and intercellular communication via the transfer of a broad range of biomolecules such as modulatory proteins, nucleic acids (DNA and RNA), lipids, cytokines, and metabolites. EVs derived from MSCs display the exact properties of MSCs and can be safer and more beneficial than their parent cells. In this review, we will discuss the features of MSCs and their EVs, EVs biogenesis, and their cargos, and then we will highlight the existing discoveries on the impacts of EVs from MSCs on autoimmune diseases such as multiple sclerosis, arthritis rheumatic, inflammatory bowel disease, Type 1 diabetes mellitus, systemic lupus erythematosus, autoimmune liver diseases, Sjögren syndrome, and osteoarthritis, suggesting a potential alternative for autoimmune conditions therapy.
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Affiliation(s)
- Geovanny Genaro Reivan Ortiz
- Laboratory of Basic Psychology, Behavioral Analysis and Programmatic Development (PAD-LAB), Catholic University of Cuenca, Cuenca, Ecuador
| | - Neelam Hazoor Zaidi
- Umanand Prasad School of Medicine and Health Science, The University of Fiji, Saweni Campus, Lautoka, Fiji
| | | | | | - Tahani Alsandook
- Dentistry Department, Al-Turath University College, Baghdad, Iraq
| | | | | | - Ali H Amin
- Zoology Department, Faculty of Science, Mansoura University, Mansoura 35516, Egypt
| | - Renato R Maaliw Iii
- College of Engineering, Southern Luzon State University, Lucban, Quezon, Philippines.
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12
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Shi J, Teo KYW, Zhang S, Lai RC, Rosa V, Tong HJ, Duggal MS, Lim SK, Toh WS. Mesenchymal stromal cell exosomes enhance dental pulp cell functions and promote pulp-dentin regeneration. BIOMATERIALS AND BIOSYSTEMS 2023; 11:100078. [PMID: 37283805 PMCID: PMC10239699 DOI: 10.1016/j.bbiosy.2023.100078] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2023] [Revised: 05/23/2023] [Accepted: 05/26/2023] [Indexed: 06/08/2023] Open
Abstract
Mesenchymal stromal/stem cell (MSC) therapies are currently being explored for dental pulp regeneration. As the therapeutic effects of MSCs in tissue repair are mediated mainly through the release of extracellular vesicles (EVs) including exosomes, we investigated here the cellular processes and molecular mechanisms modulated by MSC exosomes in dental pulp regeneration. Using dental pulp cell (DPC) cultures, we demonstrated that MSC exosomes could increase DPC migration, proliferation, and odontogenic differentiation. The enhancement of these cellular processes was mediated through exosomal CD73-mediated adenosine receptor activation of AKT and ERK signaling. Consistent with these observations, MSC exosomes increased the expression of dentin matrix proteins and promoted the formation of dentin-like tissue and bridge-like structures in a rat pulp defect model. These effects were comparable to that of mineral trioxide aggregate (MTA) treatment. MSC exosomes also yielded recellularized pulp-dentin tissues in the root canal of endodontically-treated human premolars, following subcutaneous implantation in the mouse dorsum. Together, our findings suggest that MSC exosomes could exert a multi-faceted effect on DPC functions including migration, proliferation and odontogenic differentiation to promote dental pulp regeneration. This study provides the basis for development of MSC exosomes as a cell-free MSC therapeutic alternative for pulp-dentin regeneration.
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Affiliation(s)
- Jiajun Shi
- Faculty of Dentistry, National University of Singapore, Singapore
| | | | - Shipin Zhang
- Faculty of Dentistry, National University of Singapore, Singapore
| | - Ruenn Chai Lai
- Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore
| | - Vinicius Rosa
- Faculty of Dentistry, National University of Singapore, Singapore
- Oral Care Health Innovations and Designs Singapore, National University of Singapore, Singapore
| | - Huei Jinn Tong
- Faculty of Dentistry, National University of Singapore, Singapore
| | | | - Sai Kiang Lim
- Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore
| | - Wei Seong Toh
- Faculty of Dentistry, National University of Singapore, Singapore
- Department of Orthopaedic Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
- Department of Biomedical Engineering, Faculty of Engineering, National University of Singapore, Singapore
- Tissue Engineering Program, Life Sciences Institute, National University of Singapore, Singapore
- Integrative Sciences and Engineering Program, NUS Graduate School, National University of Singapore, Singapore
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Kim H, Goh YS, Park SE, Hwang J, Kang N, Jung JS, Kim YB, Choi EK, Park KM. Preventive Effects of Exosome-Rich Conditioned Medium From Amniotic Membrane-Derived Mesenchymal Stem Cells for Diabetic Retinopathy in Rats. Transl Vis Sci Technol 2023; 12:18. [PMID: 37610767 PMCID: PMC10461646 DOI: 10.1167/tvst.12.8.18] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2023] [Accepted: 07/22/2023] [Indexed: 08/24/2023] Open
Abstract
PURPOSE Diabetic retinopathy (DR) is an important disease that causes vision loss in many diabetic patients. Stem cell therapy has been attempted for treatment of this disease; however, it has some limitations. This study aimed to evaluate the preventive efficacy of exosome-rich conditioned medium (ERCM) derived from amniotic membrane stem cells for DR in rats. METHODS Twenty-eight 8-week-old male Sprague-Dawley rats were divided into three groups: group 1, normal control (Con) group; group 2, diabetes mellitus (DM) group; and group 3, DM with ERCM-treated (DM-ERCM) group. DM was induced by intraperitoneal injection of streptozotocin. The DM-ERCM group received ERCM containing 1.2 × 10⁹ exosomes into subconjunctival a total of four times every 2 weeks. RESULTS On electroretinogram, the DM-ERCM group had significantly higher b-wave and flicker amplitudes than those in the DM group. In fundoscopy, retinal vascular attenuation was found in both the DM and DM-ERCM groups; however, was more severe in the DM group. On histology, the ganglion cell and nerve fiber layer rates of the total retinal layer significantly increased in the DM group compared with the Con group, whereas the DM-ERCM group showed no significant difference compared with the Con group. Cataracts progressed significantly more in the DM group than that in the DM-ERCM group and there was no uveitis in the DM-ERCM group. CONCLUSIONS Subconjunctival ERCM delayed the progression of DR and cataracts and significantly reduced the incidence of uveitis. TRANSLATIONAL RELEVANCE Our study shows the clinical potential of minimally invasive exosome-rich conditioned medium treatment to prevent diabetic retinopathy.
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Affiliation(s)
- Hyemin Kim
- Laboratory of Veterinary Surgery and Ophthalmology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Korea
| | - Yeong-Seok Goh
- Laboratory of Veterinary Surgery and Ophthalmology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Korea
| | - Sang-Eun Park
- Laboratory of Veterinary Surgery and Ophthalmology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Korea
| | - Jiyi Hwang
- Laboratory of Veterinary Surgery and Ophthalmology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Korea
| | - Nanyoung Kang
- Laboratory of Veterinary Surgery and Ophthalmology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Korea
| | - Ji Seung Jung
- Laboratory of Veterinary Surgery and Ophthalmology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Korea
| | - Yun-Bae Kim
- Laboratory of Toxicology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Korea
- Central Research Institute, Designed Cells Co., Ltd., Cheongju, Korea
| | - Ehn-Kyoung Choi
- Central Research Institute, Designed Cells Co., Ltd., Cheongju, Korea
| | - Kyung-Mee Park
- Laboratory of Veterinary Surgery and Ophthalmology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Korea
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Li J, Yin Y, Zou J, Zhang E, Li Q, Chen L, Li J. The adipose-derived stem cell peptide ADSCP2 alleviates hypertrophic scar fibrosis via binding with pyruvate carboxylase and remodeling the metabolic landscape. Acta Physiol (Oxf) 2023; 238:e14010. [PMID: 37366253 DOI: 10.1111/apha.14010] [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: 03/28/2023] [Revised: 05/29/2023] [Accepted: 06/04/2023] [Indexed: 06/28/2023]
Abstract
AIM The purpose of this study was to investigate the function and mechanism of a novel peptide derived from adipose-derived stem cell-conditioned medium (ADSC-CM). METHODS Mass spectrometry was applied to identify expressed peptides in ADSC-CM obtained at different time points. The cell counting kit-8 assay and quantitative reverse transcription polymerase chain reactions were performed to screen the functional peptides contained within ADSC-CM. RNA-seq, western blot, a back skin excisional model of BALB/c mice, the peptide pull-down assay, rescue experiments, untargeted metabolomics, and mixOmics analysis were performed to thoroughly understand the functional mechanism of selected peptide. RESULTS A total of 93, 827, 1108, and 631 peptides were identified in ADSC-CM at 0, 24, 48, and 72 h of conditioning, respectively. A peptide named ADSCP2 (DENREKVNDQAKL) derived from ADSC-CM inhibited collagen and ACTA2 mRNAs in hypertrophic scar fibroblasts. Moreover, ADSCP2 facilitated wound healing and attenuated collagen deposition in a mouse model. ADSCP2 bound with the pyruvate carboxylase (PC) protein and inhibited PC protein expression. Overexpressing PC rescued the reduction in collagen and ACTA2 mRNAs caused by ADSCP2. Untargeted metabolomics identified 258 and 447 differential metabolites in the negative and positive mode, respectively, in the ADSCP2-treated group. The mixOmics analysis, which integrated RNA-seq and untargeted metabolomics data, provided a more holistic view of the functions of ADSCP2. CONCLUSION Overall, a novel peptide derived from ADSC-CM, named ADSCP2, attenuated hypertrophic scar fibrosis in vitro and in vivo, and the novel peptide ADSCP2 might be a promising drug candidate for clinical scar therapy.
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Affiliation(s)
- Jingyun Li
- Nanjing Maternal and Child Health Medical Institute, Women's Hospital of Nanjing Medical University (Nanjing Maternity and Child Health Care Hospital), Nanjing, China
| | - Yiliang Yin
- Department of Plastic & Cosmetic Surgery, Women's Hospital of Nanjing Medical University (Nanjing Maternity and Child Health Care Hospital), Nanjing, China
| | - Jijun Zou
- Department of Burns and Plastic Surgery, Children's Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Enyuan Zhang
- Department of Plastic & Cosmetic Surgery, Women's Hospital of Nanjing Medical University (Nanjing Maternity and Child Health Care Hospital), Nanjing, China
| | - Qian Li
- Department of Plastic & Cosmetic Surgery, Women's Hospital of Nanjing Medical University (Nanjing Maternity and Child Health Care Hospital), Nanjing, China
| | - Ling Chen
- Department of Plastic & Cosmetic Surgery, Women's Hospital of Nanjing Medical University (Nanjing Maternity and Child Health Care Hospital), Nanjing, China
| | - Jun Li
- Department of Plastic & Cosmetic Surgery, Women's Hospital of Nanjing Medical University (Nanjing Maternity and Child Health Care Hospital), Nanjing, China
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15
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Teo KYW, Zhang S, Loh JT, Lai RC, Hey HWD, Lam KP, Lim SK, Toh WS. Mesenchymal Stromal Cell Exosomes Mediate M2-like Macrophage Polarization through CD73/Ecto-5'-Nucleotidase Activity. Pharmaceutics 2023; 15:pharmaceutics15051489. [PMID: 37242732 DOI: 10.3390/pharmaceutics15051489] [Citation(s) in RCA: 25] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Revised: 05/06/2023] [Accepted: 05/10/2023] [Indexed: 05/28/2023] Open
Abstract
Mesenchymal stem/stromal cell (MSC) exosomes have been shown to alleviate immune dysfunction and inflammation in preclinical animal models. This therapeutic effect is attributed, in part, to their ability to promote the polarization of anti-inflammatory M2-like macrophages. One polarization mechanism has been shown to involve the activation of the MyD88-mediated toll-like receptor (TLR) signaling pathway by the presence of extra domain A-fibronectin (EDA-FN) within the MSC exosomes. Here, we uncovered an additional mechanism where MSC exosomes mediate M2-like macrophage polarization through exosomal CD73 activity. Specifically, we observed that polarization of M2-like macrophages by MSC exosomes was abolished in the presence of inhibitors of CD73 activity, adenosine receptors A2A and A2B, and AKT/ERK phosphorylation. These findings suggest that MSC exosomes promote M2-like macrophage polarization by catalyzing the production of adenosine, which then binds to adenosine receptors A2A and A2B to activate AKT/ERK-dependent signaling pathways. Thus, CD73 represents an additional critical attribute of MSC exosomes in mediating M2-like macrophage polarization. These findings have implications for predicting the immunomodulatory potency of MSC exosome preparations.
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Affiliation(s)
- Kristeen Ye Wen Teo
- Department of Orthopaedic Surgery, Yong Loo Lin School of Medicine, National University of Singapore, 1E Kent Ridge Road, Singapore 119228, Singapore
- Faculty of Dentistry, National University of Singapore, 9 Lower Kent Ridge Road, Singapore 119085, Singapore
| | - Shipin Zhang
- Department of Orthopaedic Surgery, Yong Loo Lin School of Medicine, National University of Singapore, 1E Kent Ridge Road, Singapore 119228, Singapore
- Faculty of Dentistry, National University of Singapore, 9 Lower Kent Ridge Road, Singapore 119085, Singapore
| | - Jia Tong Loh
- Singapore Immunology Network, Agency for Science, Technology and Research (A*STAR), 8A Biomedical Grove, Singapore 138648, Singapore
| | - Ruenn Chai Lai
- Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Proteos, Singapore 138673, Singapore
| | - Hwee Weng Dennis Hey
- Department of Orthopaedic Surgery, Yong Loo Lin School of Medicine, National University of Singapore, 1E Kent Ridge Road, Singapore 119228, Singapore
| | - Kong-Peng Lam
- Singapore Immunology Network, Agency for Science, Technology and Research (A*STAR), 8A Biomedical Grove, Singapore 138648, Singapore
| | - Sai Kiang Lim
- Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Proteos, Singapore 138673, Singapore
| | - Wei Seong Toh
- Department of Orthopaedic Surgery, Yong Loo Lin School of Medicine, National University of Singapore, 1E Kent Ridge Road, Singapore 119228, Singapore
- Faculty of Dentistry, National University of Singapore, 9 Lower Kent Ridge Road, Singapore 119085, Singapore
- Tissue Engineering Program, Life Sciences Institute, National University of Singapore, 27 Medical Drive, Singapore 117510, Singapore
- Integrative Sciences and Engineering Program, NUS Graduate School, National University of Singapore, 21 Lower Kent Ridge Road, Singapore 119077, Singapore
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16
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Zhang B, Zhang B, Lai RC, Sim WK, Lam KP, Lim SK. MSC-sEV Treatment Polarizes Pro-Fibrotic M2 Macrophages without Exacerbating Liver Fibrosis in NASH. Int J Mol Sci 2023; 24:ijms24098092. [PMID: 37175803 PMCID: PMC10179074 DOI: 10.3390/ijms24098092] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Revised: 04/20/2023] [Accepted: 04/21/2023] [Indexed: 05/15/2023] Open
Abstract
Mesenchymal stem/stromal cell small extracellular vesicles (MSC-sEVs) have shown promise in treating a wide range of animal models of various human diseases, which has led to their consideration for clinical translation. However, the possibility of contraindication for MSC-sEV use is an important consideration. One concern is that MSC-sEVs have been shown to induce M2 macrophage polarization, which is known to be pro-fibrotic, potentially indicating contraindication in fibrotic diseases such as liver fibrosis. Despite this concern, previous studies have shown that MSC-sEVs alleviate high-fat diet (HFD)-induced non-alcoholic steatohepatitis (NASH). To assess whether the pro-fibrotic M2 macrophage polarization induced by MSC-sEVs could worsen liver fibrosis, we first verified that our MSC-sEV preparations could promote M2 polarization in vitro prior to their administration in a mouse model of NASH. Our results showed that treatment with MSC-sEVs reduced or had comparable NAFLD Activity Scores and liver fibrosis compared to vehicle- and Telmisartan-treated animals, respectively. Although CD163+ M2 macrophages were increased in the liver, and serum IL-6 levels were reduced in MSC-sEV treated animals, our data suggests that MSC-sEV treatment was efficacious in reducing liver fibrosis in a mouse model of NASH despite an increase in pro-fibrotic M2 macrophage polarization.
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Affiliation(s)
- Bin Zhang
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Proteos, Singapore 138673, Singapore
| | - Biyan Zhang
- Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), 8A Biomedical Grove, Immunos, Singapore 138648, Singapore
| | - Ruenn Chai Lai
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Proteos, Singapore 138673, Singapore
| | - Wei Kian Sim
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Proteos, Singapore 138673, Singapore
| | - Kong Peng Lam
- Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), 8A Biomedical Grove, Immunos, Singapore 138648, Singapore
- Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, 5 Science Drive 2, Singapore 117545, Singapore
- School of Biological Sciences, College of Science, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Singapore
| | - Sai Kiang Lim
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Proteos, Singapore 138673, Singapore
- Department of Surgery, YLL School of Medicine, NUS, 5 Lower Kent Ridge Road, Singapore 119074, Singapore
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17
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Ong HS, Riau AK, Yam GHF, Yusoff NZBM, Han EJY, Goh TW, Lai RC, Lim SK, Mehta JS. Mesenchymal Stem Cell Exosomes as Immunomodulatory Therapy for Corneal Scarring. Int J Mol Sci 2023; 24:7456. [PMID: 37108619 PMCID: PMC10144287 DOI: 10.3390/ijms24087456] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2023] [Revised: 04/14/2023] [Accepted: 04/15/2023] [Indexed: 04/29/2023] Open
Abstract
Corneal scarring is a leading cause of worldwide blindness. Human mesenchymal stem cells (MSC) have been reported to promote corneal wound healing through secreted exosomes. This study investigated the wound healing and immunomodulatory effects of MSC-derived exosomes (MSC-exo) in corneal injury through an established rat model of corneal scarring. After induction of corneal scarring by irregular phototherapeutic keratectomy (irrPTK), MSC exosome preparations (MSC-exo) or PBS vehicle as controls were applied to the injured rat corneas for five days. The animals were assessed for corneal clarity using a validated slit-lamp haze grading score. Stromal haze intensity was quantified using in-vivo confocal microscopy imaging. Corneal vascularization, fibrosis, variations in macrophage phenotypes, and inflammatory cytokines were evaluated using immunohistochemistry techniques and enzyme-linked immunosorbent assays (ELISA) of the excised corneas. Compared to the PBS control group, MSC-exo treatment group had faster epithelial wound closure (0.041), lower corneal haze score (p = 0.002), and reduced haze intensity (p = 0.004) throughout the follow-up period. Attenuation of corneal vascularisation based on CD31 and LYVE-1 staining and reduced fibrosis as measured by fibronectin and collagen 3A1 staining was also observed in the MSC-exo group. MSC-exo treated corneas also displayed a regenerative immune phenotype characterized by a higher infiltration of CD163+, CD206+ M2 macrophages over CD80+, CD86+ M1 macrophages (p = 0.023), reduced levels of pro-inflammatory IL-1β, IL-8, and TNF-α, and increased levels of anti-inflammatory IL-10. In conclusion, topical MSC-exo could alleviate corneal insults by promoting wound closure and reducing scar development, possibly through anti-angiogenesis and immunomodulation towards a regenerative and anti-inflammatory phenotype.
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Affiliation(s)
- Hon Shing Ong
- Tissue Engineering and Cell Therapy Group, Singapore Eye Research Institute, Singapore 169856, Singapore
- Ophthalmology and Visual Sciences Academic Clinical Program, Duke-NUS Medical School, Singapore 169857, Singapore
- Corneal and External Diseases Department, Singapore National Eye Centre, Singapore 168751, Singapore
| | - Andri K. Riau
- Tissue Engineering and Cell Therapy Group, Singapore Eye Research Institute, Singapore 169856, Singapore
- Ophthalmology and Visual Sciences Academic Clinical Program, Duke-NUS Medical School, Singapore 169857, Singapore
| | - Gary Hin-Fai Yam
- Tissue Engineering and Cell Therapy Group, Singapore Eye Research Institute, Singapore 169856, Singapore
- Department of Ophthalmology, University of Pittsburgh, Pittsburgh, PA 15213, USA
| | | | - Evelina J. Y. Han
- Tissue Engineering and Cell Therapy Group, Singapore Eye Research Institute, Singapore 169856, Singapore
| | - Tze-Wei Goh
- Tissue Engineering and Cell Therapy Group, Singapore Eye Research Institute, Singapore 169856, Singapore
| | - Ruenn Chai Lai
- Institute of Medical Biology & Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore 138648, Singapore
| | - Sai Kiang Lim
- Institute of Medical Biology & Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore 138648, Singapore
| | - Jodhbir S. Mehta
- Tissue Engineering and Cell Therapy Group, Singapore Eye Research Institute, Singapore 169856, Singapore
- Ophthalmology and Visual Sciences Academic Clinical Program, Duke-NUS Medical School, Singapore 169857, Singapore
- Corneal and External Diseases Department, Singapore National Eye Centre, Singapore 168751, Singapore
- School of Materials Science and Engineering, Nanyang Technological University, Singapore 639798, Singapore
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18
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Feng Z, Su X, Wang T, Sun X, Yang H, Guo S. The Role of Microsphere Structures in Bottom-Up Bone Tissue Engineering. Pharmaceutics 2023; 15:pharmaceutics15020321. [PMID: 36839645 PMCID: PMC9964570 DOI: 10.3390/pharmaceutics15020321] [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: 11/17/2022] [Revised: 01/04/2023] [Accepted: 01/12/2023] [Indexed: 01/20/2023] Open
Abstract
Bone defects have caused immense healthcare concerns and economic burdens throughout the world. Traditional autologous allogeneic bone grafts have many drawbacks, so the emergence of bone tissue engineering brings new hope. Bone tissue engineering is an interdisciplinary biomedical engineering method that involves scaffold materials, seed cells, and "growth factors". However, the traditional construction approach is not flexible and is unable to adapt to the specific shape of the defect, causing the cells inside the bone to be unable to receive adequate nourishment. Therefore, a simple but effective solution using the "bottom-up" method is proposed. Microspheres are structures with diameters ranging from 1 to 1000 µm that can be used as supports for cell growth, either in the form of a scaffold or in the form of a drug delivery system. Herein, we address a variety of strategies for the production of microspheres, the classification of raw materials, and drug loading, as well as analyze new strategies for the use of microspheres in bone tissue engineering. We also consider new perspectives and possible directions for future development.
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Affiliation(s)
- Ziyi Feng
- Department of Plastic Surgery, The First Hospital of China Medical University, No. 155, Nanjing North Street, Heping District, Shenyang 110002, China; (Z.F.); (X.S.); (T.W.)
| | - Xin Su
- Department of Plastic Surgery, The First Hospital of China Medical University, No. 155, Nanjing North Street, Heping District, Shenyang 110002, China; (Z.F.); (X.S.); (T.W.)
| | - Ting Wang
- Department of Plastic Surgery, The First Hospital of China Medical University, No. 155, Nanjing North Street, Heping District, Shenyang 110002, China; (Z.F.); (X.S.); (T.W.)
| | - Xiaoting Sun
- School of Forensic Medicine, China Medical University, No. 77, Puhe Road, Shenyang 110122, China
- Correspondence: (X.S.); (S.G.)
| | - Huazhe Yang
- School of Intelligent Medicine, China Medical University, No. 77, Puhe Road, Shenyang 110122, China;
| | - Shu Guo
- Department of Plastic Surgery, The First Hospital of China Medical University, No. 155, Nanjing North Street, Heping District, Shenyang 110002, China; (Z.F.); (X.S.); (T.W.)
- Correspondence: (X.S.); (S.G.)
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19
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Sharun K, Muthu S, Mankuzhy PD, Pawde AM, Chandra V, Lorenzo JM, Dhama K, Amarpal, Sharma GT. Cell-free therapy for canine osteoarthritis: current evidence and prospects. Vet Q 2022; 42:224-230. [PMID: 36336651 PMCID: PMC9673808 DOI: 10.1080/01652176.2022.2145620] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Revised: 10/18/2022] [Accepted: 11/06/2022] [Indexed: 11/09/2022] Open
Abstract
Osteoarthritis is a progressive degenerative disease affecting joints. It is associated with structural and functional changes that cause lameness and pain in dogs. Mesenchymal stem cells (MSCs) are considered an ideal therapeutic candidate for treating inflammatory musculoskeletal conditions due to their paracrine and immunomodulatory characteristics. They are delivered intravenously or as intra-articular injections for treating canine osteoarthritis. However, ex vivo studies have confirmed that the osteoarthritic synovial fluid is cytotoxic to cultured MSCs. Therefore, intra-articular transplantation of viable MSCs should be considered counterproductive since it minimizes cellular viability. Similarly, the intravenous administration of MSCs limits the therapeutic effects on the organ of interest since most of the administered cells get trapped in the lungs. Therefore, cell-free therapeutic strategies such as conditioned media and extracellular vesicles (EVs) can potentially become the future of MSC-based therapy in managing canine osteoarthritis. It overcomes the limitations of MSC-based therapy, such as tumor differentiation, immunogenicity, and pulmonary embolization, and has advantages like low immunogenicity and off-shelf availability. In addition, they eliminate problems such as low cell survival, transmission of infections, and unpredictable behavior of the transplanted MSCs, thereby acting as a safe alternative to cell-based therapeutics. However, very limited data is available on the efficacy and safety of cell-free therapy using MSCs for managing canine osteoarthritis. Therefore, large-scale, multicentric, randomized clinical controlled trials are required to establish the therapeutic efficacy and safety of MSC-based cell-free therapy in clinical cases of canine osteoarthritis.
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Affiliation(s)
- Khan Sharun
- Division of Surgery, ICAR-Indian Veterinary Research Institute, Bareilly, India
| | - Sathish Muthu
- Department of Biotechnology, School of Engineering and Technology, Sharda University, Greater Noida, India
- Orthopaedic Research Group, Coimbatore, India
- Department of Orthopedics, Government Medical College and Hospital, Dindigul, India
| | - Pratheesh D. Mankuzhy
- Department of Physiology, Kerala Veterinary and Animal Sciences University, Pookode, India
| | - Abhijit M. Pawde
- Division of Surgery, ICAR-Indian Veterinary Research Institute, Bareilly, India
| | - Vikash Chandra
- Division of Physiology and Climatology, ICAR-Indian Veterinary Research Institute, Bareilly, India
| | - Jose M. Lorenzo
- Centro Tecnológico de la Carne de Galicia, Adva. Galicia n° 4, Parque Tecnológico de Galicia, Ourense, Spain
- Área de Tecnoloxía dos Alimentos, Facultade de Ciencias de Ourense, Universidade de Vigo, Ourense, Spain
| | - Kuldeep Dhama
- Division of Pathology, ICAR-Indian Veterinary Research Institute, Bareilly, India
| | - Amarpal
- Division of Surgery, ICAR-Indian Veterinary Research Institute, Bareilly, India
| | - G. Taru Sharma
- National Institute of Animal Biotechnology, Hyderabad, India
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Shephard MT, Merkhan MM, Forsyth NR. Human Mesenchymal Stem Cell Secretome Driven T Cell Immunomodulation Is IL-10 Dependent. Int J Mol Sci 2022; 23:13596. [PMID: 36362383 PMCID: PMC9658100 DOI: 10.3390/ijms232113596] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2022] [Revised: 11/01/2022] [Accepted: 11/02/2022] [Indexed: 09/01/2023] Open
Abstract
The Human Mesenchymal Stem Cell (hMSC) secretome has pleiotropic effects underpinning its therapeutic potential. hMSC serum-free conditioned media (SFCM) contains a variety of cytokines, with previous studies linking a changed secretome composition to physoxia. The Jurkat T cell model allowed the efficacy of SFCM vs. serum-free media (SFM) in the suppression of immunological aspects, including proliferation and polarisation, to be explored. Cell growth in SFM was higher [(21% O2 = 5.3 × 105 ± 1.8 × 104 cells/mL) and (2% O2 = 5.1 × 105 ± 3.0 × 104 cells/mL)], compared to SFCM [(21% O2 = 2.4 × 105 ± 2.5 × 104 cells/mL) and (2% O2 = 2.2 × 105 ± 5.8 × 103 cells/mL)]. SFM supported IL-2 release following activation [(21% O2 = 5305 ± 211 pg/mL) and (2% O2 = 5347 ± 327 pg/mL)] whereas SFCM suppressed IL-2 secretion [(21% O2 = 2461 ± 178 pg/mL) and (2% O2 = 1625 ± 159 pg/mL)]. Anti-inflammatory cytokines, namely IL-4, IL-10, and IL-13, which we previously confirmed as components of hMSC SFCM, were tested. IL-10 neutralisation in SFCM restored proliferation in both oxygen environments (SFM/SFCM+antiIL-10 ~1-fold increase). Conversely, IL-4/IL-13 neutralisation showed no proliferation restoration [(SFM/SFM+antiIL-4 ~2-fold decrease), and (SFM/SFCM+antiIL-13 ~2-fold decrease)]. Present findings indicate IL-10 played an immunosuppressive role by reducing IL-2 secretion. Identification of immunosuppressive components of the hMSC secretome and a mechanistic understanding of their action allow for the advancement and refinement of potential future cell-free therapies.
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Affiliation(s)
- Matthew T. Shephard
- Guy Hilton Research Centre, School of Pharmacy and Bioengineering, Keele University, Staffordshire ST4 7QB, UK
| | - Marwan M. Merkhan
- Guy Hilton Research Centre, School of Pharmacy and Bioengineering, Keele University, Staffordshire ST4 7QB, UK
- Department of Pharmacology and Toxicology, College of Pharmacy, University of Mosul, Mosul 41002, Iraq
| | - Nicholas R. Forsyth
- Guy Hilton Research Centre, School of Pharmacy and Bioengineering, Keele University, Staffordshire ST4 7QB, UK
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21
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Ferreira MJS, Mancini FE, Humphreys PA, Ogene L, Buckley M, Domingos MAN, Kimber SJ. Pluripotent stem cells for skeletal tissue engineering. Crit Rev Biotechnol 2022; 42:774-793. [PMID: 34488516 DOI: 10.1080/07388551.2021.1968785] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Here, we review the use of human pluripotent stem cells for skeletal tissue engineering. A number of approaches have been used for generating cartilage and bone from both human embryonic stem cells and induced pluripotent stem cells. These range from protocols relying on intrinsic cell interactions and signals from co-cultured cells to those attempting to recapitulate the series of steps occurring during mammalian skeletal development. The importance of generating authentic tissues rather than just differentiated cells is emphasized and enabling technologies for doing this are reported. We also review the different methods for characterization of skeletal cells and constructs at the tissue and single-cell level, and indicate newer resources not yet fully utilized in this field. There have been many challenges in this research area but the technologies to overcome these are beginning to appear, often adopted from related fields. This makes it more likely that cost-effective and efficacious human pluripotent stem cell-engineered constructs may become available for skeletal repair in the near future.
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Affiliation(s)
- Miguel J S Ferreira
- Department of Mechanical, Aerospace and Civil Engineering, School of Engineering, Faculty of Science and Engineering & Henry Royce Institute, The University of Manchester, Manchester, UK
| | - Fabrizio E Mancini
- Division of Cell Matrix Biology and Regenerative Medicine, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK
| | - Paul A Humphreys
- Department of Mechanical, Aerospace and Civil Engineering, School of Engineering, Faculty of Science and Engineering & Henry Royce Institute, The University of Manchester, Manchester, UK
- Division of Cell Matrix Biology and Regenerative Medicine, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK
| | - Leona Ogene
- Division of Cell Matrix Biology and Regenerative Medicine, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK
| | - Michael Buckley
- Manchester Institute of Biotechnology, The University of Manchester, Manchester, UK
| | - Marco A N Domingos
- Department of Mechanical, Aerospace and Civil Engineering, School of Engineering, Faculty of Science and Engineering & Henry Royce Institute, The University of Manchester, Manchester, UK
| | - Susan J Kimber
- Division of Cell Matrix Biology and Regenerative Medicine, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK
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22
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Kou M, Huang L, Yang J, Chiang Z, Chen S, Liu J, Guo L, Zhang X, Zhou X, Xu X, Yan X, Wang Y, Zhang J, Xu A, Tse HF, Lian Q. Mesenchymal stem cell-derived extracellular vesicles for immunomodulation and regeneration: a next generation therapeutic tool? Cell Death Dis 2022; 13:580. [PMID: 35787632 PMCID: PMC9252569 DOI: 10.1038/s41419-022-05034-x] [Citation(s) in RCA: 273] [Impact Index Per Article: 91.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Revised: 06/08/2022] [Accepted: 06/22/2022] [Indexed: 02/06/2023]
Abstract
Mesenchymal stem cells (MSCs) can be widely isolated from various tissues including bone marrow, umbilical cord, and adipose tissue, with the potential for self-renewal and multipotent differentiation. There is compelling evidence that the therapeutic effect of MSCs mainly depends on their paracrine action. Extracellular vesicles (EVs) are fundamental paracrine effectors of MSCs and play a crucial role in intercellular communication, existing in various body fluids and cell supernatants. Since MSC-derived EVs retain the function of protocells and have lower immunogenicity, they have a wide range of prospective therapeutic applications with advantages over cell therapy. We describe some characteristics of MSC-EVs, and discuss their role in immune regulation and regeneration, with emphasis on the molecular mechanism and application of MSC-EVs in the treatment of fibrosis and support tissue repair. We also highlight current challenges in the clinical application of MSC-EVs and potential ways to overcome the problem of quality heterogeneity.
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Affiliation(s)
- Meng Kou
- Cord Blood Bank Centre, Guangzhou Women and Children's Medical Centre, Guangzhou Medical University, Guangzhou, China
| | - Li Huang
- Cord Blood Bank Centre, Guangzhou Women and Children's Medical Centre, Guangzhou Medical University, Guangzhou, China
| | - Jinjuan Yang
- Cord Blood Bank Centre, Guangzhou Women and Children's Medical Centre, Guangzhou Medical University, Guangzhou, China
| | - Zhixin Chiang
- Department of Allied Health Sciences Faculty of Science, Tunku Abdul Rahman University, Ipoh, Malaysia
| | - Shaoxiang Chen
- Cord Blood Bank Centre, Guangzhou Women and Children's Medical Centre, Guangzhou Medical University, Guangzhou, China
| | - Jie Liu
- State Key Laboratory of Pharmaceutical Biotechnology, the University of Hong Kong, Hong Kong SAR, China
- Department of Medicine, the University of Hong Kong, Hong Kong SAR, China
| | - Liyan Guo
- Cord Blood Bank Centre, Guangzhou Women and Children's Medical Centre, Guangzhou Medical University, Guangzhou, China
| | - Xiaoxian Zhang
- Cord Blood Bank Centre, Guangzhou Women and Children's Medical Centre, Guangzhou Medical University, Guangzhou, China
| | - Xiaoya Zhou
- Cord Blood Bank Centre, Guangzhou Women and Children's Medical Centre, Guangzhou Medical University, Guangzhou, China
| | - Xiang Xu
- Department of Stem Cell & Regenerative Medicine, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital, Army Medical University, Chongqing, 400042, China
| | - Xiaomei Yan
- Department of Chemical Biology, The MOE Key Laboratory of Spectrochemical Analysis & Instrumentation, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, Fujian, 361005, China
| | - Yan Wang
- Xiamen Cardiovascular Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
| | - Jinqiu Zhang
- Cord Blood Bank Centre, Guangzhou Women and Children's Medical Centre, Guangzhou Medical University, Guangzhou, China
| | - Aimin Xu
- State Key Laboratory of Pharmaceutical Biotechnology, the University of Hong Kong, Hong Kong SAR, China
- Department of Medicine, the University of Hong Kong, Hong Kong SAR, China
| | - Hung-Fat Tse
- Department of Medicine, the University of Hong Kong, Hong Kong SAR, China
- HKUMed Laboratory of Cellular Therapeutics, the University of Hong Kong, Hong Kong SAR, China
| | - Qizhou Lian
- Cord Blood Bank Centre, Guangzhou Women and Children's Medical Centre, Guangzhou Medical University, Guangzhou, China.
- State Key Laboratory of Pharmaceutical Biotechnology, the University of Hong Kong, Hong Kong SAR, China.
- Department of Medicine, the University of Hong Kong, Hong Kong SAR, China.
- HKUMed Laboratory of Cellular Therapeutics, the University of Hong Kong, Hong Kong SAR, China.
- Department of Surgery, Shenzhen Hong Kong University Hospital, Shenzhen, 518053, China.
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23
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Loh JT, Zhang B, Teo JKH, Lai RC, Choo ABH, Lam KP, Lim SK. Mechanism for the attenuation of neutrophil and complement hyperactivity by MSC exosomes. Cytotherapy 2022; 24:711-719. [PMID: 35177337 PMCID: PMC8843421 DOI: 10.1016/j.jcyt.2021.12.003] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Revised: 11/08/2021] [Accepted: 12/29/2021] [Indexed: 12/15/2022]
Abstract
Complements and neutrophils are two key players of the innate immune system that are widely implicated as drivers of severe COVID-19 pathogenesis, as evident by the direct correlation of respiratory failure and mortality with elevated levels of terminal complement complex C5b-9 and neutrophils. In this study, we identified a feed-forward loop between complements and neutrophils that could amplify and perpetuate the cytokine storm seen in severe SARS-CoV-2-infected patients. We observed for the first time that the terminal complement activation complex C5b-9 directly triggered neutrophil extracellular trap (NET) release and interleukin (IL)-17 production by neutrophils. This is also the first report that the production of NETs and IL-17 induced by C5b-9 assembly on neutrophils could be abrogated by mesenchymal stem cell (MSC) exosomes. Neutralizing anti-CD59 antibodies abolished this abrogation. Based on our findings, we hypothesize that MSC exosomes could alleviate the immune dysregulation in acute respiratory failure, such as that observed in severe COVID-19 patients, by inhibiting complement activation through exosomal CD59, thereby disrupting the feed-forward loop between complements and neutrophils to inhibit the amplification and perpetuation of inflammation during SARS-CoV-2 infection.
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Affiliation(s)
- Jia Tong Loh
- Singapore Immunology Network, Agency for Science, Technology and Research, Republic of Singapore
| | - Bin Zhang
- Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Republic of Singapore
| | - Joey Kay Hui Teo
- Singapore Immunology Network, Agency for Science, Technology and Research, Republic of Singapore
| | - Ruenn Chai Lai
- Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Republic of Singapore
| | - Andre Boon Hwa Choo
- Bioprocessing Technology Institute, Agency for Science, Technology and Research, Republic of Singapore
| | - Kong-Peng Lam
- Singapore Immunology Network, Agency for Science, Technology and Research, Republic of Singapore; Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Republic of Singapore; School of Biological Sciences, College of Science, Nanyang Technological University, Republic of Singapore.
| | - Sai Kiang Lim
- Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Republic of Singapore; Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Republic of Singapore.
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24
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Zhang X, Lu Y, Wu S, Zhang S, Li S, Tan J. An Overview of Current Research on Mesenchymal Stem Cell-Derived Extracellular Vesicles: A Bibliometric Analysis From 2009 to 2021. Front Bioeng Biotechnol 2022; 10:910812. [PMID: 35814000 PMCID: PMC9268551 DOI: 10.3389/fbioe.2022.910812] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Accepted: 06/06/2022] [Indexed: 12/31/2022] Open
Abstract
Background: Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) are important mediators of intercellular communication and participate in numerous physiological and pathological processes in the body. This study aims to introduce the research status, analyze the research hotspots, and predict the development trend through bibliometric analysis of MSC-EVs. Methods: We searched all relevant literature on MSC-EVs from 2009 to 2021 in the Web of Science. R-bibliometrix, VOSviewer, and CiteSpace software were used to visualize the quantitative analysis of the published literature, including co-authorship, co-occurrence, citation, and co-citation, to provide objective presentation and predictions in the field. Results: A total of 1595 articles and reviews on MSC-EVs published between 2009 and 2021 were identified. The annual publication outputs increased at an exponential rate, reaching as high as 555 publications in 2021. China contributed the most publications (n = 899, 56.36%) and had the most citations (n = 24,210). The United States had the strongest intensity of cooperation in this field. Shanghai Jiao Tong University had the maximum number of publications (n = 79). In terms of the number of publications and co-citations, the journal of Stem cell research & therapy ranked first. Camussi G was the most productive and most cited author. The top three themes in the research area were cell biology, research experimental medicine, and biochemistry molecular biology. Keyword co-occurrence and co-citation clustering analysis revealed that studies of MSC-EVs covered cellular origin (bone marrow mesenchymal stem cell, adipose-derived mesenchymal stem cell), injurious diseases (spinal cord injury, acute lung injury, ischemia/reperfusion injury, acute kidney injury, traumatic brain injury), tumor (breast cancer, tumor microenvironment), biological processes (drug delivery system, angiogenesis, inflammation, proliferation, differentiation, senescence), and molecular mechanisms (signaling pathway, signal transduction, oxidative stress, VEGF, TGF β). Conclusions: Studies on MSC-EVs have shown a steep growth trend in recent years. Available studies mostly focused on the therapeutic effects and underlying mechanisms of MSC-EVs in aplastic diseases. Multidisciplinary integration is a development trend in this field, and senescence-related topics might be the focus of future research on MSC-EVs.
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Affiliation(s)
- Xudong Zhang
- Center of Reproductive Medicine, Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China
- Key Laboratory of Reproductive Dysfunction Disease and Fertility Remodeling of Liaoning Province, Shenyang, China
| | - Yimeng Lu
- Center of Reproductive Medicine, Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China
- Key Laboratory of Reproductive Dysfunction Disease and Fertility Remodeling of Liaoning Province, Shenyang, China
| | - Shanshan Wu
- Center of Reproductive Medicine, Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China
- Key Laboratory of Reproductive Dysfunction Disease and Fertility Remodeling of Liaoning Province, Shenyang, China
| | - Siwen Zhang
- Center of Reproductive Medicine, Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China
- Key Laboratory of Reproductive Dysfunction Disease and Fertility Remodeling of Liaoning Province, Shenyang, China
| | - Shuyu Li
- Center of Reproductive Medicine, Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China
- Key Laboratory of Reproductive Dysfunction Disease and Fertility Remodeling of Liaoning Province, Shenyang, China
| | - Jichun Tan
- Center of Reproductive Medicine, Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China
- Key Laboratory of Reproductive Dysfunction Disease and Fertility Remodeling of Liaoning Province, Shenyang, China
- *Correspondence: Jichun Tan,
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25
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Asgari Taei A, Dargahi L, Khodabakhsh P, Kadivar M, Farahmandfar M. Hippocampal neuroprotection mediated by secretome of human mesenchymal stem cells against experimental stroke. CNS Neurosci Ther 2022; 28:1425-1438. [PMID: 35715988 PMCID: PMC9344087 DOI: 10.1111/cns.13886] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Revised: 05/21/2022] [Accepted: 05/24/2022] [Indexed: 12/26/2022] Open
Abstract
Aims Regenerative medicine literature has demonstrated that the therapeutic potentials of mesenchymal stem cells (MSCs) in experimental stroke are attributed to secreted bioactive factors rather than to cell replacement. Here, we explored the effects of secretome or conditioned medium (CM) derived from human embryonic stem cell‐derived MSCs (hESC‐MSCs) on hippocampal neurogenesis, inflammation, and apoptosis in experimental stroke. Methods Ischemic stroke was induced by right middle cerebral artery occlusion (MCAO) in male Wistar rats, and CM was infused either one time (1‐h post‐stroke; CM1) or three times (1‐, 24‐, and 48‐h post‐stroke; CM3) into left lateral ventricle. Neurogenesis markers (Nestin, Ki67, Doublecortin, and Reelin) were assessed at transcript and protein levels in the dentate gyrus of the hippocampus on day seven following MCAO. In parallel, changes in the gene expression of markers of apoptosis (Bax and Bim, as well as an anti‐apoptotic marker of Bcl2), inflammation (IL‐1β and IL‐6, as well as IL‐10 as an anti‐inflammatory cytokine), trophic factors (BDNF, GDNF, NGF, and NT‐3), and angiogenesis (CD31 and VEGF) in the hippocampus were assessed. Results Our results demonstrate that CM3 treatment could stimulate neurogenesis and angiogenesis concomitant with inhibition of inflammation, apoptosis, and neuronal loss in ischemic brains. Furthermore, rats treated with CM3 exhibited upregulation in neurotrophic factors. Conclusion Our results suggest that hESC‐MSC‐CM could promote neurogenesis and protect brain tissue from ischemic injury, partly mediated by induction of angiogenesis and neurotrophic factors and inhibition of inflammatory and apoptotic factors expression.
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Affiliation(s)
- Afsaneh Asgari Taei
- Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.,Department of Neuroscience and Addiction Studies, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Leila Dargahi
- Neurobiology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Pariya Khodabakhsh
- Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mehdi Kadivar
- Department of Biochemistry, Pasteur Institute of Iran, Tehran, Iran
| | - Maryam Farahmandfar
- Department of Neuroscience and Addiction Studies, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
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26
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Wong KL, Zhang S, Tan SSH, Cheow YA, Lai RC, Lim SK, Hui JHP, Toh WS. Mesenchymal Stem Cell Exosomes Promote Growth Plate Repair and Reduce Limb-Length Discrepancy in Young Rats. J Bone Joint Surg Am 2022; 104:1098-1106. [PMID: 35175995 DOI: 10.2106/jbjs.21.00789] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
BACKGROUND The objective of this study was to examine the therapeutic effects of human mesenchymal stromal/stem cell (MSC) exosomes in a rat model of growth plate injury. METHODS A growth plate defect was surgically created on the distal part of the right femur of 40 female Sprague-Dawley rats. A single intra-articular injection of 100 µg of MSC exosomes in 100 µL of phosphate-buffered saline solution (PBS), or an equivalent volume of PBS alone, was administered to the right knee immediately after surgery. At 4 and 8 weeks post-treatment, limb length was measured with micro-CT, and tissue repair was assessed with histological, immunohistochemical, and histomorphometric analyses. RESULTS A single injection of MSC exosomes significantly increased limb length from 3.29 ± 0.07 cm at 4 weeks to 3.37 ± 0.11 cm at 8 weeks (p = 0.047). However, no improvement in limb length was observed in the PBS control group. The limb-length discrepancy between the involved limb and the contralateral limb in the exosome-treated group was significantly less than the discrepancy in the PBS-treated group at both 4 weeks (2.52% ± 1.30% versus 4.11% ± 0.93%; p = 0.006) and 8 weeks (5.27% ± 2.11% versus 8.06% ± 2.56%; p = 0.016). Consistent with the reduced limb-length discrepancy, the exosome-treated defects displayed significantly more chondrocytes (p < 0.05) and a higher area percentage with deposition of sulphated glycosaminoglycan (p < 0.05) and collagen II (p < 0.05) than PBS-treated defects at 8 weeks. However, bone bridge formation was not inhibited in either group. CONCLUSIONS A single intra-articular injection of MSC exosomes significantly enhanced physeal repair and reduced limb-length discrepancy but did not inhibit bone-bridge formation. CLINICAL RELEVANCE This proof-of-concept study demonstrates for the first time the potential use of MSC exosomes as a minimally invasive cell-free therapeutic to promote physeal repair and reduce limb-length discrepancy following growth plate injuries.
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Affiliation(s)
- Keng Lin Wong
- Department of Orthopaedic Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.,Department of Orthopaedic Surgery, Sengkang General Hospital, Singhealth, Singapore
| | - Shipin Zhang
- Department of Orthopaedic Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.,Faculty of Dentistry, National University of Singapore, Singapore
| | - Sharon Si Heng Tan
- Department of Orthopaedic Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Yi Ann Cheow
- Faculty of Dentistry, National University of Singapore, Singapore
| | - Ruenn Chai Lai
- Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore
| | - Sai Kiang Lim
- Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore.,Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - James Hoi Po Hui
- Department of Orthopaedic Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.,Tissue Engineering Program, Life Sciences Institute, National University of Singapore, Singapore
| | - Wei Seong Toh
- Department of Orthopaedic Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.,Faculty of Dentistry, National University of Singapore, Singapore.,Tissue Engineering Program, Life Sciences Institute, National University of Singapore, Singapore.,Integrative Sciences and Engineering Program, NUS Graduate School, National University of Singapore, Singapore
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27
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Hussein MAA, Hussein HAM, Thabet AA, Selim KM, Dawood MA, El-Adly AM, Wardany AA, Sobhy A, Magdeldin S, Osama A, Anwar AM, Abdel-Wahab M, Askar H, Bakhiet EK, Sultan S, Ezzat AA, Abdel Raouf U, Afifi MM. Human Wharton's Jelly Mesenchymal Stem Cells Secretome Inhibits Human SARS-CoV-2 and Avian Infectious Bronchitis Coronaviruses. Cells 2022; 11:1408. [PMID: 35563714 PMCID: PMC9101656 DOI: 10.3390/cells11091408] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Revised: 04/19/2022] [Accepted: 04/20/2022] [Indexed: 02/04/2023] Open
Abstract
Human SARS-CoV-2 and avian infectious bronchitis virus (IBV) are highly contagious and deadly coronaviruses, causing devastating respiratory diseases in humans and chickens. The lack of effective therapeutics exacerbates the impact of outbreaks associated with SARS-CoV-2 and IBV infections. Thus, novel drugs or therapeutic agents are highly in demand for controlling viral transmission and disease progression. Mesenchymal stem cells (MSC) secreted factors (secretome) are safe and efficient alternatives to stem cells in MSC-based therapies. This study aimed to investigate the antiviral potentials of human Wharton’s jelly MSC secretome (hWJ-MSC-S) against SARS-CoV-2 and IBV infections in vitro and in ovo. The half-maximal inhibitory concentrations (IC50), cytotoxic concentration (CC50), and selective index (SI) values of hWJ-MSC-S were determined using Vero-E6 cells. The virucidal, anti-adsorption, and anti-replication antiviral mechanisms of hWJ-MSC-S were evaluated. The hWJ-MSC-S significantly inhibited infection of SARS-CoV-2 and IBV, without affecting the viability of cells and embryos. Interestingly, hWJ-MSC-S reduced viral infection by >90%, in vitro. The IC50 and SI of hWJ-MSC secretome against SARS-CoV-2 were 166.6 and 235.29 µg/mL, respectively, while for IBV, IC50 and SI were 439.9 and 89.11 µg/mL, respectively. The virucidal and anti-replication antiviral effects of hWJ-MSC-S were very prominent compared to the anti-adsorption effect. In the in ovo model, hWJ-MSC-S reduced IBV titer by >99%. Liquid chromatography-tandem mass spectrometry (LC/MS-MS) analysis of hWJ-MSC-S revealed a significant enrichment of immunomodulatory and antiviral proteins. Collectively, our results not only uncovered the antiviral potency of hWJ-MSC-S against SARS-CoV-2 and IBV, but also described the mechanism by which hWJ-MSC-S inhibits viral infection. These findings indicate that hWJ-MSC-S could be utilized in future pre-clinical and clinical studies to develop effective therapeutic approaches against human COVID-19 and avian IB respiratory diseases.
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Affiliation(s)
- Mohamed A. A. Hussein
- Department of Microbiology, Faculty of Science, Al-Azhar University, Assiut 71524, Egypt; (M.A.A.H.); (A.M.E.-A.); (A.A.W.); (E.K.B.); (M.M.A.)
| | - Hosni A. M. Hussein
- Department of Microbiology, Faculty of Science, Al-Azhar University, Assiut 71524, Egypt; (M.A.A.H.); (A.M.E.-A.); (A.A.W.); (E.K.B.); (M.M.A.)
| | - Ali A. Thabet
- Department of Zoology, Faculty of Science, Al-Azhar University, Assiut 71524, Egypt; (A.A.T.); (M.A.-W.); (H.A.)
| | - Karim M. Selim
- Reference Laboratory for Veterinary Quality Control on Poultry Production, Animal Health Research Institute, Agricultural Research Center, Dokki, Giza 12618, Egypt;
| | - Mervat A. Dawood
- Clinical Pathology, Mansoura Research Center for Cord Stem Cells (MARC-CSC), Faculty of Medicine, Mansoura University, El Mansoura 35516, Egypt;
| | - Ahmed M. El-Adly
- Department of Microbiology, Faculty of Science, Al-Azhar University, Assiut 71524, Egypt; (M.A.A.H.); (A.M.E.-A.); (A.A.W.); (E.K.B.); (M.M.A.)
| | - Ahmed A. Wardany
- Department of Microbiology, Faculty of Science, Al-Azhar University, Assiut 71524, Egypt; (M.A.A.H.); (A.M.E.-A.); (A.A.W.); (E.K.B.); (M.M.A.)
| | - Ali Sobhy
- Department of Clinical Pathology, Faculty of Medicine, Al-Azhar University, Assiut 71524, Egypt;
| | - Sameh Magdeldin
- Proteomics and Metabolomics Research Program, Basic Research Department, Children’s Cancer Hospital, (CCHE-57357), Cairo 57357, Egypt; (S.M.); (A.O.); (A.M.A.)
- Department of Physiology, Faculty of Veterinary Medicine, Suez Canal University, Ismailia 41522, Egypt
| | - Aya Osama
- Proteomics and Metabolomics Research Program, Basic Research Department, Children’s Cancer Hospital, (CCHE-57357), Cairo 57357, Egypt; (S.M.); (A.O.); (A.M.A.)
| | - Ali M. Anwar
- Proteomics and Metabolomics Research Program, Basic Research Department, Children’s Cancer Hospital, (CCHE-57357), Cairo 57357, Egypt; (S.M.); (A.O.); (A.M.A.)
| | - Mohammed Abdel-Wahab
- Department of Zoology, Faculty of Science, Al-Azhar University, Assiut 71524, Egypt; (A.A.T.); (M.A.-W.); (H.A.)
| | - Hussam Askar
- Department of Zoology, Faculty of Science, Al-Azhar University, Assiut 71524, Egypt; (A.A.T.); (M.A.-W.); (H.A.)
| | - Elsayed K. Bakhiet
- Department of Microbiology, Faculty of Science, Al-Azhar University, Assiut 71524, Egypt; (M.A.A.H.); (A.M.E.-A.); (A.A.W.); (E.K.B.); (M.M.A.)
| | - Serageldeen Sultan
- Department of Microbiology, Virology Division, Faculty of Veterinary Medicine, South Valley University, Qena 83523, Egypt;
| | - Amgad A. Ezzat
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Al-Azhar University, Assiut 71524, Egypt;
| | - Usama Abdel Raouf
- Department of Botany and Microbiology, Faculty of Science, Aswan University, Aswan 81528, Egypt;
| | - Magdy M. Afifi
- Department of Microbiology, Faculty of Science, Al-Azhar University, Assiut 71524, Egypt; (M.A.A.H.); (A.M.E.-A.); (A.A.W.); (E.K.B.); (M.M.A.)
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Arifka M, Wilar G, Elamin KM, Wathoni N. Polymeric Hydrogels as Mesenchymal Stem Cell Secretome Delivery System in Biomedical Applications. Polymers (Basel) 2022; 14:polym14061218. [PMID: 35335547 PMCID: PMC8955913 DOI: 10.3390/polym14061218] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Revised: 03/09/2022] [Accepted: 03/10/2022] [Indexed: 01/27/2023] Open
Abstract
Secretomes of mesenchymal stem cells (MSCs) have been successfully studied in preclinical models for several biomedical applications, including tissue engineering, drug delivery, and cancer therapy. Hydrogels are known to imitate a three-dimensional extracellular matrix to offer a friendly environment for stem cells; therefore, hydrogels can be used as scaffolds for tissue construction, to control the distribution of bioactive compounds in tissues, and as a secretome-producing MSC culture media. The administration of a polymeric hydrogel-based MSC secretome has been shown to overcome the fast clearance of the target tissue. In vitro studies confirm the bioactivity of the secretome encapsulated in the gel, allowing for a controlled and sustained release process. The findings reveal that the feasibility of polymeric hydrogels as MSC -secretome delivery systems had a positive influence on the pace of tissue and organ regeneration, as well as an enhanced secretome production. In this review, we discuss the widely used polymeric hydrogels and their advantages as MSC secretome delivery systems in biomedical applications.
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Affiliation(s)
- Mia Arifka
- Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, Universitas Padjadjaran, Jatinangor 45363, Indonesia;
| | - Gofarana Wilar
- Department of Pharmacology and Clinical Pharmacy, Faculty of Pharmacy, Universitas Padjadjaran, Jatinangor 45363, Indonesia;
| | - Khaled M. Elamin
- Global Center for Natural Resources Sciences, Faculty of Life Sciences, Kumamoto University, Kumamoto 862-0973, Japan;
| | - Nasrul Wathoni
- Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, Universitas Padjadjaran, Jatinangor 45363, Indonesia;
- Correspondence: ; Tel.: +62-22-842-888-888
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Li H, Su Y, Wang F, Tao F. Exosomes: a new way of protecting and regenerating optic nerve after injury. Hum Cell 2022; 35:771-778. [PMID: 35258808 DOI: 10.1007/s13577-022-00688-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Accepted: 02/22/2022] [Indexed: 12/29/2022]
Abstract
As an important part of the central nervous system (CNS), the optic nerve usually cannot regenerate directly after injury. Therefore, treating the injury and restoring the function of the optic nerve are a historical problem in the medical field. Due to the special anatomical position of the optic nerve, the microenvironment needed for protection and regeneration after injury is lacking. Therefore, preventing the continued loss of neurons, protecting the functional nerves, and promoting the effective protection of nerves are the main ways to solve the problem. Exosomes are nano-sized vesicles with a diameter of 30-150 nm, composed of lipid bilayers, proteins, and genetic material. They have key functions in cell-to-cell communication, immune regulation, inflammation, and regeneration. More and more shreds of evidence show that exosomes not only play an important role in systemic diseases such as cancer, cardiovascular diseases, and brain diseases; they also play a key role in ophthalmological diseases. This article reviews the role of exosomes in the protection and regeneration of the optic nerve after optic nerve injury in related experimental studies and clinical treatment methods. GRAPHICAL ABSTARCT: .
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Affiliation(s)
- Huazhang Li
- Department of Ophthalmology, The Fourth Affiliated Hospital, Harbin Medical University, Harbin, 150001, China
| | - Ying Su
- Department of Ophthalmology, The First Affiliated Hospital, Harbin Medical University, Harbin, 150001, China.
| | - Feng Wang
- Department of Ophthalmology, The Fourth Affiliated Hospital, Harbin Medical University, Harbin, 150001, China.
| | - Feng Tao
- Department of Neurology, The Hospital of Heilongjiang Province, Harbin, 150001, China.
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30
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Cheng L, Hill AF. Therapeutically harnessing extracellular vesicles. Nat Rev Drug Discov 2022; 21:379-399. [PMID: 35236964 DOI: 10.1038/s41573-022-00410-w] [Citation(s) in RCA: 398] [Impact Index Per Article: 132.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/20/2022] [Indexed: 02/06/2023]
Abstract
The field of extracellular vesicle (EV) research has developed rapidly over the last decade from the study of fundamental biology to a subject of significant clinical relevance. The potential of harnessing EVs in the diagnosis and treatment of diseases - including cancer and neurological and cardiovascular disorders - is now being recognized. Accordingly, the applications of EVs as therapeutic targets, biomarkers, novel drug delivery agents and standalone therapeutics are being actively explored. This Review provides a brief overview of the characteristics and physiological functions of the various classes of EV, focusing on their association with disease and emerging strategies for their therapeutic exploitation.
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Affiliation(s)
- Lesley Cheng
- La Trobe Institute for Molecular Science, La Trobe University, Bundoora, Victoria, Australia
| | - Andrew F Hill
- La Trobe Institute for Molecular Science, La Trobe University, Bundoora, Victoria, Australia. .,Institute for Health and Sport, Victoria University, Melbourne, Victoria, Australia.
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31
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Zhang S, Wong KL, Ren X, Teo KYW, Afizah H, Choo ABH, Lai RC, Lim SK, Hui JHP, Toh WS. Mesenchymal Stem Cell Exosomes Promote Functional Osteochondral Repair in a Clinically Relevant Porcine Model. Am J Sports Med 2022; 50:788-800. [PMID: 35099327 DOI: 10.1177/03635465211068129] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
BACKGROUND Previous studies have reported the efficacy of human mesenchymal stem cell (MSC) exosomes for the repair of osteochondral defects in rats and rabbits. However, the safety and efficacy of MSC exosomes remain to be validated in a clinically relevant large animal model. PURPOSE To validate the safety and efficacy of human MSC exosomes for osteochondral repair in a clinically relevant micropig model. STUDY DESIGN Controlled laboratory study. METHODS Bilateral osteochondral defects (6-mm diameter and 1-mm depth) were surgically created in the medial femoral condyles in knees of 12 micropigs. The pigs then received 2-mL intra-articular injections of MSC exosomes and hyaluronic acid (HA) (Exosome+HA) or HA alone after surgery and thereafter at 8 and 15 days. Osteochondral repair was assessed by magnetic resonance imaging (MRI) at 15 days and at 2 and 4 months after surgery as well as by macroscopic, histological, biomechanical, and micro-computed tomography (micro-CT) analyses at 4 months after surgery. RESULTS Exosome+HA-treated defects demonstrated significantly better MRI scores than HA-treated defects at 15 days and at 2 and 4 months. Additionally, Exosome+HA-treated defects demonstrated functional cartilage and subchondral bone repair, with significantly better macroscopic and histological scores and biomechanical properties (Young modulus and stiffness) than HA-treated defects at 4 months. Micro-CT further showed significantly higher bone volume and trabecular thickness in the subchondral bone of Exosome+HA-treated defects than that of HA-treated defects. Importantly, no adverse response or major systemic alteration was observed in any of the animals. CONCLUSION This study shows that the combination of MSC exosomes and HA administered at a clinically acceptable frequency of 3 weekly intra-articular injections can promote functional cartilage and subchondral bone repair, with significantly improved morphological, histological, and biomechanical outcomes in a clinically relevant porcine model. CLINICAL RELEVANCE Our findings provide a robust scientific rationale to support a phase 1/2 clinical trial to test MSC exosomes in patients with osteochondral lesions.
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Affiliation(s)
- Shipin Zhang
- Faculty of Dentistry, National University of Singapore, Singapore.,Department of Orthopaedic Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Keng Lin Wong
- Department of Orthopaedic Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.,Department of Orthopaedic Surgery, Sengkang General Hospital, Singhealth, Singapore
| | - Xiafei Ren
- Department of Orthopaedic Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.,Tissue Engineering Program, Life Sciences Institute, National University of Singapore, Singapore
| | | | - Hassan Afizah
- Department of Orthopaedic Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.,Tissue Engineering Program, Life Sciences Institute, National University of Singapore, Singapore
| | - Andre Boon Hwa Choo
- Bioprocessing Technology Institute, Agency for Science, Technology and Research (A*STAR), Singapore.,Department of Biomedical Engineering, Faculty of Engineering, National University of Singapore, Singapore
| | - Ruenn Chai Lai
- Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore
| | - Sai Kiang Lim
- Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore.,Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - James Hoi Po Hui
- Department of Orthopaedic Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.,Tissue Engineering Program, Life Sciences Institute, National University of Singapore, Singapore
| | - Wei Seong Toh
- Faculty of Dentistry, National University of Singapore, Singapore.,Department of Orthopaedic Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.,Tissue Engineering Program, Life Sciences Institute, National University of Singapore, Singapore.,Department of Biomedical Engineering, Faculty of Engineering, National University of Singapore, Singapore.,Integrative Sciences and Engineering Program, NUS Graduate School, National University of Singapore, Singapore
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32
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Tan L, Liu X, Dou H, Hou Y. Characteristics and regulation of mesenchymal stem cell plasticity by the microenvironment — specific factors involved in the regulation of MSC plasticity. Genes Dis 2022; 9:296-309. [PMID: 35224147 PMCID: PMC8843883 DOI: 10.1016/j.gendis.2020.10.006] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Revised: 10/05/2020] [Accepted: 10/22/2020] [Indexed: 02/07/2023] Open
Abstract
Mesenchymal stem cells (MSCs), multipotent stromal cells, have attracted extensive attention in the field of regenerative medicine and cell therapy due to the capacity of self-renewal, multilineage differentiation, and immune regulation. MSCs have different cellular effects in different diseases, and even have markedly different curative effects with different tissue sources, indicating the plasticity of MSCs. The phenotypes, secreted factors, and proliferative, migratory, differentiating, and immunomodulatory effects of MSCs depend on certain mediators present in their microenvironment. Understanding microenvironmental factors and their internal mechanisms in MSC responses may help in subsequent prediction and improvement of clinical benefits. This review highlighted the recent advances in MSC plasticity in the physiological and pathological microenvironment and multiple microenvironmental factors regulating MSC plasticity. It also highlighted some progress in the underlying molecular mechanisms of MSC remodeling in the microenvironment. It might provide references for the improvement in vitro culture of MSCs, clinical application, and in vivo induction.
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Tan TT, Toh WS, Lai RC, Lim SK. Practical considerations in transforming MSC therapy for neurological diseases from cell to EV. Exp Neurol 2021; 349:113953. [PMID: 34921846 DOI: 10.1016/j.expneurol.2021.113953] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2021] [Revised: 11/19/2021] [Accepted: 12/13/2021] [Indexed: 12/11/2022]
Abstract
Cell-based therapy using Mesenchymal Stromal Cell (MSC) has generally been efficacious in treating a myriad of diseases in animal models and clinical trials. The rationale for MSC therapy was predicated on the potential of MSC to differentiate and form new replacement cells in the diseased tissue. However, pre-clinical animal and clinical data were more consistent with a secretion- and not a differentiation-based rationale. Analysis of MSC secretion led to the identification of small extracellular vesicles (sEVs) as therapeutically active, secretory agents. MSC-sEVs are defined as bi-lipid membrane vesicles of 50-200 nm in diameter that are secreted by MSCs. They reportedly exert similar therapeutic efficacy as MSCs in many diseases including neurological diseases. MSC-sEVs being small and non-living are intrinsically safer than living MSCs. Manufacturing of MSC-sEVs may also be less complex. Nevertheless, realising the therapeutic potential of MSC-sEVs will require exacting scientific rigor and robustness, as well as compliance to regulatory oversight. This review summarises the scientific rationale for the transition of MSC therapy from a cell- to an EV-based therapy and discusses critical scientific issues in the development of MSC-sEVs therapy.
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Affiliation(s)
- Thong Teck Tan
- Institute of Molecular and Cellular Biology, A*STAR, 8A Biomedical Grove, Singapore 138648, Singapore
| | - Wei Seong Toh
- Faculty of Dentistry, National University of Singapore, Singapore; Department of Orthopaedic Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Ruenn Chai Lai
- Institute of Molecular and Cellular Biology, A*STAR, 8A Biomedical Grove, Singapore 138648, Singapore
| | - Sai Kiang Lim
- Institute of Molecular and Cellular Biology, A*STAR, 8A Biomedical Grove, Singapore 138648, Singapore; Department of Surgery, YLL School of Medicine, National University of Singapore (NUS) Lower Kent Ridge Road, Singapore 119074, Singapore.
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34
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Merkhan MM, Shephard MT, Forsyth NR. Physoxia alters human mesenchymal stem cell secretome. J Tissue Eng 2021; 12:20417314211056132. [PMID: 34733464 PMCID: PMC8558798 DOI: 10.1177/20417314211056132] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Accepted: 10/12/2021] [Indexed: 12/12/2022] Open
Abstract
The human mesenchymal stem cell (hMSC) secretome has pleiotropic effects which underpin their therapeutic potential. hMSC serum-free conditioned media (SFCM) has been determined to contain a variety of cytokines with roles in regeneration and suppression of inflammation. Physiological oxygen (physoxia) has been demonstrated to impact upon a number of facets of hMSC biology and we hypothesized that the secretome would be similarly modified. We tested a range of oxygen conditions; 21% O2 (air oxygen (AO)), 2% O2 (intermittent hypoxia (IH)) and 2% O2 Workstation (physoxia (P)) to evaluate their effect on hMSC secretome profiles. Total protein content of secretome was upregulated in IH and P (>3 fold vs AO) and IH (>1 fold vs P). Focused cytokine profiling indicated global upregulation in IH of all 31 biomolecules tested in comparison to AO and P with basic-nerve growth factor (bNGF) and granulocyte colony-stimulating factor (GCSF) (>3 fold vs AO) and bNGF and Rantes (>3 fold vs P) of note. Similarly, upregulation of interferon gamma-induced protein 10 (IP10) was noted in P (>3 fold vs AO). Interleukin-2 (IL2) and Rantes (in AO and P) and adiponectin, IL17a, and epidermal growth factor (EGF) (in AO only) were entirely absent or below detection limits. Quantitative analysis validated the pattern of IH-induced upregulation in vascular endothelial growth factor (VEGF), placental growth factor-1 (PIGF1), Tumor necrosis factor alpha (TNFa), IL2, IL4, and IL10 when compared to AO and P. In summary, modulation of environmental oxygen alters both secretome concentration and composition. This consideration will likely impact on delivering improved mechanistic understanding and potency effects of hMSC-based therapeutics.
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Affiliation(s)
- Marwan M Merkhan
- Guy Hilton Research Centre, School of Pharmacy and Bioengineering, Keele University, Staffordshire, UK.,College of Pharmacy, University of Mosul, Mosul, Iraq
| | - Matthew T Shephard
- Guy Hilton Research Centre, School of Pharmacy and Bioengineering, Keele University, Staffordshire, UK
| | - Nicholas R Forsyth
- Guy Hilton Research Centre, School of Pharmacy and Bioengineering, Keele University, Staffordshire, UK
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35
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Lin H, Chen H, Zhao X, Chen Z, Zhang P, Tian Y, Wang Y, Ding T, Wang L, Shen Y. Advances in mesenchymal stem cell conditioned medium-mediated periodontal tissue regeneration. J Transl Med 2021; 19:456. [PMID: 34736500 PMCID: PMC8567704 DOI: 10.1186/s12967-021-03125-5] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2021] [Accepted: 10/22/2021] [Indexed: 12/19/2022] Open
Abstract
Periodontitis is a chronic inflammatory disease that leads to the destruction of both soft and hard periodontal tissues. Complete periodontal regeneration in clinics using the currently available treatment approaches is still a challenge. Mesenchymal stem cells (MSCs) have shown promising potential to regenerate periodontal tissue in various preclinical and clinical studies. The poor survival rate of MSCs during in vivo transplantation and host immunogenic reaction towards MSCs are the main drawbacks of direct use of MSCs in periodontal tissue regeneration. Autologous MSCs have limited sources and possess patient morbidity during harvesting. Direct use of allogenic MSCs could induce host immune reaction. Therefore, the MSC-based indirect treatment approach could be beneficial for periodontal regeneration in clinics. MSC culture conditioned medium (CM) contains secretomes that had shown immunomodulatory and tissue regenerative potential in pre-clinical and clinical studies. MSC-CM contains a cocktail of growth factors, cytokines, chemokines, enzymes, and exosomes, extracellular vesicles, etc. MSC-CM-based indirect treatment has the potential to eliminate the drawbacks of direct use of MSCs for periodontal tissue regeneration. MSC-CM holds the tremendous potential of bench-to-bed translation in periodontal regeneration applications. This review focuses on the accumulating evidence indicating the therapeutic potential of the MSC-CM in periodontal regeneration-related pre-clinical and clinical studies. Recent advances on MSC-CM-based periodontal regeneration, existing challenges, and prospects are well summarized as guidance to improve the effectiveness of MSC-CM on periodontal regeneration in clinics.
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Affiliation(s)
- Hongbing Lin
- Department of Periodontics, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou Key laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangzhou, Guangdong, 510182, China
| | - Huishan Chen
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, Jilin, 130021, People's Republic of China
| | - Xuetao Zhao
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, Jilin, 130021, People's Republic of China
| | - Zhen Chen
- Department of Periodontics, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou Key laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangzhou, Guangdong, 510182, China
| | - Peipei Zhang
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, Jilin, 130021, People's Republic of China
| | - Yue Tian
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, Jilin, 130021, People's Republic of China
| | - Yawei Wang
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, Jilin, 130021, People's Republic of China
| | - Tong Ding
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, Jilin, 130021, People's Republic of China
| | - Lijing Wang
- Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou, China.,Vascular Biology Research Institute, School of Life Sciences and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou, China
| | - Yuqin Shen
- Department of Periodontics, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou Key laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangzhou, Guangdong, 510182, China.
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Zhou T, Rong M, Wang Z, Chu H, Chen C, Zhang J, Tian Z. Conditioned medium derived from 3D tooth germs: A novel cocktail for stem cell priming and early in vivo pulp regeneration. Cell Prolif 2021; 54:e13129. [PMID: 34585454 PMCID: PMC8560607 DOI: 10.1111/cpr.13129] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Revised: 08/13/2021] [Accepted: 09/03/2021] [Indexed: 12/12/2022] Open
Abstract
OBJECTIVES Conditioned medium (CM) from 2D cell culture can mitigate the weakened regenerative capacity of the implanted stem cells. However, the capacity of 3D CM to prime dental pulp stem cells (DPSCs) for pulp regeneration and its protein profile are still elusive. We aim to investigate the protein profile of CM derived from 3D tooth germs, and to unveil its potential for DPSCs-based pulp regeneration. MATERIALS AND METHODS We prepared CM of 3D ex vivo cultured tooth germ organs (3D TGO-CM) and CM of 2D cultured tooth germ cells (2D TGC-CM) and applied them to prime DPSCs. Influences on cell behaviours and protein profiles of CMs were compared. In vivo pulp regeneration of CMs-primed DPSCs was explored using a tooth root fragment model on nude mice. RESULTS TGO-CM enhanced DPSCs proliferation, migration, in vitro mineralization, odontogenic differentiation, and angiogenesis performances. The TGO-CM group generated superior pulp structures, more odontogenic cells attachment, and enhanced vasculature at 4 weeks post-surgery, compared with the TGC-CM group. Secretome analysis revealed that TGO-CM contained more odontogenic and angiogenic growth factors and fewer pro-inflammatory cytokines. Mechanisms leading to the differential CM profiles may be attributed to the cytokine-cytokine receptor interaction and PI3K-Akt signalling pathway. CONCLUSIONS The unique secretome profile of 3D TGO-CM made it a successful priming cocktail to enhance DPSCs-based early pulp regeneration.
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Affiliation(s)
- Tengfei Zhou
- Department of Periodontology and Oral Implantology, Stomatological Hospital, Southern Medical University, Guangzhou, China
| | - Mingdeng Rong
- Department of Periodontology and Oral Implantology, Stomatological Hospital, Southern Medical University, Guangzhou, China
| | - Zijie Wang
- Department of Stomatology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Hongxing Chu
- Department of Periodontology and Oral Implantology, Stomatological Hospital, Southern Medical University, Guangzhou, China
| | - Chuying Chen
- Department of Stomatology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jiayi Zhang
- Department of Stomatology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Zhihui Tian
- Department of Stomatology, Nanfang Hospital, Southern Medical University, Guangzhou, China
- School of Stomatology, Southern Medical University, Guangzhou, China
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37
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Sikora B, Skubis-Sikora A, Prusek A, Gola J. Paracrine activity of adipose derived stem cells on limbal epithelial stem cells. Sci Rep 2021; 11:19956. [PMID: 34620960 PMCID: PMC8497478 DOI: 10.1038/s41598-021-99435-1] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2021] [Accepted: 09/13/2021] [Indexed: 12/13/2022] Open
Abstract
Limbal stem cells deficiency (LSCD) is an eye disease caused by the loss of stem cells in the corneal limbus as a succession of an injury due physical, biological, or chemical agents. Current therapies of LSCD are focused on the transplantation of donor corneas or tissue equivalents produced from autologous limbal stem cells. Every year there are waiting millions of patients for the cornea transplantation all over the world and the list is growing due to the relatively low number of cornea donors. On the other hand, the transplantation of tissue or cells into the recipient’s body is associated with the higher risk of possible side effects. The possibility of the application of an indirect treatment using the properties of the paracrine activity of stem cells, would be beneficial for the patients with transplant failures. This study was to evaluate the paracrine effect of mesenchymal stem cells derived from adipose tissue (ADSC) on the viability of limbal epithelial stem cells (LESC). The paracrine effect was assessed by treating LESC with conditioned medium collected from ADSC culture. Cell viability, cytotoxicity, apoptosis and proliferation were evaluated using in vitro assays in standard conditions and induced inflammation. After the exposure to the examined conditions, the expression of genes related to pro- and anti- inflammatory factors was evaluated and compared to the secretion of selected cytokines by ELISA test. Moreover, the changes in LESC phenotype were assessed using of phenotype microarrays. Our findings suggest that paracrine activity of ADSC on LESC promotes its proliferation and has a potential role in mitigation of the adverse impact of inflammation induced by lipopolysaccharide.
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Affiliation(s)
- Bartosz Sikora
- Department of Cytophysiology, Chair of Histology and Embryology, Faculty of Medical Sciences in Katowice, Medical University of Silesia in Katowice, ul. Medyków 18, C2/103, 40-752, Katowice, Poland.
| | - Aleksandra Skubis-Sikora
- Department of Cytophysiology, Chair of Histology and Embryology, Faculty of Medical Sciences in Katowice, Medical University of Silesia in Katowice, ul. Medyków 18, C2/103, 40-752, Katowice, Poland
| | - Agnieszka Prusek
- Department of Cytophysiology, Chair of Histology and Embryology, Faculty of Medical Sciences in Katowice, Medical University of Silesia in Katowice, ul. Medyków 18, C2/103, 40-752, Katowice, Poland
| | - Joanna Gola
- Department of Molecular Biology, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia in Katowice, Katowice, Poland
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Feng ZY, Yang SD, Wang T, Guo S. Effect of Melatonin for Regulating Mesenchymal Stromal Cells and Derived Extracellular Vesicles. Front Cell Dev Biol 2021; 9:717913. [PMID: 34540834 PMCID: PMC8440901 DOI: 10.3389/fcell.2021.717913] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Accepted: 08/04/2021] [Indexed: 12/20/2022] Open
Abstract
Melatonin is a hormone, synthesized in the pineal gland, which primarily controls the circadian rhythm of the body. In recent years, melatonin has also been shown to regulate metabolism, provide neuroprotection, and act as an anti-inflammatory, free radical scavenger. There has also been a recent research interest in the role of melatonin in regulating mesenchymal stromal cells (MSCs). MSCs are pivotal for their ability to differentiate into a variety of different tissues. There is also increasing evidence for the therapeutic prospects of MSCs via paracrine signaling. In addition to secreting cytokines and chemokines, MSCs can secrete extracellular vesicles (EVs), allowing them to respond to injury and promote tissue regeneration. While there has been a major research interest in the use of MSCs for regenerative medicine, the clinical application is limited by many risks, including tumorigenicity, senescence, and sensitivity to toxic environments. The use of MSC-derived EVs for cell-free therapy can potentially avoid the disadvantages of MSCs, which makes this an exciting prospect for regenerative medicine. Prior research has shown that MSCs, via paracrine mechanisms, can identify receptor-independent responses to melatonin and then activate a series of downstream pathways, which exert a variety of effects, including anti-tumor and anti-inflammatory effects. Here we review the synthesis of melatonin, its mechanisms of action, and the effect of melatonin on MSCs via paracrine signaling. Furthermore, we summarize the current clinical applications of melatonin and discuss future prospects.
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Affiliation(s)
- Zi-Yi Feng
- Department of Plastic Surgery, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Shu-De Yang
- Department of Plastic Surgery, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Ting Wang
- Department of Plastic Surgery, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Shu Guo
- Department of Plastic Surgery, The First Affiliated Hospital of China Medical University, Shenyang, China
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Pluripotent-derived Mesenchymal Stem/stromal Cells: an Overview of the Derivation Protocol Efficacies and the Differences Among the Derived Cells. Stem Cell Rev Rep 2021; 18:94-125. [PMID: 34545529 DOI: 10.1007/s12015-021-10258-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/02/2021] [Indexed: 10/20/2022]
Abstract
Mesenchymal stem/stromal cells (MSCs) are remarkable tools for regenerative medicine. Therapeutic approaches using these cells can promote increased activity and viability in several cell types through diverse mechanisms such as paracrine and immunomodulatory activities, contributing substantially to tissue regeneration and functional recovery. However, biological samples of human MSCs, usually obtained from adult tissues, often exhibit variable behavior during in vitro culture, especially with respect to cell population heterogeneity, replicative senescence, and consequent loss of functionality. Accordingly, it is necessary to establish standard protocols to generate high-quality, stable cell cultures, for example, by using pluripotent stem cells (PSCs) in derivation protocols of MSC-like cells since PSCs maintain their characteristics consistently during culture. However, the available protocols seem to generate distinct populations of PSC-derivedMSCs (PSC-MSCs) with peculiar attributes, which do not always resemble bona fide primary MSCs. The present review addresses the developmental basis behind some of these derivation protocols, exposing the differences among them and discussing the functional properties of PSC-MSCs, shedding light on elements that may help determine standard characterizations and criteria to evaluate and define these cells.
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Liang X, He M, Zhu B, Zhu Y, He X, Liu D, Wei Q. TMT-Based Proteomic Explores the Influence of DHEA on the Osteogenic Differentiation of hBMSCs. Front Cell Dev Biol 2021; 9:726549. [PMID: 34490274 PMCID: PMC8418125 DOI: 10.3389/fcell.2021.726549] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Accepted: 07/26/2021] [Indexed: 11/17/2022] Open
Abstract
Dehydroepiandrosterone (DHEA) has been revealed to implicate in facilitating osteoblast differentiation of human bone marrow mesenchymal stem cells (hBMSCs) and inhibiting osteoporosis (OP). However, the underlying molecular mechanism remains largely unknown. Here, we induced osteogenic differentiation of hBMSCs derived from elders using an osteogenic induction medium with or without DHEA. The results showed that osteogenic induction medium (OIM) with DHEA could significantly promote the proliferation and osteogenic differentiation of hBMSCs than OIM alone. By using a Tandem Mass Tag (TMT) labeling and liquid chromatography-tandem mass spectrometry (LC-MS/MS) technology, we screened out 604 differentially expressed proteins (DEPs) with at least one unique peptide were identified [524: OIM vs. complete medium (CM), and 547: OIM+DHEA vs. CM], among these proteins, 467 DEPs were shared in these two different comparative groups. Bioinformatic analysis revealed these DEPs are mainly enriched in metabolic pathways. Interestingly, the expression levels of the DEPs in the metabolic pathways showed a more noticeable change in the OIM+DHEA vs. CM group than OIM vs. CM group. Moreover, the protein-protein interaction (PPI) network analysis revealed that three potential proteins, ATP5B, MT-CYB, and MT-ATP6, involved in energy metabolism, might play a key role in osteogenic differentiation induced by OIM+DHEA. These findings offer a valuable clue for us to better understand the underlying mechanisms involved in osteoblast differentiation of hBMSCs caused by DHEA and assist in applying DHEA in hBMSCs-based therapy for osteogenic regeneration.
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Affiliation(s)
- Xiaonan Liang
- Department of Orthopedics Trauma and Hand Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Mingwei He
- Guangxi Collaborative Innovation Center for Biomedicine, Guangxi Medical University, Nanning, China
| | - Bo Zhu
- Guangxi Engineering Center in Biomedical Materials for Tissue and Organ Regeneration, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Yongjia Zhu
- Nanning Second People's Hospital, The Third Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Xixi He
- Department of Orthopedics Trauma and Hand Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Dachang Liu
- Department of Orthopedics Trauma and Hand Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Qingjun Wei
- Department of Orthopedics Trauma and Hand Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
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Therapeutic Applications of Stem Cells and Extracellular Vesicles in Emergency Care: Futuristic Perspectives. Stem Cell Rev Rep 2021; 17:390-410. [PMID: 32839921 PMCID: PMC7444453 DOI: 10.1007/s12015-020-10029-2] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Regenerative medicine (RM) is an interdisciplinary field that aims to repair, replace or regenerate damaged or missing tissue or organs to function as close as possible to its physiological architecture and functions. Stem cells, which are undifferentiated cells retaining self-renewal potential, excessive proliferation and differentiation capacity into offspring or daughter cells that form different lineage cells of an organism, are considered as an important part of the RM approaches. They have been widely investigated in preclinical and clinical studies for therapeutic purposes. Extracellular vesicles (EVs) are the vital mediators that regulate the therapeutic effects of stem cells. Besides, they carry various types of cargo between cells which make them a significant contributor of intercellular communication. Given their role in physiological and pathological conditions in living cells, EVs are considered as a new therapeutic alternative solution for a variety of diseases in which there is a high unmet clinical need. This review aims to summarize and identify therapeutic potential of stem cells and EVs in diseases requiring acute emergency care such as trauma, heart diseases, stroke, acute respiratory distress syndrome and burn injury. Diseases that affect militaries or societies including acute radiation syndrome, sepsis and viral pandemics such as novel coronavirus disease 2019 are also discussed. Additionally, featuring and problematic issues that hamper clinical translation of stem cells and EVs are debated in a comparative manner with a futuristic perspective. Graphical Abstract.
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Tan TT, Lai RC, Padmanabhan J, Sim WK, Choo ABH, Lim SK. Assessment of Tumorigenic Potential in Mesenchymal-Stem/Stromal-Cell-Derived Small Extracellular Vesicles (MSC-sEV). Pharmaceuticals (Basel) 2021; 14:ph14040345. [PMID: 33918628 PMCID: PMC8069985 DOI: 10.3390/ph14040345] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Revised: 03/29/2021] [Accepted: 04/07/2021] [Indexed: 12/11/2022] Open
Abstract
Mesenchymal-stem/stromal-cell-derived small extracellular vesicles (MSC-sEV) have been shown to ameliorate many diseases in preclinical studies. However, translating MSC-sEV into clinical use requires the development of scalable manufacturing processes for highly reproducible preparations of safe and potent MSC-sEVs. A major source of variability in MSC-sEV preparations is EV producer cells. To circumvent variability in producer cells, clonal immortalized MSC lines as EV producer lines are increasingly being used for sEV production. The use of sEVs from immortalized producer cells inevitably raises safety concerns regarding the tumorigenicity or tumor promoting potential of the EV products. In this study, cells from E1-MYC line, a MSC cell line immortalized with the MYC gene, were injected subcutaneously into athymic nude mice. At 84 days post-injection, no tumor formation was observed at the injection site, lungs, or lymph nodes. E1-MYC cells pre-and post-sEV production did not exhibit anchorage-independent growth in soft agar. Daily intraperitoneal injections of 1 or 5 μg sEVs from E1-MYC into athymic nude mice with FaDu human head and neck cancer xenografts for 28 days did not promote or inhibit tumor growth relative to the xenograft treated with vehicle control. Therefore, MYC-immortalized MSCs are not tumorigenic and sEVs from these MSCs do not promote tumor growth.
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Affiliation(s)
- Thong Teck Tan
- Institute of Molecular and Cellular Biology, A*STAR, 8A Biomedical Grove, Singapore 138648, Singapore; (T.T.T.); (R.C.L.); (W.K.S.)
| | - Ruenn Chai Lai
- Institute of Molecular and Cellular Biology, A*STAR, 8A Biomedical Grove, Singapore 138648, Singapore; (T.T.T.); (R.C.L.); (W.K.S.)
| | - Jayanthi Padmanabhan
- Bioprocessing Technology Institute, A*STAR, 20 Biopolis Way, Singapore 138668, Singapore; (J.P.); (A.B.H.C.)
| | - Wei Kian Sim
- Institute of Molecular and Cellular Biology, A*STAR, 8A Biomedical Grove, Singapore 138648, Singapore; (T.T.T.); (R.C.L.); (W.K.S.)
| | - Andre Boon Hwa Choo
- Bioprocessing Technology Institute, A*STAR, 20 Biopolis Way, Singapore 138668, Singapore; (J.P.); (A.B.H.C.)
- Department of Biomedical Engineering, Faculty of Engineering, National University of Singapore (NUS), 9 Engineering Drive 1, Singapore 117575, Singapore
| | - Sai Kiang Lim
- Institute of Molecular and Cellular Biology, A*STAR, 8A Biomedical Grove, Singapore 138648, Singapore; (T.T.T.); (R.C.L.); (W.K.S.)
- Department of Surgery, YLL School of Medicine, National University of Singapore (NUS), 5 Lower Kent Ridge Road, Singapore 119074, Singapore
- Correspondence: ; Tel.: +65-64-070161
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The Future of Regenerative Medicine: Cell Therapy Using Pluripotent Stem Cells and Acellular Therapies Based on Extracellular Vesicles. Cells 2021; 10:cells10020240. [PMID: 33513719 PMCID: PMC7912181 DOI: 10.3390/cells10020240] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Revised: 01/13/2021] [Accepted: 01/23/2021] [Indexed: 12/11/2022] Open
Abstract
The rapid progress in the field of stem cell research has laid strong foundations for their use in regenerative medicine applications of injured or diseased tissues. Growing evidences indicate that some observed therapeutic outcomes of stem cell-based therapy are due to paracrine effects rather than long-term engraftment and survival of transplanted cells. Given their ability to cross biological barriers and mediate intercellular information transfer of bioactive molecules, extracellular vesicles are being explored as potential cell-free therapeutic agents. In this review, we first discuss the state of the art of regenerative medicine and its current limitations and challenges, with particular attention on pluripotent stem cell-derived products to repair organs like the eye, heart, skeletal muscle and skin. We then focus on emerging beneficial roles of extracellular vesicles to alleviate these pathological conditions and address hurdles and operational issues of this acellular strategy. Finally, we discuss future directions and examine how careful integration of different approaches presented in this review could help to potentiate therapeutic results in preclinical models and their good manufacturing practice (GMP) implementation for future clinical trials.
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Zhang B, Lai RC, Sim WK, Choo ABH, Lane EB, Lim SK. Topical Application of Mesenchymal Stem Cell Exosomes Alleviates the Imiquimod Induced Psoriasis-Like Inflammation. Int J Mol Sci 2021; 22:720. [PMID: 33450859 PMCID: PMC7828312 DOI: 10.3390/ijms22020720] [Citation(s) in RCA: 76] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Revised: 01/05/2021] [Accepted: 01/08/2021] [Indexed: 12/14/2022] Open
Abstract
Severe psoriasis, a chronic inflammatory skin disease is increasingly being effectively managed by targeted immunotherapy but long-term immunotherapy poses health risk and loss of response. Therefore, there is a need for alternative therapy strategies. Mesenchymal stem/stromal cell (MSC) exosomes are widely known for their potent immunomodulatory properties. Here we investigated if topically applied MSC exosomes could alleviate psoriasis-associated inflammation. Topically applied fluorescent exosomes on human skin explants were confined primarily to the stratum corneum with <1% input fluorescence exiting the explant over a 24-h period. Nevertheless, topically applied MSC exosomes in a mouse model of imiquimod (IMQ) psoriasis significantly reduced IL-17 and terminal complement activation complex C5b-9 in the mouse skin. MSC exosomes were previously shown to inhibit complement activation, specifically C5b-9 complex formation through CD59. Infiltration of neutrophils into the stratum corneum is characteristic of psoriasis and neutrophils are a major cellular source of IL-17 in psoriasis through the release of neutrophil extracellular traps (NETs). We propose that topically applied MSC exosomes inhibit complement activation in the stratum corneum and this alleviates IL-17 release by NETS from neutrophils that accumulate in and beneath the stratum corneum.
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Affiliation(s)
- Bin Zhang
- Institute of Molecular and Cell Biology (IMCB)—A*STAR, 8A Biomedical Grove, #05-39 Immunos, Singapore 138648, Singapore; (B.Z.); (R.C.L.); (W.K.S.)
| | - Ruenn Chai Lai
- Institute of Molecular and Cell Biology (IMCB)—A*STAR, 8A Biomedical Grove, #05-39 Immunos, Singapore 138648, Singapore; (B.Z.); (R.C.L.); (W.K.S.)
| | - Wei Kian Sim
- Institute of Molecular and Cell Biology (IMCB)—A*STAR, 8A Biomedical Grove, #05-39 Immunos, Singapore 138648, Singapore; (B.Z.); (R.C.L.); (W.K.S.)
| | - Andre Boon Hwa Choo
- Bioprocessing Technology Institute (BTI)—A*STAR, 20 Biopolis Way, Singapore 138668, Singapore;
| | - Ellen Birgit Lane
- Skin Research Institute of Singapore (SRIS)—A*STAR, 8A Biomedical Grove, #06-06 Immunos, Singapore 138648, Singapore;
| | - Sai Kiang Lim
- Institute of Molecular and Cell Biology (IMCB)—A*STAR, 8A Biomedical Grove, #05-39 Immunos, Singapore 138648, Singapore; (B.Z.); (R.C.L.); (W.K.S.)
- Department of Surgery, YLL School of Medicine, National University of Singapore c/o NUHS Tower Block, Level 8. IE Kent Ridge Road, Singapore 119228, Singapore
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Wang Y, Shan SK, Guo B, Li F, Zheng MH, Lei LM, Xu QS, Ullah MHE, Xu F, Lin X, Yuan LQ. The Multi-Therapeutic Role of MSCs in Diabetic Nephropathy. Front Endocrinol (Lausanne) 2021; 12:671566. [PMID: 34163437 PMCID: PMC8216044 DOI: 10.3389/fendo.2021.671566] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2021] [Accepted: 05/20/2021] [Indexed: 12/16/2022] Open
Abstract
Diabetic nephropathy (DN) is one of the most common diabetes mellitus (DM) microvascular complications, which always ends with end-stage renal disease (ESRD). Up to now, as the treatment of DN in clinic is still complicated, ESRD has become the main cause of death in diabetic patients. Mesenchymal stem cells (MSCs), with multi-differentiation potential and paracrine function, have attracted considerable attention in cell therapy recently. Increasing studies concerning the mechanisms and therapeutic effect of MSCs in DN emerged. This review summarizes several mechanisms of MSCs, especially MSCs derived exosomes in DN therapy, including hyperglycemia regulation, anti-inflammatory, anti-fibrosis, pro-angiogenesis, and renal function protection. We also emphasize the limitation of MSCs application in the clinic and the enhanced therapeutic role of pre-treated MSCs in the DN therapy. This review provides balanced and impartial views for MSC therapy as a promising strategy in diabetic kidney disease amelioration.
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Affiliation(s)
- Yi Wang
- Department of Metabolism and Endocrinology, National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory of Metabolic Bone Diseases, the Second Xiangya Hospital, Central South University, Changsha, China
| | - Su-Kang Shan
- Department of Metabolism and Endocrinology, National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory of Metabolic Bone Diseases, the Second Xiangya Hospital, Central South University, Changsha, China
| | - Bei Guo
- Department of Metabolism and Endocrinology, National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory of Metabolic Bone Diseases, the Second Xiangya Hospital, Central South University, Changsha, China
| | - Fuxingzi Li
- Department of Metabolism and Endocrinology, National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory of Metabolic Bone Diseases, the Second Xiangya Hospital, Central South University, Changsha, China
| | - Ming-Hui Zheng
- Department of Metabolism and Endocrinology, National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory of Metabolic Bone Diseases, the Second Xiangya Hospital, Central South University, Changsha, China
| | - Li-Min Lei
- Department of Metabolism and Endocrinology, National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory of Metabolic Bone Diseases, the Second Xiangya Hospital, Central South University, Changsha, China
| | - Qiu-Shuang Xu
- Department of Metabolism and Endocrinology, National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory of Metabolic Bone Diseases, the Second Xiangya Hospital, Central South University, Changsha, China
| | - Muhammad Hasnain Ehsan Ullah
- Department of Metabolism and Endocrinology, National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory of Metabolic Bone Diseases, the Second Xiangya Hospital, Central South University, Changsha, China
| | - Feng Xu
- Department of Metabolism and Endocrinology, National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory of Metabolic Bone Diseases, the Second Xiangya Hospital, Central South University, Changsha, China
| | - Xiao Lin
- Department of Radiology, the Second Xiangya Hospital, Central South University, Changsha, China
| | - Ling-Qing Yuan
- Department of Metabolism and Endocrinology, National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory of Metabolic Bone Diseases, the Second Xiangya Hospital, Central South University, Changsha, China
- *Correspondence: Ling-Qing Yuan,
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Hou Y, Lin W, Li Y, Sun Y, Liu Y, Chen C, Jiang X, Li G, Xu L. De-osteogenic-differentiated mesenchymal stem cells accelerate fracture healing by mir-92b. J Orthop Translat 2020; 27:25-32. [PMID: 33344169 PMCID: PMC7736910 DOI: 10.1016/j.jot.2020.10.009] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Revised: 10/05/2020] [Accepted: 10/23/2020] [Indexed: 12/20/2022] Open
Abstract
Background Mesenchymal stem cells (MSCs) are promising targets for therapeutic use in regenerative medicine and tissue engineering. In the previous study, we have found that MSCs could be reverted to a primitive stem cell population after in vitro induction of osteogenic and de-osteogenic differentiation (de-osteogenic differentiated MSCs, De-Os-MSCs). De-Os-MSCs showed improved cell survival and osteogenic potential. However, the underlying mechanism and its potential effect on fracture healing has not been explored. Methods MSCs were isolated from the rat bone marrow. MicroRNAs were cloned into lentiviral vectors and transduced into MSCs to observe the effects on osteogenesis. The expression levels of marker genes were evaluated by quantitative RT-PCR. Ectopic bone formation model was used to evaluate the bone regeneration ability of mir-92b transduced MSCs in vivo. An open femur fracture model was established, and MSCs or De-Os-MSCs were administrated to the fracture sites. Histological, biomechanical and microCT analysis were used to evaluate the quality of bone. Results In the present study, we found that mir-92b was significantly increased in the secretions of De-Os-MSCs. And mir-92b could promote the osteogenic differentiation potential of MSCs by activating pERK and JNK signaling pathways. The ectopic bone formation assay showed that MSCs overexpressing mir-92b formed more bone like tissues in vivo. Most importantly, we found local administration of De-Os-MSCs could accelerate fracture healing using an open femur fracture model in rats. The quality of bone property was much better as shown by microCT and biomechanical testing. Conclusion Taken together, our study demonstrated that mir-92b promoted osteogenesis of MSCs, which was partially accounted for the enhanced osteogenic differentiation potential of De-Os-MSCs. And De-Os-MSCs had shown better regenerative capacity in accelerating fracture healing when they were locally given. The translational potential of this article De-Os-MSCs could be used to accelerate fracture healing, and reduce the occurrence of delayed unions and non-unions.
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Affiliation(s)
- Yonghui Hou
- Key Laboratory of Orthopaedics & Traumatology, Guangdong Provincial Hospital of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China.,Lingnan Medical Research Center, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Weiping Lin
- Department of Orthopaedics & Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, PR China
| | - Ying Li
- Lingnan Medical Research Center, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yuxin Sun
- Department of Orthopaedics and Traumatology, Bao-An District People's Hospital, Shenzhen, PR China
| | - Yamei Liu
- Departments of Diagnostics of Traditional Chinese Medicine, Guangzhou University of Traditional Chinese Medicine, Guangzhou, Guangdong, 510006, PR China
| | - Chen Chen
- Departments of Diagnostics of Traditional Chinese Medicine, Guangzhou University of Traditional Chinese Medicine, Guangzhou, Guangdong, 510006, PR China
| | - Xiaohua Jiang
- Epithelial Cell Biology Research Center, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, PR China
| | - Gang Li
- Department of Orthopaedics & Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, PR China.,Stem Cells and Regenerative Medicine Laboratory, Lui Che Woo Institute of Innovative Medicine, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, PR China
| | - Liangliang Xu
- Lingnan Medical Research Center, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
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Charles CJ, Li RR, Yeung T, Mazlan SMI, Lai RC, de Kleijn DPV, Lim SK, Richards AM. Systemic Mesenchymal Stem Cell-Derived Exosomes Reduce Myocardial Infarct Size: Characterization With MRI in a Porcine Model. Front Cardiovasc Med 2020; 7:601990. [PMID: 33304934 PMCID: PMC7701257 DOI: 10.3389/fcvm.2020.601990] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Accepted: 10/16/2020] [Indexed: 12/26/2022] Open
Abstract
The observations that mesenchymal stem cells (MSCs) exert cardiac protection and repair via their secretome with the active component(s) identified as exosomes underpinned our test of the efficacy of MSC exosomes in a porcine model of myocardial infarction (MI) when administered systemically by the convenient method of intravenous (IV) bolus injection. Results show that 7 days of IV exosomes results in clear reduction (30-40%) of infarct size measured at both 7 and 28 days post-MI, despite near identical release of hs Troponin T. Together with reduced infarct size, exosome treatment reduced transmurality and lessened wall thinning in the infarct zone. Exosome treated pigs showed relative preservation of LV function with significant amelioration of falls in fractional wall thickening compared with control. However, global measures of LV function were less protected by exosome treatment. It is possible that greater preservation of global LV function may have been attenuated by increased cardiac fibrosis, as T1 values showed significant increase in the exosome pigs compared to control particularly in the infarct related segments. Taken together, these results show clear effects of IV exosomes administered over 7 days to reduce infarct size with relatively preserved cardiac function compared to control treated infarct pigs.
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Affiliation(s)
- Christopher J. Charles
- Cardiovascular Research Institute (CVRI), National University Heart Centre, Singapore, Singapore
- Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Department of Medicine, Christchurch Heart Institute, University of Otago, Christchurch, New Zealand
| | - Renee R. Li
- Cardiovascular Research Institute (CVRI), National University Heart Centre, Singapore, Singapore
- Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Teresa Yeung
- Cardiovascular Research Institute (CVRI), National University Heart Centre, Singapore, Singapore
- Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Stephane M. Ibraham Mazlan
- Cardiovascular Research Institute (CVRI), National University Heart Centre, Singapore, Singapore
- Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Ruenn Chai Lai
- Institute of Medical Biology, Agency for Science, Technology and Research (ASTAR), Singapore, Singapore
| | - Dominique P. V. de Kleijn
- Department of Vascular Surgery, University Medical Centre, Utrecht, and Netherlands Heart Institute, Utrecht, Netherlands
| | - Sai Kiang Lim
- Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Institute of Medical Biology, Agency for Science, Technology and Research (ASTAR), Singapore, Singapore
| | - A. Mark Richards
- Cardiovascular Research Institute (CVRI), National University Heart Centre, Singapore, Singapore
- Department of Medicine, Christchurch Heart Institute, University of Otago, Christchurch, New Zealand
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Effect of Mesenchymal Stem Cell-Derived Exosomes on Retinal Injury: A Review of Current Findings. Stem Cells Int 2020; 2020:8883616. [PMID: 33082789 PMCID: PMC7556062 DOI: 10.1155/2020/8883616] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Revised: 09/14/2020] [Accepted: 09/21/2020] [Indexed: 02/08/2023] Open
Abstract
In recent years, various studies have followed in the literature on the therapeutic effects of mesenchymal stem cells (MSC) on damage in retinal cells. The evidence that MSCs exert their regenerative and damage reduction effect in a paracrine way, through the release of soluble factors and exosomes, is now consolidated. Exosomes are microvesicles formed by a double layer of phospholipid membrane and carry proteins and RNA, through which they play a therapeutic role on target cells. Scientific research has recently focused on the use of exosomes derived from MSC in various models of retinal damage in vitro and in vivo as they, compared to MSCs, have similar functions and at the same time have different advantages such as greater stability and handling, a lower chance of immunological rejection and no risk of malignant transformation. The purpose of this review is to summarize current knowledge on the therapeutic use of exosomes derived from MSCs in retinal damage and to stimulate new clinical perspectives regarding their use.
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Extracellular vesicles derived from mesenchymal stromal cells mitigate intestinal toxicity in a mouse model of acute radiation syndrome. Stem Cell Res Ther 2020; 11:371. [PMID: 32854778 PMCID: PMC7457304 DOI: 10.1186/s13287-020-01887-1] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Revised: 08/04/2020] [Accepted: 08/17/2020] [Indexed: 02/07/2023] Open
Abstract
Background Human exposure to high doses of radiation resulting in acute radiation syndrome and death can rapidly escalate to a mass casualty catastrophe in the event of nuclear accidents or terrorism. The primary reason is that there is presently no effective treatment option, especially for radiation-induced gastrointestinal syndrome. This syndrome results from disruption of mucosal barrier integrity leading to severe dehydration, blood loss, and sepsis. In this study, we tested whether extracellular vesicles derived from mesenchymal stromal cells (MSC) could reduce radiation-related mucosal barrier damage and reduce radiation-induced animal mortality. Methods Human MSC-derived extracellular vesicles were intravenously administered to NUDE mice, 3, 24, and 48 h after lethal whole-body irradiation (10 Gy). Integrity of the small intestine epithelial barrier was assessed by morphologic analysis, immunostaining for tight junction protein (claudin-3), and in vivo permeability to 4 kDa FITC-labeled dextran. Renewal of the small intestinal epithelium was determined by quantifying epithelial cell apoptosis (TUNEL staining) and proliferation (Ki67 immunostaining). Statistical analyses were performed using one-way ANOVA followed by a Tukey test. Statistical analyses of mouse survival were performed using Kaplan-Meier and Cox methods. Results We demonstrated that MSC-derived extracellular vesicle treatment reduced by 85% the instantaneous mortality risk in mice subjected to 10 Gy whole-body irradiation and so increased their survival time. This effect could be attributed to the efficacy of MSC-derived extracellular vesicles in reducing mucosal barrier disruption. We showed that the MSC-derived extracellular vesicles improved the renewal of the small intestinal epithelium by stimulating proliferation and inhibiting apoptosis of the epithelial crypt cells. The MSC-derived extracellular vesicles also reduced radiation-induced mucosal permeability as evidenced by the preservation of claudin-3 immunostaining at the tight junctions of the epithelium. Conclusions MSC-derived extracellular vesicles promote epithelial repair and regeneration and preserve structural integrity of the intestinal epithelium in mice exposed to radiation-induced gastrointestinal toxicity. Our results suggest that the administration of MSC-derived extracellular vesicles could be an effective therapy for limiting acute radiation syndrome.
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Varderidou-Minasian S, Lorenowicz MJ. Mesenchymal stromal/stem cell-derived extracellular vesicles in tissue repair: challenges and opportunities. Theranostics 2020; 10:5979-5997. [PMID: 32483432 PMCID: PMC7254996 DOI: 10.7150/thno.40122] [Citation(s) in RCA: 186] [Impact Index Per Article: 37.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2019] [Accepted: 02/24/2020] [Indexed: 02/07/2023] Open
Abstract
Mesenchymal stem/stromal cells (MSCs) are important players in tissue homeostasis and regeneration owing to their immunomodulatory potential and release of trophic factors that promote healing. They have been increasingly used in clinical trials to treat multiple conditions associated with inflammation and tissue damage such as graft versus host disease, orthopedic injuries and cardiac and liver diseases. Recent evidence demonstrates that their beneficial effects are derived, at least in part, from their secretome. In particular, data from animal models and first-in-man studies indicate that MSC-derived extracellular vesicles (MSC-EVs) can exert similar therapeutic potential as their cells of origin. MSC-EVs are membranous structures loaded with proteins, lipids, carbohydrates and nucleic acids, which play an important role in cell-cell communication and may represent an attractive alternative for cell-based therapy. In this article we summarize recent advances in the use of MSC-EVs for tissue repair. We highlight several isolation and characterization approaches used to enrich MSC-derived EVs. We discuss our current understanding of the relative contribution of the MSC-EVs to the immunomodulatory and regenerative effects mediated by MSCs and MSC secretome. Finally we highlight the challenges and opportunities, which come with the potential use of MSC-EVs as cell free therapy for conditions that require tissue repair.
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