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1
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Azarfarin M, Shahla MM, Mohaddes G, Dadkhah M. Non-pharmacological therapeutic paradigms in stress-induced depression: from novel therapeutic perspective with focus on cell-based strategies. Acta Neuropsychiatr 2025; 37:e10. [PMID: 39973753 DOI: 10.1017/neu.2024.39] [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] [Indexed: 02/21/2025]
Abstract
Major depressive disorder (MDD) is considered a psychiatric disorder and have a relationship with stressful events. Although the common therapeutic approaches against MDD are diverse, a large number of patients do not present an adequate response to antidepressant treatments. On the other hand, effective non-pharmacological treatments for MDD and their tolerability are addressed. Several affective treatments for MDD are used but non-pharmacological strategies for decreasing the common depression-related drugs side effects have been focused recently. However, the potential of extracellular vesicles (EVs) derived from mesenchymal stem cells (MSCs), microRNAs (miRNAs) as cell-based therapeutic paradigms, besides other non-pharmacological strategies including mitochondrial transfer, plasma, transcranial direct current stimulation (tDCS), transcranial magnetic stimulation (TMS), and exercise therapy needs to further study. This review explores the therapeutic potential of cell-based therapeutic non-pharmacological paradigms for MDD treatment. In addition, plasma therapy, mitotherapy, and exercise therapy in several in vitro and in vivo conditions in experimental disease models along with tDCS and TMS will be discussed as novel non-pharmacological promising therapeutic approaches.
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Affiliation(s)
- Maryam Azarfarin
- Neuroscience Research center, Tabriz University of Medical Sciences, Tabriz, Iran
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Neuroscience, Faculty of Advanced Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Gisou Mohaddes
- Neuroscience Research center, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Biomedical Education, College of Osteopathic Medicine, California Health Sciences University, Clovis, CA, USA
| | - Masoomeh Dadkhah
- Pharmaceutical Sciences Research Center, Ardabil University of Medical Sciences, Ardabil, Iran
- Neuroscience Research Group, Pharmaceutical Sciences Research Center, Ardabil University of Medical Sciences, Ardabil, Iran
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2
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Jafar H, Alqudah D, Rahmeh R, Al-Hattab D, Ahmed K, Rayyan R, Abusneinah A, Rasheed M, Rayyan Y, Awidi A. Safety and Potential Efficacy of Expanded Umbilical Cord-Derived Mesenchymal Stromal Cells in Luminal Ulcerative Colitis Patients. Stem Cells Dev 2024; 33:645-651. [PMID: 39446772 DOI: 10.1089/scd.2024.0102] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2024] Open
Abstract
Inflammatory bowel disease (IBD) is characterized by periods of flare-ups and remission. It is likely to be an autoimmune in origin, presenting persistent therapeutic challenges despite current therapies. This study aims to investigate the potential of umbilical cord mesenchymal stromal cells (UCMSCs) in treating ulcerative colitis (UC). This study is a prospective phase 1 pilot, open-label, single-arm, and single-center study. UCMSCs were cultured under current Good Manufacturing Practice (cGMP) conditions and intravenously administered to six patients with UC. Safety and efficacy were evaluated using the Mayo Score/Disease Activity Index. Among the six enrolled adult patients, five completed long-term follow-ups. All exhibited at diagnosis active UC confirmed through comprehensive assessment methods. Each patient received three injections intravenously 2 weeks apart with a dose of 100 million UCMSC each. No significant short-term or intermediate-term adverse events were detected post-UCMSC administration. Long-term follow-up at 12 and 24 months showed sustained safety and no adverse events. Notably, three out of five patients achieved a Mayo score of 0 for UC, maintained at both 12 and 24 months, indicating a highly significant response (P < 0.001). This study demonstrates the safety and potential efficacy of UCMSCs in active UC. However, larger trials are warranted to validate these preliminary findings and to establish the role of UCMSC therapy as an option for managing UC.
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Affiliation(s)
- Hanan Jafar
- Cell Therapy Center, The University of Jordan, Amman, Jordan
| | - Dana Alqudah
- Cell Therapy Center, The University of Jordan, Amman, Jordan
| | - Reem Rahmeh
- Cell Therapy Center, The University of Jordan, Amman, Jordan
| | - Dana Al-Hattab
- Cell Therapy Center, The University of Jordan, Amman, Jordan
- Electrical and Mathematical Sciences and Engineering Department, King Abdulla University of Science and Technology, Thuwal, ThuwalSaudi Arabia
| | - Khalid Ahmed
- School of Medicine, The University of Jordan, Amman, Jordan
| | - Rama Rayyan
- School of Medicine, The University of Jordan, Amman, Jordan
| | - Awni Abusneinah
- School of Medicine, The University of Jordan, Amman, Jordan
- Internal Medicine Department, Jordan University Hospital, Amman, Jordan
| | - Mohammad Rasheed
- School of Medicine, The University of Jordan, Amman, Jordan
- Internal Medicine Department, Jordan University Hospital, Amman, Jordan
| | - Yaser Rayyan
- School of Medicine, The University of Jordan, Amman, Jordan
- Internal Medicine Department, Jordan University Hospital, Amman, Jordan
| | - Abdalla Awidi
- Cell Therapy Center, The University of Jordan, Amman, Jordan
- School of Medicine, The University of Jordan, Amman, Jordan
- Internal Medicine Department, Jordan University Hospital, Amman, Jordan
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3
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Li L, Zhang X, Wu Y, Xing C, Du H. Challenges of mesenchymal stem cells in the clinical treatment of COVID-19. Cell Tissue Res 2024; 396:293-312. [PMID: 38512548 DOI: 10.1007/s00441-024-03881-y] [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: 06/17/2023] [Accepted: 02/19/2024] [Indexed: 03/23/2024]
Abstract
The 2019 coronavirus disease (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has brought an enormous public health burden to the global society. The duration of the epidemic, the number of infected people, and the widespread of the epidemic are extremely rare in modern society. In the initial stage of infection, people generally show fever, cough, and dyspnea, which can lead to pneumonia, acute respiratory syndrome, kidney failure, and even death in severe cases. The strong infectivity and pathogenicity of SARS-CoV-2 make it more urgent to find an effective treatment. Mesenchymal stem cells (MSCs) are a kind of pluripotent stem cells with the potential for self-renewal and multi-directional differentiation. They are widely used in clinical experiments because of their low immunogenicity and immunomodulatory function. Mesenchymal stem cell-derived exosomes (MSC-Exo) can play a physiological role similar to that of stem cells. Since the COVID-19 pandemic, a series of clinical trials based on MSC therapy have been carried out. The results show that MSCs are safe and can significantly improve patients' respiratory function and prognosis of COVID-19. Here, the effects of MSCs and MSC-Exo in the treatment of COVID-19 are reviewed, and the clinical challenges that may be faced in the future are clarified.
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Affiliation(s)
- Luping Li
- School of Chemistry and Biological Engineering, University of Science and Technology Beijing, No. 30 XueYuan Road, Haidian District, Beijing, 100083, China
- Daxing Research Institute, University of Science and Technology Beijing, Beijing, 100083, China
| | - Xiaoshuang Zhang
- School of Chemistry and Biological Engineering, University of Science and Technology Beijing, No. 30 XueYuan Road, Haidian District, Beijing, 100083, China
- Daxing Research Institute, University of Science and Technology Beijing, Beijing, 100083, China
| | - Yawen Wu
- School of Chemistry and Biological Engineering, University of Science and Technology Beijing, No. 30 XueYuan Road, Haidian District, Beijing, 100083, China
- Daxing Research Institute, University of Science and Technology Beijing, Beijing, 100083, China
| | - Cencan Xing
- Daxing Research Institute, University of Science and Technology Beijing, Beijing, 100083, China.
| | - Hongwu Du
- School of Chemistry and Biological Engineering, University of Science and Technology Beijing, No. 30 XueYuan Road, Haidian District, Beijing, 100083, China.
- Daxing Research Institute, University of Science and Technology Beijing, Beijing, 100083, China.
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Chen QQ, Wang C, Wang WH, Gong Y, Chen HX. Histopathological and Immunohistochemical Mechanisms of Bone Marrow-Derived Mesenchymal Stem Cells in Reversion of Gastric Precancerous Lesions. FRONT BIOSCI-LANDMRK 2024; 29:127. [PMID: 38538255 DOI: 10.31083/j.fbl2903127] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Revised: 11/24/2023] [Accepted: 12/13/2023] [Indexed: 01/02/2025]
Abstract
BACKGROUND Gastric cancer (GC) stands as one of the most prevalent cancer types worldwide, holding the position of the second leading cause of cancer-related deaths. Gastric lesions represent pathological alterations to the gastric mucosa, with an elevated propensity to advance to gastric cancer. Limited research has explored the potential of stem cells in the treatment of gastric lesions. METHODS This study aimed to explore the potential of intravenous transplantation of labeled bone marrow-derived mesenchymal stem cells (BMMSCs) to inhibit the progression of precancerous gastric lesions. RESULTS In the gastric lesion disease model group, the rat tissue exhibited noteworthy mucosal atrophy, intestinal metaplasia, dysplasia, and inflammatory cell infiltration. Following the infusion of BMMSCs, a notable decrease in gastric lesions was found, with atrophic gastritis being the sole remaining lesion, which was confirmed by morphological and histological examinations. BMMSCs that were colonized at gastric lesions could differentiate into epithelial and stromal cells, as determined by the expression of pan-keratin or vimentin. The expression of vascular endothelial growth factor was significantly elevated following BMMSC transplantation. BMMSCs could also upregulate the production of humoral immune response cytokines, including interleukin (IL)-4 and IL-10, and downregulate the production of IL-17 and interferon-gamma, which could be highly associated with the cellular immune response and inflammation severity of the lesions. CONCLUSIONS BMMSC transplantation significantly reduced inflammation and reversed gastric lesion progression.
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Affiliation(s)
- Qian-Qian Chen
- Department of Gastroenterology and Hepatology, The First Medical Center, Chinese PLA General Hospital, 100853 Beijing, China
| | - Cong Wang
- Department of Gastroenterology and Hepatology, The Second Medical Center, Chinese PLA General Hospital, 100853 Beijing, China
- Medical School of Chinese PLA, 100853 Beijing, China
| | - Wei-Hua Wang
- Department of Gastroenterology and Hepatology, The Second Medical Center, Chinese PLA General Hospital, 100853 Beijing, China
| | - Yuan Gong
- Department of Gastroenterology and Hepatology, The Second Medical Center, Chinese PLA General Hospital, 100853 Beijing, China
| | - Hai-Xu Chen
- Department of Gastroenterology and Hepatology, The Second Medical Center, Chinese PLA General Hospital, 100853 Beijing, China
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Sun T, Zhou C, Lu F, Dong Z, Gao J, Li B. Adipose-derived stem cells in immune-related skin disease: a review of current research and underlying mechanisms. Stem Cell Res Ther 2024; 15:37. [PMID: 38331803 PMCID: PMC10854049 DOI: 10.1186/s13287-023-03561-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Accepted: 11/06/2023] [Indexed: 02/10/2024] Open
Abstract
Adipose-derived stem cells (ASCs) are a critical adult stem cell subpopulation and are widely utilized in the fields of regenerative medicine and stem cell research due to their abundance, ease of harvest, and low immunogenicity. ASCs, which are homologous with skin by nature, can treat immune-related skin diseases by promoting skin regeneration and conferring immunosuppressive effects, with the latter being the most important therapeutic mechanism. ASCs regulate the immune response by direct cell-cell communication with immune cells, such as T cells, macrophages, and B cells. In addition to cell-cell interactions, ASCs modulate the immune response indirectly by secreting cytokines, interleukins, growth factors, and extracellular vesicles. The immunomodulatory effects of ASCs have been exploited to treat many immune-related skin diseases with good therapeutic outcomes. This article reviews the mechanisms underlying the immunomodulatory effects of ASCs, as well as progress in research on immune-related skin diseases.
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Affiliation(s)
- Tianyi Sun
- The Department of Plastic and Cosmetic Surgery, Nanfang Hospital, Southern Medical University, 1838 Guangzhou North Road, Guangzhou, 510515, Guangdong, China
| | - Cheng Zhou
- The Department of Plastic and Cosmetic Surgery, Nanfang Hospital, Southern Medical University, 1838 Guangzhou North Road, Guangzhou, 510515, Guangdong, China
| | - Feng Lu
- The Department of Plastic and Cosmetic Surgery, Nanfang Hospital, Southern Medical University, 1838 Guangzhou North Road, Guangzhou, 510515, Guangdong, China
| | - Ziqing Dong
- The Department of Plastic and Cosmetic Surgery, Nanfang Hospital, Southern Medical University, 1838 Guangzhou North Road, Guangzhou, 510515, Guangdong, China
| | - Jianhua Gao
- The Department of Plastic and Cosmetic Surgery, Nanfang Hospital, Southern Medical University, 1838 Guangzhou North Road, Guangzhou, 510515, Guangdong, China.
| | - Bin Li
- The Department of Plastic and Cosmetic Surgery, Nanfang Hospital, Southern Medical University, 1838 Guangzhou North Road, Guangzhou, 510515, Guangdong, China.
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Wang J, Donohoe E, Canning A, Moosavizadeh S, Buckley F, Brennan MÁ, Ryan AE, Ritter T. Immunomodulatory function of licensed human bone marrow mesenchymal stromal cell-derived apoptotic bodies. Int Immunopharmacol 2023; 125:111096. [PMID: 37871378 DOI: 10.1016/j.intimp.2023.111096] [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: 08/23/2023] [Revised: 10/02/2023] [Accepted: 10/18/2023] [Indexed: 10/25/2023]
Abstract
BACKGROUND Mesenchymal stromal cells (MSCs) show great potential for immunomodulatory and anti-inflammatory treatments. Clinical trials have been performed for the treatment of Type 1 diabetes, graft-versus-host disease and organ transplantation, which offer a promise of MSCs as an immunomodulatory therapy. Nevertheless, their unstable efficacy and immunogenicity concerns present challenges to clinical translation. It has emerged that the MSC-derived secretome, which includes secreted proteins, exosomes, apoptotic bodies (ABs) and other macromolecules, may have similar therapeutic effects to parent MSCs. Among all of the components of the MSC-derived secretome, most interest thus far has been garnered by exosomes for their therapeutic potential. However, since MSCs were reported to undergo apoptosis after in vivo transplantation and release ABs, we speculated as to whether ABs have immunomodulatory effects. In this study, cytokine licensing was used to enhance the immunomodulatory potency of MSCs and ABs derived from licensed MSCs in vitro were isolated to explore their immunomodulatory effects as an effective non-viable cell therapy. RESULTS IFN-γ and IFN-γ/TGF-β1 licensing enhanced the immunomodulatory effect of MSCs on T cell proliferation. Further, TGF-β1 and IFN-γ licensing strengthened the immunomodulatory effect of MSC on reducing the TNF-α and IL-1β expression by M1 macrophage-like THP-1 cells. Additionally, we discovered the immunomodulatory effect mediated by MSC-derived apoptotic bodies. Licensing impacted the uptake of ABs by recipient immune cells and importantly altered their phenotypes. CONCLUSION ABs derived from IFN-γ/TGF-β1-licensed apoptotic MSCs significantly inhibited T cell proliferation, induced more regulatory T cells, and maintained immunomodulatory T cells but reduced pro-inflammatory T cells.
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Affiliation(s)
- Jiemin Wang
- Regenerative Medicine Institute, School of Medicine, University of Galway, Galway, Ireland
| | - Ellen Donohoe
- Regenerative Medicine Institute, School of Medicine, University of Galway, Galway, Ireland
| | - Aoife Canning
- Regenerative Medicine Institute, School of Medicine, University of Galway, Galway, Ireland
| | - Seyedmohammad Moosavizadeh
- Regenerative Medicine Institute, School of Medicine, University of Galway, Galway, Ireland; CURAM Centre for Research in Medical Devices, University of Galway, Galway, Ireland
| | - Fiona Buckley
- Regenerative Medicine Institute, School of Medicine, University of Galway, Galway, Ireland; Biomedical Engineering, School of Engineering, University of Galway, Galway, Ireland
| | - Meadhbh Á Brennan
- Regenerative Medicine Institute, School of Medicine, University of Galway, Galway, Ireland; CURAM Centre for Research in Medical Devices, University of Galway, Galway, Ireland
| | - Aideen E Ryan
- Regenerative Medicine Institute, School of Medicine, University of Galway, Galway, Ireland; CURAM Centre for Research in Medical Devices, University of Galway, Galway, Ireland; Discipline of Pharmacology and Therapeutics, School of Medicine, University of Galway, Galway, Ireland
| | - Thomas Ritter
- Regenerative Medicine Institute, School of Medicine, University of Galway, Galway, Ireland; CURAM Centre for Research in Medical Devices, University of Galway, Galway, Ireland.
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Nie M, Huang D, Chen G, Zhao Y, Sun L. Bioadhesive Microcarriers Encapsulated with IL-27 High Expressive MSC Extracellular Vesicles for Inflammatory Bowel Disease Treatment. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2023; 10:e2303349. [PMID: 37759399 PMCID: PMC10646269 DOI: 10.1002/advs.202303349] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Revised: 07/24/2023] [Indexed: 09/29/2023]
Abstract
Mesenchymal stem cell (MSC) therapy is a promising candidate for inflammatory bowel disease (IBD) treatment, while overcoming the limitations of naive seeding cells function and realizing efficient intestinal targeting remains a challenge. Here, a bioadhesive microparticle carrying interleukin-27 (IL-27) MSC-derived extracellular vesicles (MSCIL-27 EVs) is developed to treat IBD. The MSCIL-27 EVs prepared through lentivirus-mediated gene transfection technology show ideal anti-inflammatory and damage repair function. By encapsulating MSCIL-27 EVs into dopamine methacrylamide-modified hydrogel, a bioadhesive EVs microcarrier via microfluidic technology is fabricated. The resultant microcarriers exhibit ideal MSCIL-27 EVs sustained release effect and effective wet adhesion property. Furthermore, the therapeutic potential of MSCIL-27 EVs-loaded microcarriers in treating IBD is demonstrated. Through giving IBD rats a rectal administration, it is found that the microcarriers can firmly anchor to the surface of colon, reduce the inflammatory response, and repair the damaged barrier. Therefore, the bioadhesive MSCIL-27 EVs-loaded microcarriers provide a promising strategy for the biomedical application of MSC-derived EVs, and broaden the clinical potential of MSC therapy.
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Affiliation(s)
- Min Nie
- Department of Rheumatology and ImmunologyNanjing Drum Tower HospitalAffiliated Hospital of Medical SchoolNanjing UniversityNanjing210002China
| | - Danqing Huang
- Department of Rheumatology and ImmunologyNanjing Drum Tower HospitalAffiliated Hospital of Medical SchoolNanjing UniversityNanjing210002China
| | - Guopu Chen
- Department of Rheumatology and ImmunologyNanjing Drum Tower HospitalAffiliated Hospital of Medical SchoolNanjing UniversityNanjing210002China
| | - Yuanjin Zhao
- Department of Rheumatology and ImmunologyNanjing Drum Tower HospitalAffiliated Hospital of Medical SchoolNanjing UniversityNanjing210002China
- State Key Laboratory of BioelectronicsSchool of Biological Science and Medical EngineeringSoutheast UniversityNanjing210096China
| | - Lingyun Sun
- Department of Rheumatology and ImmunologyNanjing Drum Tower HospitalAffiliated Hospital of Medical SchoolNanjing UniversityNanjing210002China
- Department of Rheumatology and ImmunologyThe First Affiliated Hospital of Anhui Medical UniversityHefei230000China
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Ntampakis G, Pramateftakis MG, Ioannidis O, Bitsianis S, Christidis P, Symeonidis S, Koliakos G, Karakota M, Bekiari C, Tsakona A, Cheva A, Aggelopoulos S. The Role of Adipose Tissue Mesenchymal Stem Cells in Colonic Anastomosis Healing in Inflammatory Bowel Disease: Experimental Study in Rats. J Clin Med 2023; 12:6336. [PMID: 37834980 PMCID: PMC10573964 DOI: 10.3390/jcm12196336] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2023] [Revised: 09/28/2023] [Accepted: 09/30/2023] [Indexed: 10/15/2023] Open
Abstract
(1) Background: A surgical operation on an inflamed bowel is, diachronically, a challenge for the surgeon, especially for patients with inflammatory bowel disease. Adipose tissue-derived mesenchymal stromal cells are already in use in clinical settings for their anti-inflammatory properties. The rationale of the current study was to use AdMSCs in high-risk anastomoses to monitor if they attenuate inflammation and prevent anastomotic leak. (2) Methods: a total of 4 groups of rats were subjected to a surgical transection of the large intestine and primary anastomosis. In two groups, DSS 5% was administered for 7 days prior to the procedure, to induce acute intestinal inflammation. After the anastomosis, 5 × 106 autologous AdMSCs or an acellular solution was injected locally. Macroscopic evaluation, bursting pressure, hydroxyproline, and inflammatory cytokine expression were the parameters measured on the 8th post-operative day. (3) Results: Significantly less intra-abdominal complications, higher bursting pressures, and a decrease in pro-inflammatory markers were found in the groups that received AdMSCs. No difference in VEGF expression was observed on the 8th post-operative day. (4) Conclusions: AdMSCs attenuate inflammation in cases of acutely inflamed anastomosis.
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Affiliation(s)
- Georgios Ntampakis
- 4th Department of General Surgery, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece; (G.N.)
| | | | - Orestis Ioannidis
- 4th Department of General Surgery, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece; (G.N.)
| | - Stefanos Bitsianis
- 4th Department of General Surgery, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece; (G.N.)
| | - Panagiotis Christidis
- 4th Department of General Surgery, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece; (G.N.)
| | - Savvas Symeonidis
- 4th Department of General Surgery, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece; (G.N.)
| | - Georgios Koliakos
- Laboratory of Biochemistry, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
| | - Maria Karakota
- Laboratory of Biochemistry, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
| | - Chrysanthi Bekiari
- Experimental and Research Center, Papageorgiou General Hospital of Thessaloniki, 56403 Thessaloniki, Greece
- Laboratory of Anatomy and Histology, Veterinary School, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
| | - Anastasia Tsakona
- Pathology Department, Faculty of Medicine, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
| | - Angeliki Cheva
- Pathology Department, Faculty of Medicine, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
| | - Stamatios Aggelopoulos
- 4th Department of General Surgery, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece; (G.N.)
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9
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Zhu Y, Wang Y, Xia G, Zhang X, Deng S, Zhao X, Xu Y, Chang G, Tao Y, Li M, Li H, Huang X, Chan HF. Oral Delivery of Bioactive Glass-Loaded Core-Shell Hydrogel Microspheres for Effective Treatment of Inflammatory Bowel Disease. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2023; 10:e2207418. [PMID: 37092589 PMCID: PMC10288274 DOI: 10.1002/advs.202207418] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Revised: 03/13/2023] [Indexed: 05/03/2023]
Abstract
Resolving inflammation and promoting intestinal tissue regeneration are critical for inflammatory bowel disease (IBD) treatment. Bioactive glass (BG) is a clinically approved bone graft material and has been shown to modulate inflammatory response, but it is unknown whether BG can be applied to treat IBD. Here, it is reported that BG attenuates pro-inflammatory response of lipopolysaccharide (LPS)-stimulated macrophages and hence reduces inflammatory damage to intestinal organoids in vitro. In addition, zein/sodium alginate-based core-shell microspheres (Zein/SA/BG) are developed for oral delivery of BG, which helps prevent premature dissolution of BG in the stomach. The results show that Zein/SA/BG protects BG from a gastric-simulated environment while dissolved in an intestinal-simulated environment. When administered to acute and chronic colitis mice model, Zein/SA/BG significantly reduces intestinal inflammation, promotes epithelial tissue regeneration, and partially restores microbiota homeostasis. These findings are the first to reveal the therapeutic efficacy of BG against IBD, which may provide a new therapeutic approach at low cost for effective IBD treatment.
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Affiliation(s)
- Yanlun Zhu
- Key Laboratory for Regenerative Medicine of the Ministry of Education of ChinaSchool of Biomedical SciencesFaculty of MedicineThe Chinese University of Hong KongShatinHong Kong SAR999077China
- Institute for Tissue Engineering and Regenerative MedicineThe Chinese University of Hong KongShatinHong Kong SAR999077China
| | - Yiwei Wang
- Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine600 Yishan RdShanghai200233China
| | - Guanggai Xia
- Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine600 Yishan RdShanghai200233China
| | - Xuerao Zhang
- Key Laboratory for Regenerative Medicine of the Ministry of Education of ChinaSchool of Biomedical SciencesFaculty of MedicineThe Chinese University of Hong KongShatinHong Kong SAR999077China
- Institute for Tissue Engineering and Regenerative MedicineThe Chinese University of Hong KongShatinHong Kong SAR999077China
| | - Shuai Deng
- Key Laboratory for Regenerative Medicine of the Ministry of Education of ChinaSchool of Biomedical SciencesFaculty of MedicineThe Chinese University of Hong KongShatinHong Kong SAR999077China
- Institute for Tissue Engineering and Regenerative MedicineThe Chinese University of Hong KongShatinHong Kong SAR999077China
- Cell Therapy and Cell Drugs of Luzhou Key LaboratorySchool of PharmacySouthwest Medical UniversityLuzhouSichuan646000China
| | - Xiaoyu Zhao
- Key Laboratory for Regenerative Medicine of the Ministry of Education of ChinaSchool of Biomedical SciencesFaculty of MedicineThe Chinese University of Hong KongShatinHong Kong SAR999077China
- Institute for Tissue Engineering and Regenerative MedicineThe Chinese University of Hong KongShatinHong Kong SAR999077China
| | - Yanteng Xu
- Laboratory of Biomaterials and Translational MedicineCenter for NanomedicineThe Third Affiliated HospitalSun Yat‐sen UniversityGuangzhou510630China
| | - Guozhu Chang
- Key Laboratory for Regenerative Medicine of the Ministry of Education of ChinaSchool of Biomedical SciencesFaculty of MedicineThe Chinese University of Hong KongShatinHong Kong SAR999077China
- Institute for Tissue Engineering and Regenerative MedicineThe Chinese University of Hong KongShatinHong Kong SAR999077China
| | - Yu Tao
- Laboratory of Biomaterials and Translational MedicineCenter for NanomedicineThe Third Affiliated HospitalSun Yat‐sen UniversityGuangzhou510630China
| | - Mingqiang Li
- Laboratory of Biomaterials and Translational MedicineCenter for NanomedicineThe Third Affiliated HospitalSun Yat‐sen UniversityGuangzhou510630China
- Guangdong Provincial Key Laboratory of Liver DiseaseGuangzhou510630China
| | - Haiyan Li
- Chemical and Environmental EngineeringSchool of EngineeringRMIT University124 La Trobe StMelbourneVIC3000Australia
| | - Xinyu Huang
- Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine600 Yishan RdShanghai200233China
| | - Hon Fai Chan
- Key Laboratory for Regenerative Medicine of the Ministry of Education of ChinaSchool of Biomedical SciencesFaculty of MedicineThe Chinese University of Hong KongShatinHong Kong SAR999077China
- Institute for Tissue Engineering and Regenerative MedicineThe Chinese University of Hong KongShatinHong Kong SAR999077China
- Hong Kong Branch of CAS Center for Excellence in Animal Evolution and Genetics999077Hong Kong SARChina
- Center for Neuromusculoskeletal Restorative MedicineHong Kong Science ParkHong Kong SAR999077China
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10
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Ivanisova D, Bohac M, Culenova M, Smolinska V, Danisovic L. Mesenchymal-Stromal-Cell-Conditioned Media and Their Implication for Osteochondral Regeneration. Int J Mol Sci 2023; 24:9054. [PMID: 37240400 PMCID: PMC10218888 DOI: 10.3390/ijms24109054] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Revised: 05/09/2023] [Accepted: 05/17/2023] [Indexed: 05/28/2023] Open
Abstract
Despite significant advances in biomedical research, osteochondral defects resulting from injury, an autoimmune condition, cancer, or other pathological conditions still represent a significant medical problem. Even though there are several conservative and surgical treatment approaches, in many cases, they do not bring the expected results and further permanent damage to the cartilage and bones occurs. Recently, cell-based therapies and tissue engineering have gradually become promising alternatives. They combine the use of different types of cells and biomaterials to induce regeneration processes or replace damaged osteochondral tissue. One of the main challenges of this approach before clinical translation is the large-scale in vitro expansion of cells without changing their biological properties, while the use of conditioned media which contains various bioactive molecules appears to be very important. The presented manuscript provides a review of the experiments focused on osteochondral regeneration by using conditioned media. In particular, the effect on angiogenesis, tissue healing, paracrine signaling, and enhancing the properties of advanced materials are pointed out.
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Affiliation(s)
- Dana Ivanisova
- Regenmed Ltd., Medena 29, 811 01 Bratislava, Slovakia; (D.I.); (M.B.)
- Institute of Medical Biology, Genetics and Clinical Genetics, Faculty of Medicine, Comenius University, Sasinkova 4, 811 08 Bratislava, Slovakia; (M.C.); (V.S.)
| | - Martin Bohac
- Regenmed Ltd., Medena 29, 811 01 Bratislava, Slovakia; (D.I.); (M.B.)
- Centre for Tissue Engineering and Regenerative Medicine–Translational Research Unit in the Branch of Regenerative Medicine, Faculty of Medicine, Comenius University, Sasinkova 4, 811 08 Bratislava, Slovakia
| | - Martina Culenova
- Institute of Medical Biology, Genetics and Clinical Genetics, Faculty of Medicine, Comenius University, Sasinkova 4, 811 08 Bratislava, Slovakia; (M.C.); (V.S.)
- National Institute of Rheumatic Diseases, Nábrežie I. Krasku 4, 921 12 Piešťany, Slovakia
| | - Veronika Smolinska
- Institute of Medical Biology, Genetics and Clinical Genetics, Faculty of Medicine, Comenius University, Sasinkova 4, 811 08 Bratislava, Slovakia; (M.C.); (V.S.)
- National Institute of Rheumatic Diseases, Nábrežie I. Krasku 4, 921 12 Piešťany, Slovakia
| | - Lubos Danisovic
- Institute of Medical Biology, Genetics and Clinical Genetics, Faculty of Medicine, Comenius University, Sasinkova 4, 811 08 Bratislava, Slovakia; (M.C.); (V.S.)
- Centre for Tissue Engineering and Regenerative Medicine–Translational Research Unit in the Branch of Regenerative Medicine, Faculty of Medicine, Comenius University, Sasinkova 4, 811 08 Bratislava, Slovakia
- National Institute of Rheumatic Diseases, Nábrežie I. Krasku 4, 921 12 Piešťany, Slovakia
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11
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Tian CM, Zhang Y, Yang MF, Xu HM, Zhu MZ, Yao J, Wang LS, Liang YJ, Li DF. Stem Cell Therapy in Inflammatory Bowel Disease: A Review of Achievements and Challenges. J Inflamm Res 2023; 16:2089-2119. [PMID: 37215379 PMCID: PMC10199681 DOI: 10.2147/jir.s400447] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Accepted: 05/03/2023] [Indexed: 05/24/2023] Open
Abstract
Inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), is a group of chronic inflammatory diseases of the gastrointestinal tract. Repeated inflammation can lead to complications, such as intestinal fistula, obstruction, perforation, and bleeding. Unfortunately, achieving durable remission and mucosal healing (MH) with current treatments is difficult. Stem cells (SCs) have the potential to modulate immunity, suppress inflammation, and have anti-apoptotic and pro-angiogenic effects, making them an ideal therapeutic strategy to target chronic inflammation and intestinal damage in IBD. In recent years, hematopoietic stem cells (HSCs) and adult mesenchymal stem cells (MSCs) have shown efficacy in treating IBD. In addition, numerous clinical trials have evaluated the efficiency of MSCs in treating the disease. This review summarizes the current research progress on the safety and efficacy of SC-based therapy for IBD in both preclinical models and clinical trials. We discuss potential mechanisms of SC therapy, including tissue repair, paracrine effects, and the promotion of angiogenesis, immune regulation, and anti-inflammatory effects. We also summarize current SC engineering strategies aimed at enhancing the immunosuppressive and regenerative capabilities of SCs for treating intestinal diseases. Additionally, we highlight current limitations and future perspectives of SC-related therapy for IBD.
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Affiliation(s)
- Cheng-Mei Tian
- Department of Gastroenterology, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, People’s Republic of China
- Department of Emergency, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, People’s Republic of China
| | - Yuan Zhang
- Department of Medical Administration, Huizhou Institute of Occupational Diseases Control and Prevention, Huizhou, Guangdong, People’s Republic of China
| | - Mei-Feng Yang
- Department of Hematology, Yantian District People’s Hospital, Shenzhen, Guangdong, People’s Republic of China
| | - Hao-Ming Xu
- Department of Gastroenterology and Hepatology, Guangzhou Digestive Disease Center, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong, People’s Republic of China
| | - Min-Zheng Zhu
- Department of Gastroenterology and Hepatology, The Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong, People’s Republic of China
| | - Jun Yao
- Department of Gastroenterology, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, People’s Republic of China
| | - Li-Sheng Wang
- Department of Gastroenterology, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, People’s Republic of China
| | - Yu-Jie Liang
- Department of Child and Adolescent Psychiatry, Shenzhen Kangning Hospital, Shenzhen, Guangdong, People’s Republic of China
| | - De-Feng Li
- Department of Gastroenterology, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, People’s Republic of China
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12
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Serafini MA, Sirena DH, da Silveira ABT, Franco-da-Silva M, Aubin MR, Garcez TNA, Araújo A, dos Santos Pereira F, Hoogduijn MJ, da Costa Gonçalves F, Paz AH. Mesenchymal stromal cell-derived membrane particles: A novel cell-free therapy for inflammatory bowel diseases. Int Immunopharmacol 2023; 118:110076. [PMID: 37030123 DOI: 10.1016/j.intimp.2023.110076] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2023] [Revised: 03/02/2023] [Accepted: 03/21/2023] [Indexed: 04/08/2023]
Abstract
Inflammatory bowel diseases (IBD), including ulcerative colitis, are chronic and idiopathic inflammations of the gastrointestinal tract. A disruption of the epithelial barrier and an imbalance between Th1 and Th2 subsets are associated with the onset and progression of these diseases. Mesenchymal stromal cells (MSC) are a promising therapy for IBD. However, cell-tracking studies have shown that intravenously infused MSC localize to the lungs and present short-term survival. To reduce practical complexities arising from living cells, we generated membrane particles (MP) from MSC membranes, which possess some of the immunomodulatory properties of MSC. This study investigated the effect of MSC-derived MP and conditioned media (CM) as cell-free therapies in the dextran sulfate sodium (DSS)-induced colitis model. Acute colitis was induced in C57BL/6 mice by oral administration of 2% DSS in drinking water ad libitum from days 0 to 7. Mice were treated with MP, CM, or living MSC on days 2 and 5. Our findings revealed that MP, CM, and living MSC ameliorated DSS-induced colitis by reducing colonic inflammation, the loss of colonic goblet cells, and intestinal mucosa permeability, preventing apoptosis of damaged colonic cells and balancing Th1 and Th2 activity. Therefore, MSC-derived MP have high therapeutic potential for treating IBD, overcoming the deficiencies of living MSC therapy, and opening novel frontiers in inflammatory diseases medicine.
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13
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Chenari A, Hazrati A, Hosseini AZ, Motiee M, Soudi S. The effect of mesenchymal stem cell-derived supernatant nasal administration on lung inflammation and immune response in BCG-vaccinated BALB/c mice. Life Sci 2023; 317:121465. [PMID: 36731650 DOI: 10.1016/j.lfs.2023.121465] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Revised: 01/26/2023] [Accepted: 01/27/2023] [Indexed: 02/01/2023]
Abstract
Mesenchymal stem cells (MSCs) are among the known cells that can control and modulate immune responses in different circumstances, including autoimmune diseases. Also, various studies have shown that they can prevent and reduces the pulmonary inflammation caused by infectious agents. In the case of tuberculosis and inflammation caused by BCG, the granuloma has destructive effects and improper orientation of the immune response. Therefore, it is possible to prevent airway damage by preventing harmful inflammatory responses and guiding the immune system responses. This study investigates the role of nasal administration of MSCs supernatant by designing an inflammatory model in the BALB/c mice lung with BCG. MSCs are isolated from mice adipose tissue in this study and evaluated for their phenotypic and differentiation properties. After the third passage, these cells' condition medium (CM) was collected. 20 mice were divided into four groups. Group 1 receive BCG (107 CFU in 5 ml volume for 15 min) nasal administration. Group 2 treated with CM, and group 3 initially were treated with CM (in 5 ml volume for 15 min) and, after 24 h, treated with BCG nasal administration. CM treatment was continued every five days for one month. The fourth group of mice was treated with PBS nasal administration of CM and BCG. One week after the last administration, the lung tissue of mice in each group was pathologically examined. In addition, secretion of IL1-β, IL-6, TNF-α, TGF-β, and IL-10 in the alveolar fluid and secretion of IL-4 and IFN-γ cytokines in the supernatant of splenocytes was evaluated by ELISA. The TNF-α/IL-10 ratio in the alveolar lung fluid of the BCG received group is 2/9 and decreased to 0.58 after successive CM treatment. Therefore, it can be concluded that inflammatory responses to BCG infection in the presence of CM are balanced and pave the way for the induction of effective immune responses by reducing lung tissue damage.
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Affiliation(s)
- Abolfazl Chenari
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Ali Hazrati
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Ahmad Zavaran Hosseini
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.
| | - Mahdieh Motiee
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Sara Soudi
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.
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14
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CRISPR/Cas9-engineered mesenchymal stromal/stem cells and their extracellular vesicles: A new approach to overcoming cell therapy limitations. Biomed Pharmacother 2022; 156:113943. [DOI: 10.1016/j.biopha.2022.113943] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Revised: 10/21/2022] [Accepted: 10/26/2022] [Indexed: 11/11/2022] Open
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15
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Dadgar N, Altemus J, Li Y, Lightner AL. Effect of Crohn's disease mesenteric mesenchymal stem cells and their extracellular vesicles on T-cell immunosuppressive capacity. J Cell Mol Med 2022; 26:4924-4939. [PMID: 36047483 PMCID: PMC9549497 DOI: 10.1111/jcmm.17483] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Revised: 06/07/2022] [Accepted: 06/26/2022] [Indexed: 11/27/2022] Open
Abstract
Crohn's disease (CD) is a chronic inflammatory disease of the gastrointestinal intestinal tract and has characteristic hypertrophic adipose changes observed in the mesentery. To better understand the role of the mesentery in the pathophysiology of Crohn's disease (CD), we evaluated the immunomodulatory potential of mesenchymal stem cells (MSCs) and their secreted extracellular vesicles (EVs) derived from Crohn's patients. MSCs and EVs were isolated from the mesentery and subcutaneous tissues of CD patients and healthy individuals subcutaneous tissues, and were analysed for differentiation, cytokine expression, self‐renewal and proliferation. The varying capacity of these tissue‐derived MSCs and EVs to attenuate T‐cell activation was measured in in vitro and an in vivo murine model. RNA sequencing of inflamed Crohn's disease mesentery tissue revealed an enrichment of T‐cell activation compared to non‐inflamed subcutaneous tissue. MSCs and MSC‐derived EVs isolated from Crohn's mesentery lose their ability to attenuate DSS‐induced colitis compared to subcutaneous tissue‐derived cell or EV therapy. We found that treatment with subcutaneous isolated MSCs and their EV product compared to Crohn's mesentery MSCs or EVs, the inhibition of T‐cell proliferation and IFN‐γ, IL‐17a production increased, suggesting a non‐inflamed microenvironment allows for T‐cell inhibition by MSCs/EVs. Our results demonstrate that Crohn's patient‐derived diseased mesentery tissue MSCs lose their immunosuppressive capacity in the treatment of colitis by distinct regulation of pathogenic T‐cell responses and/or T‐cell infiltration into the colon.
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Affiliation(s)
- Neda Dadgar
- Department of Colorectal Surgery, Digestive Disease Surgical Institute, Cleveland, Ohio, USA.,Department of Inflammation and Immunity, Lerner Research Institute, Cleveland, Ohio, USA
| | - Jessica Altemus
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland, Ohio, USA
| | - Yan Li
- Department of Colorectal Surgery, Digestive Disease Surgical Institute, Cleveland, Ohio, USA
| | - Amy L Lightner
- Department of Colorectal Surgery, Digestive Disease Surgical Institute, Cleveland, Ohio, USA.,Department of Inflammation and Immunity, Lerner Research Institute, Cleveland, Ohio, USA
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16
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Eiro N, Fraile M, González-Jubete A, González LO, Vizoso FJ. Mesenchymal (Stem) Stromal Cells Based as New Therapeutic Alternative in Inflammatory Bowel Disease: Basic Mechanisms, Experimental and Clinical Evidence, and Challenges. Int J Mol Sci 2022; 23:ijms23168905. [PMID: 36012170 PMCID: PMC9408403 DOI: 10.3390/ijms23168905] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Revised: 07/26/2022] [Accepted: 07/26/2022] [Indexed: 12/13/2022] Open
Abstract
Inflammatory bowel diseases (IBD) are an example of chronic diseases affecting 40% of the population, which involved tissue damage and an inflammatory process not satisfactorily controlled with current therapies. Data suggest that mesenchymal stem cells (MSC) may be a therapeutic option for these processes, and especially for IBD, due to their multifactorial approaches such as anti-inflammatory, anti-oxidative stress, anti-apoptotic, anti-fibrotic, regenerative, angiogenic, anti-tumor, or anti-microbial. However, MSC therapy is associated with important limitations as safety issues, handling difficulties for therapeutic purposes, and high economic cost. MSC-derived secretome products (conditioned medium or extracellular vesicles) are therefore a therapeutic option in IBD as they exhibit similar effects to their parent cells and avoid the issues of cell therapy. In this review, we proposed further studies to choose the ideal tissue source of MSC to treat IBD, the implementation of new standardized production strategies, quality controls and the integration of other technologies, such as hydrogels, which may improve the therapeutic effects of derived-MSC secretome products in IBD.
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Affiliation(s)
- Noemi Eiro
- Research Unit, Fundación Hospital de Jove, Av. de Eduardo Castro, 161, 33290 Gijón, Spain
- Correspondence: (N.E.); (F.J.V.); Tel.: +34-98-5320050 (ext. 84216) (N.E.); Fax: +34-98-531570 (N.E.)
| | - Maria Fraile
- Research Unit, Fundación Hospital de Jove, Av. de Eduardo Castro, 161, 33290 Gijón, Spain
| | | | - Luis O. González
- Department of Anatomical Pathology, Fundación Hospital de Jove, Av. de Eduardo Castro, 161, 33290 Gijón, Spain
| | - Francisco J. Vizoso
- Research Unit, Fundación Hospital de Jove, Av. de Eduardo Castro, 161, 33290 Gijón, Spain
- Department of Surgery, Fundación Hospital de Jove, Av. de Eduardo Castro, 161, 33290 Gijón, Spain
- Correspondence: (N.E.); (F.J.V.); Tel.: +34-98-5320050 (ext. 84216) (N.E.); Fax: +34-98-531570 (N.E.)
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17
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Yang M, Wang L, Chen Z, Hao W, You Q, Lin J, Tang J, Zhao X, Gao WQ, Xu H. Topical administration of the secretome derived from human amniotic epithelial cells ameliorates psoriasis-like skin lesions in mice. Stem Cell Res Ther 2022; 13:393. [PMID: 35922852 PMCID: PMC9351215 DOI: 10.1186/s13287-022-03091-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2022] [Accepted: 07/25/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Psoriasis is a chronic inflammatory skin disease. Tissue stem cells have exhibited a therapeutic effect on psoriatic mice. However, the therapeutic effect of topical administration of the secretome derived from tissue stem cells on psoriasis has not been reported. METHODS The secretome from human amniotic epithelial cells (AEC-SC) and human umbilical cord mesenchymal stem cells (UMSC-SC) was topically administrated on the back of imiquimod-induced psoriasis-like mice. Subsequently, we observed the skin lesions and skin inflammation of psoriasis-like mice. Next, we further analyzed the paracrine factors in AEC-SC and UMSC-SC by protein chips. Lastly, the effect of the crucial paracrine factor was investigated by imiquimod-induced psoriasis-like mice. RESULTS We found that AEC-SC had a better therapeutic effect on attenuating psoriasis-like skin lesions including skin scales, skin redness and skin thickness than UMSC-SC, and it had a better regulatory effect on keratinocyte hyperproliferation and altered differentiation. Thus, we focused on AEC-SC. Further study showed that AEC-SC reduced the infiltration of neutrophils and interleukin-17-producing T cells. Next, the analysis of AEC-SC with protein chip revealed that the levels of anti-inflammatory factor interleukin-1 receptor antagonist (IL-1ra) were much higher in AEC-SC compared to that in UMSC-SC. More importantly, the beneficial effect of AEC-SC on psoriasis-like skin lesions and skin inflammation of mice were significantly impaired when neutralizing with IL-1ra antibody, while the recombinant human IL-1ra showed a less protective effect than AEC-SC. CONCLUSIONS The present study demonstrated that AEC-SC could efficiently ameliorate psoriasis-like skin lesions and skin inflammation and IL-1ra plays an essential role. Therefore, topical administration of AEC-SC may provide a novel strategy for treating psoriasis-like inflammatory skin diseases.
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Affiliation(s)
- Mengbo Yang
- State Key Laboratory of Oncogenes and Related Genes, Renji-MedX Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China
| | - Lanqi Wang
- Department of Dermatology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China
| | - Zhimin Chen
- State Key Laboratory of Oncogenes and Related Genes, Renji-MedX Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China
| | - Weijie Hao
- State Key Laboratory of Oncogenes and Related Genes, Renji-MedX Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China
| | - Qian You
- State Key Laboratory of Oncogenes and Related Genes, Renji-MedX Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China
| | - Jianhua Lin
- Department of Obstetrics and Gynecology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China
| | - Jingzhi Tang
- State Key Laboratory of Oncogenes and Related Genes, Renji-MedX Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China
| | - Xin Zhao
- Department of Dermatology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China
| | - Wei-Qiang Gao
- State Key Laboratory of Oncogenes and Related Genes, Renji-MedX Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China. .,Med-X Research Institute and School of Biological Medical Engineering, Shanghai Jiao Tong University, Shanghai, 200030, China.
| | - Huiming Xu
- State Key Laboratory of Oncogenes and Related Genes, Renji-MedX Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China.
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18
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Heidari N, Abbasi-Kenarsari H, Namaki S, Baghaei K, Zali MR, Mirsanei Z, Hashemi SM. Regulation of the Th17/Treg balance by human umbilical cord mesenchymal stem cell-derived exosomes protects against acute experimental colitis. Exp Cell Res 2022; 419:113296. [DOI: 10.1016/j.yexcr.2022.113296] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2022] [Revised: 07/15/2022] [Accepted: 07/19/2022] [Indexed: 11/04/2022]
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19
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Zhang R, Zhang Q, Chen Y, Zhao Q, Zhang B, Wang L, Zhou C, Zhang Q, Chen K, Zhang Y, Hou X, Chen H, Liu X, Ni M, Jiang B. Combined treatment with Rg1 and adipose-derived stem cells alleviates DSS-induced colitis in a mouse model. Stem Cell Res Ther 2022; 13:272. [PMID: 35729638 PMCID: PMC9210677 DOI: 10.1186/s13287-022-02940-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Accepted: 12/13/2021] [Indexed: 11/27/2022] Open
Abstract
Background Inflammatory bowel diseases, consisting of Crohn’s disease and ulcerative colitis constitute chronic inflammatory conditions that may compromise the whole gastrointestinal tract as well as the colonic mucosa. Currently, there are no curative interventions for IBD, and all available treatments have side effects that limit their use. Adipose-derived stem cell (ADSC) treatment is a prospective treatment option for IBD. Previous findings indicated that ginsenoside (Rg1) dampened inflammatory diseases like colitis by inhibiting the binding of LPS to TLR4 on macrophages and restoring the Th17/Treg ratio. The purpose of this work was to investigate whether Rg1 can increase the influence of ADSC in a mouse model of colitis triggered by dextran sulfate sodium (DSS). Methods ADSC was intravenously inoculated into mice with DSS-triggered colitis, while Rg1 was delivered via oral gavage. Colon inflammation was assessed via body weight, colon length along with H&E staining. Serum cytokine levels were measured using ELISA. Besides, flow cytometry was adopted to determine the percentage, as well as FMI of immune cells in the spleen. The effects of simultaneous Rg1 and ADSC treatment on TLR4-MyD88 signaling were assessed via immunofluorescence. Results Rg1 and ADSC effectively alleviated the impacts of colon inflammation, weight loss, and colon length reduction along with histological score. Treatment with Rg1 and ADSC reduced serum levels of the proinflammatory cytokines, IL-1β, TNF-α, IL-6, IL-4, and IL-17A and upregulated the level of immunosuppressive cytokine, IL-10. Compared with ADSC or Rg1 alone, combined treatment with Rg1 and ADSC significantly improved the structure of microbial community. Additionally, treatment with Rg1 plus ADSC selectively elevated the level of splenic regulatory T (Treg) cells and downregulated the proportion of T helper type 17 (Th17) cells, indicating restoration of intestinal homeostasis. Besides, we established that the combination of ADSC + Rg1 restored immunological balance more effectively than either ADSC or Rg1 alone, illustrating that Rg1's modulatory function on the gut microbiota may boost the impact of ADSCs in restoration of the immune balance. ADSC combined with Rg1 might downregulate the expression of TLR4 and MyD88, thereby suppressing TLR4-MyD8 signaling. The immunofluorescence results also suggested that co-therapy with Rg-1 and ADSC may optimize treatment strategies of IBD. Conclusions Here, we find that the combination of Rg1 and ADSC alleviates DSS-induced colitis in a mouse model more efficiently than ADSC alone, indicating that Rg1 enhances the effect of ADSC against colitis. Supplementary Information The online version contains supplementary material available at 10.1186/s13287-022-02940-x.
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Affiliation(s)
- Rui Zhang
- Anorectal Surgery of Zhongda Hospital Southeast University, Nanjing, 210009, China.,Graduate School of Nanjing University of Chinese Medicine, Nanjing, 210029, China
| | - Qingqing Zhang
- Department of Pathogen Biology, Key Laboratory of Pathogen of Jiangsu Province, Nanjing Medical University, Nanjing, 211166, China
| | - Yanni Chen
- Anorectal Surgery of Zhongda Hospital Southeast University, Nanjing, 210009, China
| | - Qing Zhao
- Department of Pathogen Biology, Key Laboratory of Pathogen of Jiangsu Province, Nanjing Medical University, Nanjing, 211166, China
| | - Bo Zhang
- Anorectal Surgery of Zhongda Hospital Southeast University, Nanjing, 210009, China
| | - Ling Wang
- Graduate School of Nanjing University of Chinese Medicine, Nanjing, 210029, China
| | - Chungen Zhou
- Colorectal Disease Center of Nanjing Hospital of Chinese Medicine, Affiliated to Nanjing University of Chinese Medicine, Nanjing, 210022, China
| | - Qi Zhang
- Graduate School of Nanjing University of Chinese Medicine, Nanjing, 210029, China
| | - Kun Chen
- Anorectal Surgery of Zhongda Hospital Southeast University, Nanjing, 210009, China
| | - Yuqing Zhang
- Graduate School of Nanjing University of Chinese Medicine, Nanjing, 210029, China
| | - Xiaotao Hou
- Anorectal Surgery of Zhongda Hospital Southeast University, Nanjing, 210009, China
| | - Hao Chen
- Anorectal Surgery of Zhongda Hospital Southeast University, Nanjing, 210009, China
| | - Xingyin Liu
- Department of Pathogen Biology, Key Laboratory of Pathogen of Jiangsu Province, Nanjing Medical University, Nanjing, 211166, China.
| | - Min Ni
- Colorectal Disease Center of Nanjing Hospital of Chinese Medicine, Affiliated to Nanjing University of Chinese Medicine, Nanjing, 210022, China.
| | - Bin Jiang
- Colorectal Disease Center of Nanjing Hospital of Chinese Medicine, Affiliated to Nanjing University of Chinese Medicine, Nanjing, 210022, China.
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Bozkurt MF, Bhaya MN, Dibekoğlu C, Akat A, Ateş U, Erbaş O. Mesenchymal stem cells have ameliorative effect on the colitis model via Nrf2/HO-1 pathway. Acta Cir Bras 2022; 37:e370704. [PMID: 36228298 PMCID: PMC9553072 DOI: 10.1590/acb370704] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Accepted: 06/20/2022] [Indexed: 11/22/2022] Open
Abstract
Purpose: To evaluate the ameliorative effect of mesenchymal stem cells (MSCs) on acetic acid colitis model via Nrf2/HO-1 pathway in rats. Methods: In this study, 30 rats were divided into three groups. Acute colitis was induced by rectal administration of 4% solution of acetic acid. MSCs were injected intraperitoneally in the treatment group. Results: Increased levels of tumor necrosis factor-α (TNF-α), pentraxin-3, and malondialdehyde (MDA) in colitis group were revealed biochemically. Increased level of TNF-α and decreased levels of Nrf2 and interleukin-10 (IL-10) were observed in rectum tissues. Increased fibrous tissue proliferation, vascularization and inflammatory cell infiltration were described in the colitis group. Significant improvement was observed in MSCs treated group histopathologically. Increased immunopositivity of TNF-α, vascular endothelial growth factor (VEGF) and CD68 markers was observed in the colitis group cells, and decreased level of this positivity was observed in MSCs treated group. Conclusions: Biochemical, histopathological and immunohistochemical results strongly support the ameliorative effect of MSCs against acetic induced colitis model via Nrf2/HO-1 pathway in rats.
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Affiliation(s)
| | | | | | - Ayberk Akat
- Stembio Cell and Tissue Technologies Inc, Turkey
| | - Utku Ateş
- Stembio Cell and Tissue Technologies Inc, Turkey
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Small Extracellular Vesicles Derived from Human Chorionic MSCs as Modern Perspective towards Cell-Free Therapy. Int J Mol Sci 2021; 22:ijms222413581. [PMID: 34948379 PMCID: PMC8706681 DOI: 10.3390/ijms222413581] [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: 11/13/2021] [Revised: 12/13/2021] [Accepted: 12/16/2021] [Indexed: 12/12/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are of great interest to scientists due to their application in cell therapy of many diseases, as well as regenerative medicine and tissue engineering. Recently, there has been growing evidence surrounding the research based on extracellular vesicles (EVs), especially small EVs (sEVs)/exosomes derived from MSCs. EVs/exosomes can be secreted by almost all cell types and various types of EVs show multiple functions. In addition, MSCs-derived exosomes have similar characteristics and biological activities to MSCs and their therapeutic applications are considered as a safe strategy in cell-free therapy. The aim of this study was the characterization of MSCs isolated from the chorion (CHo-MSCs) of human full-term placenta, as well as the isolation and analysis of small EVs obtained from these cells. Accordingly, in this study, the ability of small EVs' uptake is indicated by synovial fibroblasts, osteoblasts and periosteum-derived MSCs. Improvement in the understanding of the structure, characteristics, mechanism of action and potential application of MSCs-derived small EVs can provide new insight into improved therapeutic strategies.
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22
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Wu B, Gao F, Lin J, Lu L, Xu H, Xu GT. Conditioned Medium of Human Amniotic Epithelial Cells Alleviates Experimental Allergic Conjunctivitis Mainly by IL-1ra and IL-10. Front Immunol 2021; 12:774601. [PMID: 34880869 PMCID: PMC8645696 DOI: 10.3389/fimmu.2021.774601] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2021] [Accepted: 10/25/2021] [Indexed: 01/04/2023] Open
Abstract
Allergic conjunctivitis (AC) is the most prevalent form of mucosal allergy, and the conditioned medium (CM) from mesenchymal stem cells has been reported to attenuate some allergic diseases. However, the therapeutic effects of CM from different tissue stem cells (TSC-CM) on allergic diseases have not been tested. Here, we studied the effects of topical administration of different human TSC-CM on experimental AC (EAC) mice. Only human amniotic epithelial cell-CM (AECM) significantly attenuated allergic eye symptoms and reduced the infiltration of immune cells and the levels of local inflammatory factors in the conjunctiva compared to EAC mice. In addition, AECM treatment decreased immunoglobulin E (IgE) release, histamine production, and the hyperpermeability of conjunctival vessels. Protein chip assays revealed that the levels of anti-inflammatory factors, interleukin-1 receptor antagonist (IL-1ra) and IL-10, were higher in AECM compared to other TSC-CM. Furthermore, the anti-allergic effects of AECM on EAC mice were abrogated when neutralized with IL-1ra or IL-10 antibody, and the similar phenomenon was for the activation and function of B cells and mast cells. Together, the present study demonstrated that AECM alleviates EAC symptoms by multiple anti-allergic mechanisms mainly via IL-1ra and IL-10. Such topical AECM therapy may represent a novel and feasible strategy for treating AC.
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Affiliation(s)
- Binxin Wu
- Department of Ophthalmology of Shanghai Tenth People's Hospital, Laboratory of Clinical Visual Science of Tongji Eye Institute, Tongji University School of Medicine, Shanghai, China
| | - Furong Gao
- Department of Ophthalmology of Shanghai Tenth People's Hospital, Laboratory of Clinical Visual Science of Tongji Eye Institute, Tongji University School of Medicine, Shanghai, China
| | - Jianhua Lin
- Department of Obstetrics and Gynecology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Lixia Lu
- Department of Ophthalmology of Shanghai Tenth People's Hospital, Laboratory of Clinical Visual Science of Tongji Eye Institute, Tongji University School of Medicine, Shanghai, China
| | - Huiming Xu
- State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Guo-Tong Xu
- Department of Ophthalmology of Shanghai Tenth People's Hospital, Laboratory of Clinical Visual Science of Tongji Eye Institute, Tongji University School of Medicine, Shanghai, China.,Department of Pharmacology, Tongji University School of Medicine, Shanghai, China
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23
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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: 49] [Impact Index Per Article: 12.3] [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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24
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Improving the Efficacy of Mesenchymal Stem/Stromal-Based Therapy for Treatment of Inflammatory Bowel Diseases. Biomedicines 2021; 9:biomedicines9111507. [PMID: 34829736 PMCID: PMC8615066 DOI: 10.3390/biomedicines9111507] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Revised: 10/14/2021] [Accepted: 10/14/2021] [Indexed: 12/12/2022] Open
Abstract
Inflammatory bowel diseases (IBD) consisting of persistent and relapsing inflammatory processes of the intestinal mucosa are caused by genetic, environmental, and commensal microbiota factors. Despite recent advances in clinical treatments aiming to decrease inflammation, nearly 30% of patients treated with biologicals experienced drawbacks including loss of response, while others can develop severe side effects. Hence, novel effective treatments are highly needed. Mesenchymal stem/stromal cell (MSCs) therapy is an innovative therapeutic alternative currently under investigation for IBD. MSCs have the inherent capacity of modulating inflammatory immune responses as well as regenerating damaged tissues and are therefore a prime candidate to use as cell therapy in patients with IBD. At present, MSC-based therapy has been shown preclinically to modulate intestinal inflammation, whilst the safety of MSC-based therapy has been demonstrated in clinical trials. However, the successful results in preclinical studies have not been replicated in clinical trials. In this review, we will summarize the protocols used in preclinical and clinical trials and the novel approaches currently under investigation which aim to increase the beneficial effects of MSC-based therapy for IBD.
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25
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Qi LL, Fan ZY, Mao HG, Wang JB. The Therapeutic Efficacy of Adipose Tissue-Derived Mesenchymal Stem Cell Conditioned Medium on Experimental Colitis Was Improved by the Serum From Colitis Rats. Front Bioeng Biotechnol 2021; 9:694908. [PMID: 34604183 PMCID: PMC8484792 DOI: 10.3389/fbioe.2021.694908] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Accepted: 09/06/2021] [Indexed: 01/07/2023] Open
Abstract
Adipose derived mesenchymal stem cells (AD-MSCs) have shown therapeutic potential in treatments of inflammatory bowel disease (IBD). Due to the harsh host environment and poor survival of the cells, controversy concerning the homing, proliferation and differentiation of MSCs in lesion tissue still remains. It has been reported that conditioned media from MSCs could improve the colitis, whereas the therapeutic efficiency could be significantly elevated by the stimulation of pro-cytokines. In this study, we pre-treated the adipose derived MSCs with the serum from colitis rats and then the activated conditioned media (CM-AcMSC) were collected. To compare the therapeutic effects of CM-MSC and CM-AcMSC on IBD, we constructed dextran sodium sulphate (DSS)-induced colitis rat models. The colitis was induced in rats by administrating 5% DSS in drinking water for 10 days, and the disease symptoms were recorded daily. The colon histopathological changes were observed by different staining methods (H&E and PAS). The expression levels of MUC2 and tight junctions (TJs) were determined by RT-qPCR. The levels of inflammatory cytokines were analyzed by ELISA and western blot analysis. Our findings suggested that CM-AcMSC was more effective in ameliorating the clinical features and histological damage scores. Treatment with CM-AcMSC significantly increased the expression of MUC2 and TJs and suppressed the production of pro-inflammatory cytokines in colonic tissues of colitis rats. The inhibitory effects of CM-AcMSC on inflammatory responses of colitis rats were mediated by NF-κB signaling pathway. These results suggested that pre-activation of MSCs with serum from colitis rats could promote the production of paracrine factors and improve the therapeutic effects of conditioned medium on colitis rats.
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Affiliation(s)
- Li-Li Qi
- School of Biological and Chemical Engineering, Ningbo Tech University, Ningbo, China
| | - Zhe-Yu Fan
- School of Biological and Chemical Engineering, Ningbo Tech University, Ningbo, China
| | - Hai-Guang Mao
- School of Biological and Chemical Engineering, Ningbo Tech University, Ningbo, China
| | - Jin-Bo Wang
- School of Biological and Chemical Engineering, Ningbo Tech University, Ningbo, China
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Wang R, Yao Q, Chen W, Gao F, Li P, Wu J, Yu J, Cao H. Stem cell therapy for Crohn's disease: systematic review and meta-analysis of preclinical and clinical studies. Stem Cell Res Ther 2021; 12:463. [PMID: 34407875 PMCID: PMC8375136 DOI: 10.1186/s13287-021-02533-0] [Citation(s) in RCA: 55] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2021] [Accepted: 08/02/2021] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND We explored whether stem cell therapy was effective for animal models and patients with Crohn's disease (CD). METHODS We searched five online databases. The relative outcomes were analyzed with the aid of GetData Graph Digitizer 2.26 and Stata 16.0 software. The SYRCLE risk of bias tool and the MINORS tool were used to assess study quality. RESULTS We evaluated 46 studies including 28 animal works (n = 567) and 18 human trials (n = 360). In the animal studies, the disease activity index dramatically decreased in the mesenchymal stem cell (MSC) treatment groups compared to the control group. Rats and mice receiving MSCs exhibited longer colons [mice: standardized mean difference (SMD) 2.84, P = 0.000; rats: SMD 1.44, P = 0.029], lower histopathological scores (mice: SMD - 4.58, p = 0.000; rats: SMD - 1.41, P = 0.000) and lower myeloperoxidase levels (SMD - 6.22, P = 0.000). In clinical trials, stem cell transplantation reduced the CD activity index (SMD - 2.10, P = 0.000), the CD endoscopic index of severity (SMD - 3.40, P = 0.000) and simplified endoscopy score for CD (SMD - 1.71, P = 0.000) and improved the inflammatory bowel disease questionnaire score (SMD 1.33, P = 0.305) compared to control values. CD patients maintained high remission rates for 3-24 months after transplantation. CONCLUSIONS Stem cell transplantation is a valuable supplementary therapy for CD.
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Affiliation(s)
- Ruo Wang
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou City, 310003, China
- National Clinical Research Center for Infectious Diseases, 79 Qingchun Rd., Hangzhou City, 310003, China
| | - Qigu Yao
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou City, 310003, China
- National Clinical Research Center for Infectious Diseases, 79 Qingchun Rd., Hangzhou City, 310003, China
| | - Wenyi Chen
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou City, 310003, China
- National Clinical Research Center for Infectious Diseases, 79 Qingchun Rd., Hangzhou City, 310003, China
| | - Feiqiong Gao
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou City, 310003, China
- National Clinical Research Center for Infectious Diseases, 79 Qingchun Rd., Hangzhou City, 310003, China
| | - Pan Li
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou City, 310003, China
- National Clinical Research Center for Infectious Diseases, 79 Qingchun Rd., Hangzhou City, 310003, China
| | - Jian Wu
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou City, 310003, China
- National Clinical Research Center for Infectious Diseases, 79 Qingchun Rd., Hangzhou City, 310003, China
| | - Jiong Yu
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou City, 310003, China
- National Clinical Research Center for Infectious Diseases, 79 Qingchun Rd., Hangzhou City, 310003, China
| | - Hongcui Cao
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou City, 310003, China.
- National Clinical Research Center for Infectious Diseases, 79 Qingchun Rd., Hangzhou City, 310003, China.
- Zhejiang Provincial Key Laboratory for Diagnosis and Treatment of Aging and Physic-Chemical Injury Diseases, 79 Qingchun Rd., Hangzhou City, 310003, China.
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27
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Liu T, Xu J, Pan X, Ding Z, Xie H, Wang X, Xie H. Advances of adipose-derived mesenchymal stem cells-based biomaterial scaffolds for oral and maxillofacial tissue engineering. Bioact Mater 2021; 6:2467-2478. [PMID: 33553828 PMCID: PMC7850942 DOI: 10.1016/j.bioactmat.2021.01.015] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Revised: 01/03/2021] [Accepted: 01/11/2021] [Indexed: 02/05/2023] Open
Abstract
The management of oral and maxillofacial tissue defects caused by tumors, trauma, and congenital or acquired deformities has been a major challenge for surgeons over the last few decades. Autologous tissue transplantation, the gold standard of tissue reconstruction, is a valid method for repairing the oral and maxillofacial functions and aesthetics. However, several limitations hinder its clinical applications including complications of donor sites, limited tissue volume, and uncertain long-term outcomes. Adipose-derived mesenchymal stem cells (ADMSCs) widely exist in adipose tissue and can be easily obtained through liposuction. Like the bone marrow-derived mesenchymal stem cells (BMSCs), ADMSCs also have the multi-pluripotent potencies to differentiate into osteoblasts, chondrocytes, neurons, and myocytes. Therefore, the multilineage capacity of ADMSCs makes them valuable for cell-based medical therapies. In recent years, researchers have developed many candidates of ADMSCs-based biomaterial scaffolds to cater for the needs of oral and maxillofacial tissue engineering due to their superior performance. This review presents the advances and applications of ADMSCs-based biomaterial scaffolds, and explores their tissue engineering prospects in oral and maxillofacial reconstructions.
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Affiliation(s)
- Tong Liu
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Head and Neck Oncology Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China
| | - Jia Xu
- The Key Laboratory of Oral Biomedicine, Jiangxi Province, School of Stomatology, Nanchang University, Nanchang, 330006, China
| | - Xun Pan
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Head and Neck Oncology Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China
| | - Zhangfan Ding
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Head and Neck Oncology Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China
| | - Hao Xie
- General Surgery Department, The Second Affiliated Hospital of Wannan Medical College, Wuhu, Anhui Province, 241000, China
| | - Xiaoyi Wang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Head and Neck Oncology Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China
| | - Huixu Xie
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Head and Neck Oncology Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China
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28
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Heidari N, Abbasi-Kenarsari H, Namaki S, Baghaei K, Zali MR, Ghaffari Khaligh S, Hashemi SM. Adipose-derived mesenchymal stem cell-secreted exosome alleviates dextran sulfate sodium-induced acute colitis by Treg cell induction and inflammatory cytokine reduction. J Cell Physiol 2021; 236:5906-5920. [PMID: 33728664 DOI: 10.1002/jcp.30275] [Citation(s) in RCA: 97] [Impact Index Per Article: 24.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2020] [Revised: 12/09/2020] [Accepted: 12/26/2020] [Indexed: 12/16/2022]
Abstract
Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, is an inflammatory condition that results in gastrointestinal tract damage. Various factors, including environmental and genetic agents, disrupt the function of the intestinal immune system that can lead to IBD. Mesenchymal stem cells (MSCs) display an immunoregulatory function and demonstrate regenerative potential by paracrine action. In this study, we evaluated the immunomodulatory effects of MSCs' derived exosomes in the acute form of dextran sulfate sodium (DSS)-induced colitis. Exosomes were isolated from adipose-derived MSCs. Acute colitis was induced by DSS. The exosome was used by intraperitoneal injection into mice with acute colitis. Stool consistency, body weight changes, bleeding severity, colon length, and weight were examined. At the experimental endpoint (Day 7), the changes in the colon tissue were evaluated. The level of cytokines of interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), interleukin-17 (IL-17), IL-4, IL-12, transforming growth factor-β (TGF-β) and, IL-10, and Treg cells percentage were assayed. Results showed that exosome administration diminished colon shortening, bodyweight loss, bleeding, and colon injury. The levels of IFN-γ, TNF-α, IL-12, and IL-17 were decreased, and the level of TGF-β, IL-4, and IL-10 were increased in lymph node and spleen of mice treated with exosome. Percentages of CD4+ CD25+ Foxp3+ Treg cells were grown in the lymph node and spleen of mice treated with exosomes. Overall, current data suggest that MSC-derived exosome could regulate the Treg population and improves inflammation in DSS-induced acute colitis.
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Affiliation(s)
- Neda Heidari
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hajar Abbasi-Kenarsari
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Saeed Namaki
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Kaveh Baghaei
- Basic and Molecular Epidemiology of Gastrointestinal Disorder Research Center, Research Institute for Gastroenterology and Liver Disease, Shahid Beheshti University of Medical Science, Tehran, Iran
| | - Mohammad Reza Zali
- Gastroenterology and Liver Disease Research Center, Research Institute for Gastroenterology and Liver Disease, Shahid Beheshti University of Medical Science, Tehran, Iran
| | | | - Seyed Mahmoud Hashemi
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Urogenital Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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29
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Chen X, Yang X, Yuan P, Jin R, Bao L, Qiu X, Liu S, Liu T, Gooding JJ, Chen W, Liu G, Bai Y, Liu S, Jin Y. Modular immune-homeostatic microparticles promote immune tolerance in mouse autoimmune models. Sci Transl Med 2021; 13:13/584/eaaw9668. [PMID: 33692135 DOI: 10.1126/scitranslmed.aaw9668] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2019] [Revised: 03/14/2020] [Accepted: 01/26/2021] [Indexed: 12/29/2022]
Abstract
The therapeutic goal for autoimmune diseases is disease antigen-specific immune tolerance without nonspecific immune suppression. However, it is a challenge to induce antigen-specific immune tolerance in a dysregulated immune system. In this study, we developed immune-homeostatic microparticles (IHMs) that treat multiple mouse models of autoimmunity via induction of apoptosis in activated T cells and reestablishment of regulatory T cells. Specifically, in an experimental model of colitis, IHMs rapidly released monocyte chemotactic protein-1 after intravenous administration, which recruited activated T cells and then induced their apoptosis by conjugated Fas ligand on the IHM surface. This triggered professional macrophages to ingest apoptotic T cells and produce high quantities of transforming growth factor-β, which drove regulatory T cell differentiation. Furthermore, the modular design of IHMs allowed IHMs to be engineered with the autoantigen peptides that can reduce disease in an experimental autoimmune encephalomyelitis mouse model and a nonobese diabetic mouse model. This was accomplished by sustained release of the autoantigens after induction of T cell apoptosis and transforming growth factor-β production by macrophages, which promoted to establish an immune tolerant environment. Thus, IHMs may be an efficient therapeutic strategy for autoimmune diseases through induction of apoptosis and reestablishment of tolerant immune responses.
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Affiliation(s)
- Xin Chen
- School of Chemical Engineering and Technology, Shaanxi Key Laboratory of Energy Chemical Process Intensification, Institute of Polymer Science in Chemical Engineering, Xi'an Jiao Tong University, Xi'an, Shaanxi 710049, China.
| | - Xiaoshan Yang
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, Fourth Military Medical University, Xi'an, Shaanxi 710032, China
| | - Pingyun Yuan
- School of Chemical Engineering and Technology, Shaanxi Key Laboratory of Energy Chemical Process Intensification, Institute of Polymer Science in Chemical Engineering, Xi'an Jiao Tong University, Xi'an, Shaanxi 710049, China
| | - Ronghua Jin
- School of Chemical Engineering and Technology, Shaanxi Key Laboratory of Energy Chemical Process Intensification, Institute of Polymer Science in Chemical Engineering, Xi'an Jiao Tong University, Xi'an, Shaanxi 710049, China
| | - Lili Bao
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, Fourth Military Medical University, Xi'an, Shaanxi 710032, China
| | - Xinyu Qiu
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, Fourth Military Medical University, Xi'an, Shaanxi 710032, China
| | - Siying Liu
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, Fourth Military Medical University, Xi'an, Shaanxi 710032, China
| | - Tao Liu
- School of Chemical Engineering and Technology, Shaanxi Key Laboratory of Energy Chemical Process Intensification, Institute of Polymer Science in Chemical Engineering, Xi'an Jiao Tong University, Xi'an, Shaanxi 710049, China
| | - John Justin Gooding
- School of Chemistry, Australian Centre for NanoMedicine and ARC Australian Centre of Excellence in Convergent Bio-Nano Science and Technology, University of New South Wales, Sydney 2052, Australia
| | - WanJun Chen
- Mucosal Immunology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA
| | - Guozhen Liu
- Graduate School of Biomedical Engineering, ARC Centre of Excellence for Nanoscale BioPhotonics and Australian Centre for NanoMedicine, Faculty of Engineering, University of New South Wales, Sydney 2052, Australia
| | - Yongkang Bai
- School of Chemical Engineering and Technology, Shaanxi Key Laboratory of Energy Chemical Process Intensification, Institute of Polymer Science in Chemical Engineering, Xi'an Jiao Tong University, Xi'an, Shaanxi 710049, China
| | - Shiyu Liu
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
| | - Yan Jin
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
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30
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Janockova J, Slovinska L, Harvanova D, Spakova T, Rosocha J. New therapeutic approaches of mesenchymal stem cells-derived exosomes. J Biomed Sci 2021; 28:39. [PMID: 34030679 PMCID: PMC8143902 DOI: 10.1186/s12929-021-00736-4] [Citation(s) in RCA: 64] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Accepted: 05/14/2021] [Indexed: 02/07/2023] Open
Abstract
Mesenchymal stem cells (MSCs) have been demonstrated to have a great potential in the treatment of several diseases due to their differentiation and immunomodulatory capabilities and their ability to be easily cultured and manipulated. Recent investigations revealed that their therapeutic effect is largely mediated by the secretion of paracrine factors including exosomes. Exosomes reflect biophysical features of MSCs and are considered more effective than MSCs themselves. Alternative approaches based on MSC-derived exosomes can offer appreciable promise in overcoming the limitations and practical challenges observed in cell-based therapy. Furthermore, MSC-derived exosomes may provide a potent therapeutic strategy for various diseases and are promising candidates for cell-based and cell-free regenerative medicine. This review briefly summarizes the development of MSCs as a treatment for human diseases as well as describes our current knowledge about exosomes: their biogenesis and molecular composition, and how they exert their effects on target cells. Particularly, the therapeutic potential of MSC-derived exosomes in experimental models and recent clinical trials to evaluate their safety and efficacy are summarized in this study. Overall, this paper provides a current overview of exosomes as a new cell-free therapeutic agent.
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Affiliation(s)
- Jana Janockova
- Associated Tissue Bank, Faculty of Medicine, P. J. Safarik University in Kosice, Tr. SNP 1, 04011, Kosice, Slovakia.
| | - Lucia Slovinska
- Associated Tissue Bank, Faculty of Medicine, P. J. Safarik University in Kosice, Tr. SNP 1, 04011, Kosice, Slovakia
| | - Denisa Harvanova
- Associated Tissue Bank, Faculty of Medicine, P. J. Safarik University in Kosice, Tr. SNP 1, 04011, Kosice, Slovakia
| | - Timea Spakova
- Associated Tissue Bank, Faculty of Medicine, P. J. Safarik University in Kosice, Tr. SNP 1, 04011, Kosice, Slovakia
| | - Jan Rosocha
- Associated Tissue Bank, Faculty of Medicine, P. J. Safarik University in Kosice, Tr. SNP 1, 04011, Kosice, Slovakia
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Nishikawa T, Maeda K, Nakamura M, Yamamura T, Sawada T, Mizutani Y, Ito T, Ishikawa T, Furukawa K, Ohno E, Miyahara R, Kawashima H, Honda T, Ishigami M, Yamamoto T, Matsumoto S, Hotta Y, Fujishiro M. Filtrated Adipose Tissue-Derived Mesenchymal Stem Cell Lysate Ameliorates Experimental Acute Colitis in Mice. Dig Dis Sci 2021; 66:1034-1044. [PMID: 32488819 DOI: 10.1007/s10620-020-06359-3] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2019] [Accepted: 05/21/2020] [Indexed: 02/06/2023]
Abstract
BACKGROUND Inflammatory bowel disease (IBD) is a chronic, persistent, and intractable enteritis; however, an effective treatment strategy is yet to be established. Mesenchymal stem cells (MSCs) and their paracrine factors exhibit anti-inflammatory actions and have been proposed as a new therapeutic candidate for IBD treatment, although the efficacy of MSC lysate on enteritis is unclear. AIMS Here, we examined the efficacy and appropriate regimen of filtrated murine adipose-derived mesenchymal stem cell lysate (FADSTL) in an acute colitis mouse model as a novel cell-free MSC therapy. METHODS To confirm the clinical effects of FADSTL, survival rate, body weight, and disease activity index (DAI) were investigated in the DSS-induced colitis mouse model. Further, differences in efficacy with dosing frequency were assessed to optimize the proper regimen. Colon length, histological findings, gene expression of inflammatory mediators and tight junction proteins in colon tissues, and anti-apoptotic effects were also compared in 3-day continuous FADSTL administration and PBS groups. RESULTS Three-day continuous FADSTL administration significantly improved weight loss and DAI score compared to those in the PBS-treated group, whereas the effect was not observed with single administration. Additionally, colon shortening and histological inflammation were suppressed in the FADSTL-treated group. Further, this treatment decreased gene expression of inflammatory mediators, maintained expression of tight junction proteins in the colon, and showed anti-apoptotic effects. CONCLUSIONS FADSTL effects were dependent on its administration frequency, suggesting the requirement of continuous FADSTL administration. FADSTL improved colitis by maintaining the intestinal barrier function through its anti-inflammatory and anti-apoptotic actions.
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Affiliation(s)
- Takahiro Nishikawa
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Keiko Maeda
- Department of Endoscopy, Nagoya University Hospital, 65 Tsuruma-cho, Showa-ku, Nagoya, 466-8550, Japan.
| | - Masanao Nakamura
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Takeshi Yamamura
- Department of Endoscopy, Nagoya University Hospital, 65 Tsuruma-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Tsunaki Sawada
- Department of Endoscopy, Nagoya University Hospital, 65 Tsuruma-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Yasuyuki Mizutani
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Takanori Ito
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Takuya Ishikawa
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Kazuhiro Furukawa
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Eizaburo Ohno
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Ryoji Miyahara
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Hiroki Kawashima
- Department of Endoscopy, Nagoya University Hospital, 65 Tsuruma-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Takashi Honda
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Masatoshi Ishigami
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Tokunori Yamamoto
- Laboratory for Clinical Application of Adipose-Derived Regenerative Cells, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, 466-8550, Japan
- Clinical Research Support Center, Asahikawa Medical University Hospital, 2-1-1, Midorigaoka-Higashi, Asahikawa, Hokkaido, 078-8510, Japan
| | - Seiji Matsumoto
- Clinical Research Support Center, Asahikawa Medical University Hospital, 2-1-1, Midorigaoka-Higashi, Asahikawa, Hokkaido, 078-8510, Japan
- Center for Advanced Research and Education, Asahikawa Medical University, 2-1-1, Midorigaoka-Higashi, Asahikawa, Hokkaido, 078-8510, Japan
| | - Yuji Hotta
- Department of Hospital Pharmacy, Graduate School of Pharmaceutical Sciences, Nagoya City University, 1-3 Tanabedori, Mizuho-ku, Nagoya, 467-8603, Japan
| | - Mitsuhiro Fujishiro
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, 466-8550, Japan
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Regulatory Effect of Mesenchymal Stem Cells on T Cell Phenotypes in Autoimmune Diseases. Stem Cells Int 2021; 2021:5583994. [PMID: 33859701 PMCID: PMC8024100 DOI: 10.1155/2021/5583994] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 03/03/2021] [Accepted: 03/11/2021] [Indexed: 02/08/2023] Open
Abstract
Research on mesenchymal stem cells (MSCs) starts from the earliest assumption that cells derived from the bone marrow have the ability to repair tissues. Several scientists have since documented the crucial role of bone marrow-derived MSCs (BM-MSCs) in processes such as embryonic bone and cartilage formation, adult fracture and tissue repair, and immunomodulatory activities in therapeutic applications. In addition to BM-MSCs, several sources of MSCs have been reported to possess tissue repair and immunoregulatory abilities, making them potential treatment options for many diseases. Therefore, the therapeutic potential of MSCs in various diseases including autoimmune conditions has been explored. In addition to an imbalance of T cell subsets in most patients with autoimmune diseases, they also exhibit complex disease manifestations, overlapping symptoms among diseases, and difficult treatment. MSCs can regulate T cell subsets to restore their immune homeostasis toward disease resolution in autoimmune conditions. This review summarizes the role of MSCs in relieving autoimmune diseases via the regulation of T cell phenotypes.
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Nazarinia D, Dolatshahi M, Faezi M, Nasseri Maleki S, Aboutaleb N. TLR4 /NF-ĸB and JAK2/STAT3 signaling pathways: Cellular signaling pathways targeted by cell-conditioned medium therapy in protection against ischemic stroke. J Chem Neuroanat 2021; 113:101938. [PMID: 33636320 DOI: 10.1016/j.jchemneu.2021.101938] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Revised: 02/18/2021] [Accepted: 02/19/2021] [Indexed: 12/21/2022]
Abstract
Human amniotic membrane-derived mesenchymal stem cell-conditioned medium (hAMSC-CM) has been known to improve neuronal survival following ischemic stroke. The present study was designed to examine whether protective effects of hAMSC-CM against stroke can be linked to reducing neuroinflamation by targeting TLR4 /NF-ĸB and Jak2/Stat3 signaling pathways. Immunohistochemistry of hippocampus and western blot assay were performed to evaluate the expression of TLR4 /NF-ĸB and Jak2/Stat3, respectively. Real-time PCR assay was applied to investigate the mRNA levels of Jak2/Stat3. Hematoxylin and eosin (H&E) staining was used to investigate tissue damage and morphological changes in the CA1 region of hippocampus. Increased brain edema was seen in middle cerebral artery occlusion (MCAO) rats compared to sham. Post-treatment with hAMSC-CM markedly reduced brain edema in comparison with MCAO group (P < 0.05). Compared to sham, significantly increased levels of TLR4 /NF-ĸB and Jak2/Stat3 were seen in MCAO rats. Intravenous injection of hAMSC-CM after reperfusion markedly reduced levels of TLR4 /NF-ĸB and Jak2/Stat3 in hippocampus region (P < 0.05). Tissue damage and neuronal cell increased in the CA1 region of hippocampus that reversed by post-treatment by hAMSC-CM. Interestingly, our finding showed that hAMSC-CM can be considered as good candidate to reduce injury following ischemic stroke by decreasing activity of TLR4 /NF-ĸB and Jak2/Stat3 signaling pathways.
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Affiliation(s)
- Donya Nazarinia
- Department of Physiology, School of Paramedical Sciences, Dezful University of Medical Sciences, Dezful, Iran.
| | - Mojtaba Dolatshahi
- Department of Physiology, School of Medicine, Dezful University of Medical Sciences, Dezful, Iran.
| | - Masoumeh Faezi
- Physiology Research Center, Iran University of Medical Sciences, Tehran, Iran; Department of Physiology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran.
| | - Solmaz Nasseri Maleki
- Physiology Research Center, Iran University of Medical Sciences, Tehran, Iran; Department of Physiology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran.
| | - Nahid Aboutaleb
- Physiology Research Center, Iran University of Medical Sciences, Tehran, Iran; Department of Physiology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran.
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Abstract
Mucosal surfaces are distinctive sites exposed to environmental, dietary, and microbial antigens. Particularly in the gut, the host continuously actively adapts via complex interactions between the microbiota and dietary compounds and immune and other tissue cells. Regulatory T cells (Tregs) are critical for tuning the intestinal immune response to self- and non-self-antigens in the intestine. Its importance in intestinal homeostasis is illustrated by the onset of overt inflammation caused by deficiency in Treg generation, function, or stability in the gut. A substantial imbalance in Tregs has been observed in intestinal tissue during pathogenic conditions, when a tightly regulated and equilibrated system becomes dysregulated and leads to unimpeded and chronic immune responses. In this chapter, we compile and critically discuss the current knowledge on the key factors that promote Treg-mediated tolerance in the gut, such as those involved in intestinal Treg differentiation, specificity and suppressive function, and their immunophenotype during health and disease. We also discuss the current state of knowledge on Treg dysregulation in human intestine during pathological states such as inflammatory bowel disease (IBD), necrotizing enterocolitis (NEC), graft-versus-host disease (GVHD), and colorectal cancer (CRC), and how that knowledge is guiding development of Treg-targeted therapies to treat or prevent intestinal disorders.
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Li Y, Ma K, Zhang L, Xu H, Zhang N. Human Umbilical Cord Blood Derived-Mesenchymal Stem Cells Alleviate Dextran Sulfate Sodium-Induced Colitis by Increasing Regulatory T Cells in Mice. Front Cell Dev Biol 2020; 8:604021. [PMID: 33330503 PMCID: PMC7732515 DOI: 10.3389/fcell.2020.604021] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Accepted: 11/03/2020] [Indexed: 12/24/2022] Open
Abstract
Inflammatory bowel disease (IBD), which main clinical manifestations include abdominal pain and diarrhea occurring repeatedly, is a kind of autoimmune disease. It has been reported in preceding studies that mesenchymal stem cells (MSCs) can reduce inflammation by regulating the function of immune cells. But studies about the interaction between MSCs and adaptive immune cells, especially in IBD models, are insufficient. Therefore, the objective of this research was to estimate the therapeutic effects of MSCs from human umbilical cord blood (hUCB-MSCs) in an IBD model of rodent and to clarify the therapeutic mechanisms of hUCB-MSCs. Dextran sulfate sodium (DSS) was used to induce colitis in rodent. Mice with colitis were treated with intraperitoneal infusions of hUCB-MSCs and evaluated for mortality and diverse disease symptoms containing weight reduction, diarrhea, and bloody stools. The levels of histopathologic severity and generation of regulatory T cells (Treg) were also determined. Treatment with hUCB-MSCs ameliorated the clinical and histopathologic severity of acute and chronic colitis in mice. Furthermore, T cell infiltration into the inflamed colon was significantly decreased (p = 0.0175), and Foxp3+ cells were substantially higher in the hUCB-MSC group than that of the DSS group. Our results suggest that hUCB-MSCs are able to alleviate inflammation via adding Foxp3+ Tregs in an IBD model of mouse. As a result, these findings suggest the opportunity of hUCB-MSC being applied to patients with IBD.
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Affiliation(s)
- Ying Li
- Department of Gastroenterology, The First Hospital of Jilin University, Changchun, China
| | - Ke Ma
- Department of Pediatrics, The First Hospital of Jilin University, Changchun, China
| | - Luping Zhang
- Department of Gastroenterology, The First Hospital of Jilin University, Changchun, China
| | - Hong Xu
- Department of Gastroenterology, The First Hospital of Jilin University, Changchun, China
| | - Nan Zhang
- Department of Gastroenterology, The First Hospital of Jilin University, Changchun, China
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36
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Abbasi-Kenarsari H, Heidari N, Baghaei K, Amani D, Zali MR, Gaffari Khaligh S, Shafiee A, Hashemi SM. Synergistic therapeutic effect of mesenchymal stem cells and tolerogenic dendritic cells in an acute colitis mouse model. Int Immunopharmacol 2020; 88:107006. [PMID: 33182049 DOI: 10.1016/j.intimp.2020.107006] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2020] [Revised: 08/24/2020] [Accepted: 09/10/2020] [Indexed: 02/07/2023]
Abstract
Cell-based therapy with tolerizing cells has been applied for the treatment of inflammatory bowel disease (IBD) in previous experimental and clinical studies with promising results. In the current study, we utilized the dextran sulfate sodium (DSS)-induced colitis model, to investigate if tolerogenic dendritic cell-mesenchymal stem cell (tDC-MSC) combination therapy can augment the therapeutic effects of single transplantation of each cell type. The effect of MSC and tDC co-transplantation on the severity of colitis was assessed by daily monitoring of body weight, stool consistency, and rectal bleeding, and compared with control groups. Moreover, the colon length, colon weight, myeloperoxidase (MPO) activity were measured and evaluated with histological analysis of colon tissues. The Treg cell percentage and cytokine levels in spleens and mesenteric lymph nodes (MLNs) were measured by flow cytometry and ELISA, respectively. The results showed co-transplantation of MSCs and tDCs was more effective in alleviating the clinical and histological manifestations of colitis than monotherapy, especially when compared with MSC alone. The protective effects of tDC-MSC were accompanied by the induction of Treg cells and increased the production of anti-inflammatory cytokines in spleens and mesenteric lymph nodes. Together, co-transplantation of MSCs and tDCs could be a promising and effective therapeutic approach in the treatment of IBD.
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Affiliation(s)
- Hajar Abbasi-Kenarsari
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Neda Heidari
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Kaveh Baghaei
- Basic and Molecular Epidemiology of Gastrointestinal Disorder Research Center, Research Institute for Gastroenterology and Liver Disease, Shahid Beheshti University of Medical Science, Tehran, Iran
| | - Davar Amani
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Reza Zali
- Gastroenterology and Liver Disease Research Center, Research Institute for Gastroenterology and Liver Disease, Shahid Beheshti University of Medical Science, Tehran, Iran
| | | | - Abbas Shafiee
- UQ Diamantina Institute, Translational Research Institute, The University of Queensland, Brisbane, QLD 4102, Australia
| | - Seyed Mahmoud Hashemi
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Urogenital Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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Hashemi SM, Hassan ZM, Hossein-Khannazer N, Pourfathollah AA, Soudi S. Investigating the route of administration and efficacy of adipose tissue-derived mesenchymal stem cells and conditioned medium in type 1 diabetic mice. Inflammopharmacology 2020; 28:585-601. [PMID: 31741175 DOI: 10.1007/s10787-019-00661-x] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2019] [Accepted: 10/29/2019] [Indexed: 12/11/2022]
Abstract
Type 1 diabetes (T1D) is a chronic autoimmune disease destroying the insulin-producing beta cells. Recently, stem cell therapy has been tested to treat T1D. In the present study, we aim to investigate the effects of intraperitoneal and intravenous infusion of multipotent mesenchymal stem/stromal cells (MSCs) and MSC-conditioned medium (MSC-CM) in an experimental model of diabetes, induced by multiple injections of Streptozotocin (STZ). The adipose tissue-derived MSC and MSC-CM were isolated from C57Bl/6 male mice and characterized. Later, MSC and MSC-CM were injected intraperitoneally or intravenously into mice. The blood glucose, urinary glucose, and body weight were measured, and the percentages of CD4+ CD25+ FOXP3+ T cells as well as the levels of IFN-γ, TGF-β, IL-4, IL-17, and IL-10 were evaluated. Our results showed that both intraperitoneal and intravenous infusions of MSC and MSC-CM could decrease the blood glucose, recover pancreatic islets, and increase the levels of insulin-producing cells. Furthermore, the percentage of CD4+ CD25+ FOXP3+ T cells was increased after intraperitoneal injection of MSC or MSC-CM and intravenous injection of MSCs. After intraperitoneal injection of the MSC and MSC-CM, the levels of inflammatory cytokines reduced, while the levels of anti-inflammatory cytokines increased. Together current data showed that although both intraperitoneal and intravenous administration had beneficial effects on T1D animal model, but intraperitoneal injection of AD-MSC and AD-MSC-CM was more effective than systemic administration.
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Affiliation(s)
- Seyed Mahmoud Hashemi
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
- Urogenital Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Zuhair Mohammad Hassan
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.
| | - Nikoo Hossein-Khannazer
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ali Akbar Pourfathollah
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Sara Soudi
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
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38
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Abdolmohammadi K, Mahmoudi T, Nojehdehi S, Tayebi L, Hashemi SM, Noorbakhsh F, Abdollahi A, Soleimani M, Nikbin B, Nicknam MH. Effect of Hypoxia Preconditioned Adipose-Derived Mesenchymal Stem Cell Conditioned Medium on Cerulein-Induced Acute Pancreatitis in Mice. Adv Pharm Bull 2020; 10:297-306. [PMID: 32373500 PMCID: PMC7191232 DOI: 10.34172/apb.2020.036] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2019] [Revised: 09/17/2019] [Accepted: 09/18/2019] [Indexed: 12/11/2022] Open
Abstract
Purpose: Acute pancreatitis (AP) is an inflammatory disorder distinguished by tissue injury and inflammation of the pancreas. Using paracrine potential of mesenchymal stem cells (MSCs) provides a useful clinical approach in treating inflammatory diseases. We investigated the therapeutic effects of adipose-derived MSC conditioned medium (CM) and hypoxia preconditioned adipose-derived MSC conditioned medium (HCM) in cerulein-induced AP in mice. Methods: AP was induced in C57BL/6 mice by intraperitoneal injection of cerulein (75 μg/ kg/h × 7 times). One hour following the last injection of cerulein, mice were treated with intraperitoneal injection of CM and HCM (500 µL/mice/30 min × 3 times). Twelve hours following the treatment, serum levels of amylase and lipase were measured. In addition, pancreas pathological changes, immunohistochemical examinations for evaluation of IL-6 expression and pancreatic myeloperoxidase (MPO) enzyme activity were analyzed. Results: The in vitro results of the morphological, differentiation and immunophenotyping analyses confirmed that hypoxia preconditioned MSCs (HP-MSCs) conserve MSCs characteristics after preconditioning. However, HP-MSCs significantly expressed high mRNA level of hypoxia inducible factor 1-α and higher level of total protein. The in vivo findings of the current study showed that CM and HCM significantly reduced the amylase & lipase activity, the severity of pancreas tissue injury and the expression of IL-6 and MPO enzyme activity compared with the AP group. However, no significant difference between CM and HCM groups was demonstrated. Conclusion: Use of CM and HCM can attenuate cerulein-induced AP and decrease inflammation in the pancreas tissue in AP mice.
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Affiliation(s)
- Kamal Abdolmohammadi
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Tayebeh Mahmoudi
- Student Research Committee, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | | | - Lobat Tayebi
- Marquette University School of Dentistry, Milwaukee, WI, 53233, USA
| | - Seyed Mahmoud Hashemi
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.,Urogenital Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.,Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Farshid Noorbakhsh
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Alireza Abdollahi
- Department of Pathology, School of Medicine, Imam Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran.,Breast Disease Research Center (BDRC), Tehran University of Medical Sciences, Tehran, Iran
| | - Masoud Soleimani
- Department of Hematology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Behrouz Nikbin
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.,Molecular Immunology Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Hossein Nicknam
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.,Molecular Immunology Research Center, Tehran University of Medical Sciences, Tehran, Iran
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39
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Ma ZJ, Wang YH, Li ZG, Wang Y, Li BY, Kang HY, Wu XY. Immunosuppressive Effect of Exosomes from Mesenchymal Stromal Cells in Defined Medium on Experimental Colitis. Int J Stem Cells 2019; 12:440-448. [PMID: 31242720 PMCID: PMC6881044 DOI: 10.15283/ijsc18139] [Citation(s) in RCA: 60] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2018] [Revised: 04/04/2019] [Accepted: 04/11/2019] [Indexed: 12/14/2022] Open
Abstract
Background and Objectives The exosomes released by mesenchymal stromal cells (MSCs) in classical FBS-containing media have been demonstrated as an alternative, cell-free therapy in various diseases including inflammatory bowel disease (IBD). It has been found that the function of exosomes is affected by culture condition. We previously developed a serum-free, xeno-free and chemically defined medium, and umbilical cord-derived MSCs in this medium retained the immunosuppressive capability. Methods In this study, we evaluated the immunosuppressive function of exosomes from MSCs (MSC-Exo) in defined medium and their therapeutic effect on treating colitis. Results and Conclusions In vitro studies indicated that MSC-Exo reduced the concentration of pro-inflammatory cytokines IFN-γ, TNF-α and IL-1β, and increased the secretion of anti-inflammatory cytokines TGF-β1 and IL-10, but no significant change of inhibitory effect on peripheral blood mononuclear cells proliferation was shown. In vivo experimental colitis showed that administration of MSC-Exo was able to significantly ameliorate the disease activity index score, weight loss, colon shortening, and the histological colitis score through up-regulation anti-inflammatory responses and down-regulation of inflammatory responses. Moreover, the use of MSC-Exo (200 μg) led to an improved therapeutic efficacy when compared with MSCs at a dose of 1×106 cells. Our findings indicate that the exosomes from MSCs in defined medium possess a certain degree of immunosuppressive effect in vitro and exhibit a therapeutic capability in a mouse model of DSS-induced colitis through suppressing inflammation mechanism.
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Affiliation(s)
- Zhi Jie Ma
- Department of Pharmacy, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Yun Hong Wang
- Department of Technology, Stem Cell Medicine Engineering & Technology Research Center of Inner Mongolia, Huhhot, Inner Mongolia, China
| | - Zhi Gang Li
- Department of Research and Development, Beijing Jingmeng Stem Cell Technology CO., LTD, Beijing, China
| | - Ying Wang
- Health Examination Center, Tongliao City Hospital, Tongliao, Inner Mongolia, China
| | - Bing Yao Li
- Department of Medicine, Chifeng Cancer Hospital, Chifeng, Inner Mongolia, China
| | - Hui Yan Kang
- Department of Technology, Stem Cell Medicine Engineering & Technology Research Center of Inner Mongolia, Huhhot, Inner Mongolia, China.,Department of Research and Development, Beijing Jingmeng Stem Cell Technology CO., LTD, Beijing, China
| | - Xiao Yun Wu
- Department of Technology, Stem Cell Medicine Engineering & Technology Research Center of Inner Mongolia, Huhhot, Inner Mongolia, China.,Department of Research and Development, Beijing Jingmeng Stem Cell Technology CO., LTD, Beijing, China
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40
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Zhou YZ, Cheng Z, Wu Y, Wu QY, Liao XB, Zhao Y, Li JM, Zhou XM, Fu XM. Mesenchymal stem cell-derived conditioned medium attenuate angiotensin II-induced aortic aneurysm growth by modulating macrophage polarization. J Cell Mol Med 2019; 23:8233-8245. [PMID: 31583844 PMCID: PMC6850971 DOI: 10.1111/jcmm.14694] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2019] [Revised: 08/03/2019] [Accepted: 08/19/2019] [Indexed: 12/15/2022] Open
Abstract
Mesenchymal stem cells (MSCs) exhibit therapeutic benefits on aortic aneurysm (AA); however, the molecular mechanisms are not fully understood. The current study aimed to investigate the therapeutic effects and potential mechanisms of murine bone marrow MSC (BM‐MSCs)–derived conditioned medium (MSCs‐CM) on angiotensin II (AngII)‐induced AA in apolipoprotein E‐deficient (apoE−/−) mice. Murine BM‐MSCs, MSCs‐CM or control medium were intravenously administrated into AngII‐induced AA in apoE−/− mice. Mice were sacrificed at 2 weeks after injection. BM‐MSCs and MSCs‐CM significantly attenuated matrix metalloproteinase (MMP)‐2 and MMP‐9 expression, aortic elastin degradation and AA growth at the site of AA. These treatments with BM‐MSCs and MSCs‐CM also decreased Ly6chigh monocytes in peripheral blood on day 7 and M1 macrophage infiltration in AA tissues on day 14, whereas they increased M2 macrophages. In addition, BM‐MSCs and MSCs‐CM reduced MCP‐1, IL‐1Ra and IL‐6 expression and increased IL‐10 expression in AA tissues. In vitro, peritoneal macrophages were co‐cultured with BM‐MSCs or fibroblasts as control in a transwell system. The mRNA and protein expression of M2 macrophage markers were evaluated. IL‐6 and IL‐1β were reduced, while IL‐10 was increased in the BM‐MSC systems. The mRNA and protein expression of M2 markers were up‐regulated in the BM‐MSC systems. Furthermore, high concentration of IGF1, VEGF and TGF‐β1 was detected in MSCs‐CM. Our results suggest that MSCs‐CM could prevent AA growth potentially through regulating macrophage polarization. These results may provide a new insight into the mechanisms of BM‐MSCs in the therapy of AA.
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Affiliation(s)
- Yang-Zhao Zhou
- Department of Cardiovascular Surgery, The Second Xiang-ya Hospital, Central South University, Changsha, China
| | - Zhao Cheng
- Department of Hematology, The Second Xiang-ya Hospital, Central South University, Changsha, China
| | - Yin Wu
- Department of Cardiovascular Surgery, The Second Xiang-ya Hospital, Central South University, Changsha, China
| | - Qi-Ying Wu
- Department of Cardiovascular Surgery, The Second Xiang-ya Hospital, Central South University, Changsha, China
| | - Xiao-Bo Liao
- Department of Cardiovascular Surgery, The Second Xiang-ya Hospital, Central South University, Changsha, China
| | - Yuan Zhao
- Department of Cardiovascular Surgery, The Second Xiang-ya Hospital, Central South University, Changsha, China
| | - Jian-Ming Li
- Department of Cardiovascular Surgery, The Second Xiang-ya Hospital, Central South University, Changsha, China
| | - Xin-Min Zhou
- Department of Cardiovascular Surgery, The Second Xiang-ya Hospital, Central South University, Changsha, China
| | - Xian-Ming Fu
- Department of Cardiovascular Surgery, The Second Xiang-ya Hospital, Central South University, Changsha, China
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da Costa Gonçalves F, Paz AH. Cell membrane and bioactive factors derived from mesenchymal stromal cells: Cell-free based therapy for inflammatory bowel diseases. World J Stem Cells 2019; 11:618-633. [PMID: 31616539 PMCID: PMC6789183 DOI: 10.4252/wjsc.v11.i9.618] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2019] [Revised: 03/23/2019] [Accepted: 07/16/2019] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel diseases (IBD) are chronic inflammatory disorders of the gastrointestinal tract associated with multifactorial conditions such as ulcerative colitis and Crohn's disease. Although the underlying mechanisms of IBD remain unclear, growing evidence has shown that dysregulated immune system reactions in genetically susceptible individuals contribute to mucosal inflammation. However, conventional treatments have been effective in inducing remission of IBD but not in preventing the relapse of them. In this way, mesenchymal stromal cells (MSC) therapy has been recognized as a promising treatment for IBD due to their immunomodulatory properties, ability to differentiate into several tissues, and homing to inflammatory sites. Even so, literature is conflicted regarding the location and persistence of MSC in the body after transplantation. For this reason, recent studies have focused on the paracrine effect of the biofactors secreted by MSC, especially in relation to the immunomodulatory potential of soluble factors (cytokines, chemokines, and growth factors) and extracellular vehicles that are involved in cell communication and in the transfer of cellular material, such as proteins, lipids, and nucleic acids. Moreover, treatment with interferon-γ, tumor necrosis factor-α, and interleukin-1β causes MSC to express immunomodulatory molecules that mediate the suppression via cell-contact dependent mechanisms. Taken together, we present an overview of the role of bioactive factors and cell membrane proteins derived from MSC as a cell-free therapy that can improve IBD treatment.
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Affiliation(s)
- Fabiany da Costa Gonçalves
- Nephrology and Transplantation, Internal Medicine, Erasmus Medical Center, Rotterdam, GD 3015, Netherlands.
| | - Ana Helena Paz
- Experimental Research Center, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS 90035-903, Brazil
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Thomi G, Surbek D, Haesler V, Joerger-Messerli M, Schoeberlein A. Exosomes derived from umbilical cord mesenchymal stem cells reduce microglia-mediated neuroinflammation in perinatal brain injury. Stem Cell Res Ther 2019; 10:105. [PMID: 30898154 PMCID: PMC6429800 DOI: 10.1186/s13287-019-1207-z] [Citation(s) in RCA: 187] [Impact Index Per Article: 31.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2018] [Revised: 02/25/2019] [Accepted: 03/05/2019] [Indexed: 02/07/2023] Open
Abstract
Background Preterm newborns are at high risk of developing neurodevelopmental deficits caused by neuroinflammation leading to perinatal brain injury. Human Wharton’s jelly mesenchymal stem cells (hWJ-MSC) derived from the umbilical cord have been suggested to reduce neuroinflammation, in part through the release of extracellular vesicle-like exosomes. Here, we studied whether exosomes derived from hWJ-MSC have anti-inflammatory effects on microglia-mediated neuroinflammation in perinatal brain injury. Methods Using ultracentrifugation, we isolated exosomes from hWJ-MSC culture supernatants. In an in vitro model of neuroinflammation, we stimulated immortalized BV-2 microglia and primary mixed glial cells with lipopolysaccharide (LPS) in the presence or absence of exosomes. In vivo, we introduced brain damage in 3-day-old rat pups and treated them intranasally with hWJ-MSC-derived exosomes. Results hWJ-MSC-derived exosomes dampened the LPS-induced expression of inflammation-related genes by BV-2 microglia and primary mixed glial cells. The secretion of pro-inflammatory cytokines by LPS-stimulated primary mixed glial was inhibited by exosomes as well. Exosomes interfered within the Toll-like receptor 4 signaling of BV-2 microglia, as they prevented the degradation of the NFκB inhibitor IκBα and the phosphorylation of molecules of the mitogen-activated protein kinase family in response to LPS stimulation. Finally, intranasally administered exosomes reached the brain and reduced microglia-mediated neuroinflammation in rats with perinatal brain injury. Conclusions Our data suggest that the administration of hWJ-MSC-derived exosomes represents a promising therapy to prevent and treat perinatal brain injury. Electronic supplementary material The online version of this article (10.1186/s13287-019-1207-z) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Gierin Thomi
- Department of Obstetrics and Feto-maternal Medicine, University Women's Hospital, Inselspital, Bern University Hospital, Bern, Switzerland.,Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland.,Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland
| | - Daniel Surbek
- Department of Obstetrics and Feto-maternal Medicine, University Women's Hospital, Inselspital, Bern University Hospital, Bern, Switzerland.,Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
| | - Valérie Haesler
- Department of Obstetrics and Feto-maternal Medicine, University Women's Hospital, Inselspital, Bern University Hospital, Bern, Switzerland.,Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
| | - Marianne Joerger-Messerli
- Department of Obstetrics and Feto-maternal Medicine, University Women's Hospital, Inselspital, Bern University Hospital, Bern, Switzerland. .,Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland.
| | - Andreina Schoeberlein
- Department of Obstetrics and Feto-maternal Medicine, University Women's Hospital, Inselspital, Bern University Hospital, Bern, Switzerland.,Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
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Galeshi A, Ghasemi-Kasman M, Feizi F, Davoodian N, Zare L, Abedian Z. Co-administration of aspirin and adipose-derived stem cell conditioned medium improves the functional recovery of the optic pathway in a lysolecithin-induced demyelination model. Neuropsychiatr Dis Treat 2019; 15:2681-2694. [PMID: 31571884 PMCID: PMC6756276 DOI: 10.2147/ndt.s218594] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2019] [Accepted: 08/30/2019] [Indexed: 12/21/2022] Open
Abstract
INTRODUCTION Based on beneficial effects of aspirin and mesenchymal stem cells (MSCs) on myelin repair, in a preset study, effects of co-administration of aspirin and conditioned medium from adipose tissue-derived stem cells (ADSC-CM) on functional recovery of optic pathway, demyelination levels, and astrocytes' activation were evaluated in a lysolecithin (LPC)-induced demyelination model of optic chiasm. METHODS LPC (1%, 2 µL) was injected into the rat optic chiasm and animals underwent daily intraperitoneal (i.p.) injections of ADSCs-CM and oral gavage of aspirin at a dose of 25 mg/kg for 14 days post LPC injection. The conductivity of visual signals was assessed using visual evoked potential recordings (VEPs) before LPC injection and on days 7 and 14 post lesion. Immunostaining against PDGFRα as oligodendrocyte precursor cells marker, MOG as mature myelin marker, and GFAP as astrocyte marker was performed on brain sections at day 14 post LPC injection. FluoroMyelin staining was also used to measure the extent of demyelination areas. RESULTS Our results showed that administration of ADSCs-CM and aspirin significantly reduced the latency of VEP waves in LPC receiving animals. In addition, demyelination levels and GFAP expressing cells were attenuated while the number of oligodendrocyte precursor cells significantly increased in rats treated with ADSCs-CM and aspirin. CONCLUSION Overall, our results suggest that co-administration of ADSCs-CM and aspirin improves the functional recovery of optic pathway through amelioration of astrocyte activation and attenuation of demyelination level.
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Affiliation(s)
- Adel Galeshi
- Babol University of Medical Sciences, Babol, Iran.,Department of Anatomical Sciences, Faculty of Medicine, Babol University of Medical Sciences, Babol, Iran
| | - Maryam Ghasemi-Kasman
- Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran.,Neuroscience Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
| | - Farideh Feizi
- Department of Anatomical Sciences, Faculty of Medicine, Babol University of Medical Sciences, Babol, Iran.,Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
| | - Nahid Davoodian
- Molecular Medicine Research Center, Hormozgan Health Institute, Hormozgan University of Medical Sciences, Bandar Abbas, Iran.,Department of Clinical Biochemistry, Faculty of Medicine, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
| | - Leila Zare
- Department of Physiology, School of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Zeinab Abedian
- Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
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