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Hassan MNF, Yazid MD, Yunus MHBM, Lokanathan Y, Ng MH, Idrus RBH, Tang YL, Ng SN, Law JX. Comparing the growth kinetics and characteristics of Wharton's jelly derived mesenchymal stem cells expanded using different culture mediums. Cytotechnology 2025; 77:24. [PMID: 39711971 PMCID: PMC11659549 DOI: 10.1007/s10616-024-00682-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2023] [Accepted: 12/07/2024] [Indexed: 12/24/2024] Open
Abstract
Wharton's jelly-derived mesenchymal stem cells (WJ-MSCs) can be isolated from umbilical cords which is abundant and easy to obtain. Due to their potent immunosuppressive properties, multilineage differentiation potential, and lack of ethical issues, WJ-MSCs are considered a promising candidate for therapeutic applications. However, large-scale in vitro expansion is necessary to obtain enough cells for therapeutic purposes. Therefore, this study aimed to optimize cell culture conditions and determine the characteristics of expanded WJ-MSCs. WJ-MSCs were seeded in 6-well plates at a density of 5000 cells/cm2 and cultured with different mediums, including DMEM-LG+10% FBS, DMEM-LG+10% HPL, serum-free commercial medium 1, serum-free GMP grade commercial medium 2, and HPL supplemented commercial medium 3. The cell morphology and growth kinetics were compared, and the three most suitable mediums were selected for further experiments. WJ-MSCs were then cultured in the selected mediums at seeding densities ranging from 1000 to 5000 cells/cm2, and cell growth kinetics were analysed. WJ-MSCs cultured in the selected mediums were characterized by their immunophenotype, tri-lineage differentiation potential and immunosuppression property. WJ-MSCs cultured with DMEM-LG+10% HPL, commercial medium 1 and commercial medium 2 showed smaller size, significantly higher cell yield, and shorter population doubling time than those cultured in other mediums. Hence, these three mediums were selected for further experiments. Only DMEM-LG + 10% HPL medium maintained high cell yields (1.48 ± 0.14 × 106 with bFGF and 1.56 ± 0.17 × 106 without bFGF) at the lowest seeding density tested. However, WJ-MSCs cultured in all three mediums expressed the MSC surface markers, were able to suppress PBMC proliferation, and could differentiate into adipogenic, chondrogenic and osteogenic lineages. In summary, DMEM-LG+10% HPL is the best medium for WJ-MSC expansion, as it provides the highest cell yield without compromising cell characteristics and functionality. The potential of this medium for large-scale expansion using a bioreactor or multilayered flask should be investigated in the future.
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Affiliation(s)
- Muhammad Najib Fathi Hassan
- Department of Tissue Engineering and Regenerative Medicine (DTERM), Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Muhammad Dain Yazid
- Department of Tissue Engineering and Regenerative Medicine (DTERM), Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | | | - Yogeswaran Lokanathan
- Department of Tissue Engineering and Regenerative Medicine (DTERM), Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Min Hwei Ng
- Department of Tissue Engineering and Regenerative Medicine (DTERM), Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Ruszymah Bt Hj Idrus
- Department of Tissue Engineering and Regenerative Medicine (DTERM), Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Yee Loong Tang
- Department of Pathology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - See Nguan Ng
- Ming Medical Sdn Bhd, D3-3 (2Nd Floor), Block D3 Dana 1 Commercial Centre, Jalan PJU 1a/46, 47301 Petaling Jaya, Selangor Malaysia
| | - Jia Xian Law
- Department of Tissue Engineering and Regenerative Medicine (DTERM), Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
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Budagova T, Efremova A, Usman N, Mokrousova D, Goldshtein D. Differentiating Induced Pluripotent Stem Cells into Natural Killer Cells for Adoptive Cell Immunotherapies-Comparative Characterization of Current Protocols. Int J Mol Sci 2025; 26:1107. [PMID: 39940874 PMCID: PMC11816922 DOI: 10.3390/ijms26031107] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2024] [Revised: 01/23/2025] [Accepted: 01/23/2025] [Indexed: 02/16/2025] Open
Abstract
Cancers constitute a leading cause of mortality. Chimeric antigen receptor (CAR) cell therapies provide breakthrough solutions for various cancers while posing considerable risks of immunological side reactions. Of various cytotoxic lymphocyte subsets, natural killer (NK) cells are considered the least immunogenic. Obtaining viable NK cells with stable phenotypes in quantities sufficient for modification is technologically challenging. The candidate sources include primary mononuclear cell cultures and immortalized NK cell lines; alternatively, the clinical-grade NK cells can be differentiated from induced pluripotent stem cells (iPSCs) by a good manufacturing practice (GMP)-compatible xeno-free protocol. In this review, we analyze existing protocols for targeted differentiation of human iPSCs into NK cells with a focus on xeno-free requirements.
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Affiliation(s)
- Tatiana Budagova
- Research Centre for Medical Genetics, Moskvorechye Str. 1, Moscow 115522, Russia; (T.B.); (D.M.); (D.G.)
| | - Anna Efremova
- Research Centre for Medical Genetics, Moskvorechye Str. 1, Moscow 115522, Russia; (T.B.); (D.M.); (D.G.)
- Research Institute of Molecular and Cellular Medicine, Peoples’ Friendship University of Russia, Miklukho-Maklaya Str. 6, Moscow 117198, Russia
| | - Natalia Usman
- Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Samory Mashela Str. 1, Moscow 117198, Russia;
| | - Diana Mokrousova
- Research Centre for Medical Genetics, Moskvorechye Str. 1, Moscow 115522, Russia; (T.B.); (D.M.); (D.G.)
| | - Dmitry Goldshtein
- Research Centre for Medical Genetics, Moskvorechye Str. 1, Moscow 115522, Russia; (T.B.); (D.M.); (D.G.)
- Research Institute of Molecular and Cellular Medicine, Peoples’ Friendship University of Russia, Miklukho-Maklaya Str. 6, Moscow 117198, Russia
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De Berdt P, Deltour E, Pauly E, Gordillo N, Lin F, Sokal E, Najimi M. Expansion of human allogeneic liver-derived progenitor cells for liver regenerative therapy in serum-free culture conditions. Cytotherapy 2024; 26:1571-1578. [PMID: 39127924 DOI: 10.1016/j.jcyt.2024.07.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2024] [Revised: 07/09/2024] [Accepted: 07/10/2024] [Indexed: 08/12/2024]
Abstract
Human allogeneic liver-derived progenitor cells (HALPCs) display advanced ability to differentiate into hepatocyte-like cells and exhibit potent immunomodulatory, anti-inflammatory, and anti-fibrotic properties. HALPCs have been successfully manufactured under good manufacturing practice (GMP) and are currently in clinical development. A previous phase 2a trial demonstrated the safety of peripheral intravenous infusions of HALPCs and preliminary evidence of the cells' properties to restore liver function in patients with acute-on-chronic liver failure (ACLF), thus potentially improving their survival. A phase 2b trial is currently ongoing across multiple centers (NCT04229901) to obtain proof-of-concept on efficacy and additional safety. HALPCs are currently manufactured using fetal bovine serum (FBS), which can reveal qualitative and quantitative variations between batches. The use of serum-free medium (SFM) represents an alternative means to overcome this variability while also complying fully with regulations. The aim of this study was to compare current FBS-containing culture conditions with two industry-available GMP-compliant SFMs: StemMACS (Miltenyi Biotec, Bergisch Gladbach, Germany) and PRIME-XV (FUJIFILM Irvine Scientific, Santa Ana, California, USA). The proliferation of HALPCs was significantly stimulated by both SFMs, which shortened both their emergence period and population doubling time. This effect was correlated with a significant improvement in their genetic stability as analyzed by conventional karyotyping. The expression profile (identity and purity) and functionality of HALPCs cultured in SFM were maintained, as demonstrated by flow cytometry and enzyme-linked immunoassay (ELISA), respectively. Their potency, evaluated via prostaglandin E2 (PGE2) secretion, showed a similar effect on CD4+ T-cell proliferation in FBS and SFM conditions. Furthermore, a greater proportion of HALPCs cultured in SFM showed enhanced expression of tissue factor (CD142) compared with the FBS condition. Altogether, SFM conditions enabled consistent HALPC quality to be achieved without altering their expression and functional profiles.
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Affiliation(s)
| | | | | | | | | | - Etienne Sokal
- Cellaïon, Mont-Saint-Guibert, Belgium; Laboratory of Pediatric Hepatology & Cell Therapy, Institute of Experimental and Clinical Research (IREC), UCLouvain, Brussels, Belgium
| | - Mustapha Najimi
- Cellaïon, Mont-Saint-Guibert, Belgium; Laboratory of Pediatric Hepatology & Cell Therapy, Institute of Experimental and Clinical Research (IREC), UCLouvain, Brussels, Belgium.
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Patel AA, Mohamed AH, Rizaev J, Mallick AK, Qasim MT, Abdulmonem WA, Jamal A, Hattiwale HM, Kamal MA, Ahmad F. Application of mesenchymal stem cells derived from the umbilical cord or Wharton's jelly and their extracellular vesicles in the treatment of various diseases. Tissue Cell 2024; 89:102415. [PMID: 38851032 DOI: 10.1016/j.tice.2024.102415] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2024] [Revised: 04/26/2024] [Accepted: 05/20/2024] [Indexed: 06/10/2024]
Abstract
Mesenchymal stem cells (MSCs) originating from the umbilical cord (UC) or Wharton's jelly (WJ) have attracted substantial interest due to their potential to augment therapeutic approaches for a wide range of disorders. These cells demonstrate a wide range of capabilities in the process of differentiating into a multitude of cell types. Additionally, they possess a significant capacity for proliferation and are conveniently accessible. Furthermore, they possess a status of being immune-privileged, exhibit minimal tumorigenic characteristics, and raise minimal ethical concerns. Consequently, they are well-suited candidates for tissue regeneration and the treatment of diseases. Additionally, UC-derived MSCs offer a substantial yield compared to other sources. The therapeutic effects of these MSCs are closely associated with the release of nanosized extracellular vesicles (EVs), including exosomes and microvesicles (MVs), containing lipids, microRNAs, and proteins that facilitate intercellular communication. Due to their reduced tumorigenic and immunogenic characteristics, in addition to their convenient manipulability, EVs have arisen as a viable alternative for the management of disorders. The favorable characteristics of UC-MSCs or WJ-MSCs and their EVs have generated significant attention in clinical investigations encompassing diverse pathologies. Therefore, we present a review encompassing current preclinical and clinical investigations, examining the implications of UC-MSCs in diverse diseases, including those affecting bone, cartilage, skin, liver, kidney, neural, lung, cardiovascular, muscle, and retinal tissues, as well as conditions like cancer, diabetes, sepsis, and others.
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Affiliation(s)
- Ayyub Ali Patel
- Clinical Biochemistry Department, College of Medicine, King Khalid University, Abha, Saudi Arabia
| | - Asma'a H Mohamed
- Biomedical Engineering Department, College of Engineering and Technologies, Al-Mustaqbal University, Hilla, Babil 51001, Iraq.
| | - Jasur Rizaev
- Department of Public Health and Healthcare management, Rector, Samarkand State Medical University, 18, Amir Temur Street, Samarkand, Uzbekistan
| | - Ayaz Khurram Mallick
- Clinical Biochemistry Department, College of Medicine, King Khalid University, Abha, Saudi Arabia
| | - Maytham T Qasim
- College of Health and Medical Technology, Al-Ayen University, Thi-Qar 64001, Iraq
| | - Waleed Al Abdulmonem
- Department of Pathology, College of Medicine, Qassim University, Buraidah, Saudi Arabia
| | - Azfar Jamal
- Department of Biology, College of Science Al-Zulfi, Majmaah University, Al-Majmaah 11952, Saudi Arabia; Health and Basic Science Research Centre, Majmaah University, Al-Majmaah 11952, Saudi Arabia
| | - Haroonrashid M Hattiwale
- Department of Basic Medical Sciences, College of Medicine, Majmaah University, Al-Majmaah 11952, Saudi Arabia.
| | - Mohammad Azhar Kamal
- Department of Pharmaceutics, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Alkharj 11942, Saudi Arabia
| | - Fuzail Ahmad
- College of Applied Sciences, Almaarefa University, Diriya, Riyadh 13713, Saudi Arabia
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Park HS, Lee BC, Chae DH, Yu A, Park JH, Heo J, Han MH, Cho K, Lee JW, Jung JW, Dunbar CE, Oh MK, Yu KR. Cigarette smoke impairs the hematopoietic supportive property of mesenchymal stem cells via the production of reactive oxygen species and NLRP3 activation. Stem Cell Res Ther 2024; 15:145. [PMID: 38764093 PMCID: PMC11103961 DOI: 10.1186/s13287-024-03731-2] [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: 01/14/2024] [Accepted: 04/10/2024] [Indexed: 05/21/2024] Open
Abstract
BACKGROUND Mesenchymal stem cells (MSCs) play important roles in tissue homeostasis by providing a supportive microenvironmental niche for the hematopoietic system. Cigarette smoking induces systemic abnormalities, including an impeded recovery process after hematopoietic stem cell transplantation. However, the role of cigarette smoking-mediated alterations in MSC niche function have not been investigated. METHODS In the present study, we investigated whether exposure to cigarette smoking extract (CSE) disrupts the hematopoietic niche function of MSCs, and pathways impacted. To investigate the effects on bone marrow (BM)-derived MSCs and support of hematopoietic stem and progenitor cells (HSPCs), mice were repeatedly infused with the CSE named 3R4F, and hematopoietic stem and progenitor cells (HSPCs) supporting function was determined. The impact of 3R4F on MSCs at cellular level were screened by bulk-RNA sequencing and subsequently validated through qRT-PCR. Specific inhibitors were treated to verify the ROS or NLRP3-specific effects, and the cells were then transplanted into the animal model or subjected to coculture with HSPCs. RESULTS Both direct ex vivo and systemic in vivo MSC exposure to 3R4F resulted in impaired engraftment in a humanized mouse model. Furthermore, transcriptomic profile analysis showed significantly upregulated signaling pathways related to reactive oxygen species (ROS), inflammation, and aging in 3R4F-treated MSCs. Notably, ingenuity pathway analysis revealed the activation of NLRP3 inflammasome signaling pathway in 3R4F-treated MSCs, and pretreatment with the NLRP3 inhibitor MCC950 rescued the HSPC-supporting ability of 3R4F-treated MSCs. CONCLUSION In conclusion, these findings indicate that exposure to CSE reduces HSPCs supportive function of MSCs by inducing robust ROS production and subsequent NLRP3 activation.
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Affiliation(s)
- Hyun Sung Park
- Department of Agricultural Biotechnology and Research Institute of Agriculture and Life Sciences, Seoul National University, Seoul, 08826, Korea
| | - Byung-Chul Lee
- Department of Biological Sciences, Sookmyung Women's University, Seoul, Korea
- Research Institute of Women's Health, Sookmyung Women's University, Seoul, Korea
| | - Dong-Hoon Chae
- Department of Agricultural Biotechnology and Research Institute of Agriculture and Life Sciences, Seoul National University, Seoul, 08826, Korea
| | - Aaron Yu
- Department of Agricultural Biotechnology and Research Institute of Agriculture and Life Sciences, Seoul National University, Seoul, 08826, Korea
| | - Jae Han Park
- Department of Agricultural Biotechnology and Research Institute of Agriculture and Life Sciences, Seoul National University, Seoul, 08826, Korea
| | - Jiyoung Heo
- Department of Agricultural Biotechnology and Research Institute of Agriculture and Life Sciences, Seoul National University, Seoul, 08826, Korea
| | - Myoung Hee Han
- Department of Agricultural Biotechnology and Research Institute of Agriculture and Life Sciences, Seoul National University, Seoul, 08826, Korea
| | - Keonwoo Cho
- Department of Agricultural Biotechnology and Research Institute of Agriculture and Life Sciences, Seoul National University, Seoul, 08826, Korea
| | - Joong Won Lee
- Division of Allergy and Respiratory Disease Research, Department of Chronic Disease Convergence Research, Korea National Institute of Health, Cheongju, Korea
| | - Ji-Won Jung
- Division of Allergy and Respiratory Disease Research, Department of Chronic Disease Convergence Research, Korea National Institute of Health, Cheongju, Korea
| | - Cynthia E Dunbar
- Translational Stem Cell Biology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health (NIH), Bethesda, MD, USA
| | - Mi-Kyung Oh
- Department of Agricultural Biotechnology and Research Institute of Agriculture and Life Sciences, Seoul National University, Seoul, 08826, Korea.
| | - Kyung-Rok Yu
- Department of Agricultural Biotechnology and Research Institute of Agriculture and Life Sciences, Seoul National University, Seoul, 08826, Korea.
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Zhang FF, Hao Y, Zhang KX, Yang JJ, Zhao ZQ, Liu HJ, Li JT. Interplay between mesenchymal stem cells and macrophages: Promoting bone tissue repair. World J Stem Cells 2024; 16:375-388. [PMID: 38690513 PMCID: PMC11056637 DOI: 10.4252/wjsc.v16.i4.375] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2023] [Revised: 02/14/2024] [Accepted: 03/19/2024] [Indexed: 04/25/2024] Open
Abstract
The repair of bone tissue damage is a complex process that is well-orchestrated in time and space, a focus and difficulty in orthopedic treatment. In recent years, the success of mesenchymal stem cells (MSCs)-mediated bone repair in clinical trials of large-area bone defects and bone necrosis has made it a candidate in bone tissue repair engineering and regenerative medicine. MSCs are closely related to macrophages. On one hand, MSCs regulate the immune regulatory function by influencing macrophages proliferation, infiltration, and phenotype polarization, while also affecting the osteoclasts differentiation of macrophages. On the other hand, macrophages activate MSCs and mediate the multilineage differentiation of MSCs by regulating the immune microenvironment. The cross-talk between MSCs and macrophages plays a crucial role in regulating the immune system and in promoting tissue regeneration. Making full use of the relationship between MSCs and macrophages will enhance the efficacy of MSCs therapy in bone tissue repair, and will also provide a reference for further application of MSCs in other diseases.
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Affiliation(s)
- Fei-Fan Zhang
- Molecular Biology Lab, Henan Luoyang Orthopedic Hospital (Henan Provincial Orthopedic Hospital), Zhengzhou 450000, Henan Province, China
- Graduate School, Hunan University of Chinese Medicine, Changsha 410208, Hunan Province, China
| | - Yang Hao
- Molecular Biology Lab, Henan Luoyang Orthopedic Hospital (Henan Provincial Orthopedic Hospital), Zhengzhou 450000, Henan Province, China
- Graduate School, Henan University of Chinese Medicine, Zhengzhou 450046, Henan Province, China
| | - Kuai-Xiang Zhang
- Molecular Biology Lab, Henan Luoyang Orthopedic Hospital (Henan Provincial Orthopedic Hospital), Zhengzhou 450000, Henan Province, China
- Graduate School, Henan University of Chinese Medicine, Zhengzhou 450046, Henan Province, China
| | - Jiang-Jia Yang
- Molecular Biology Lab, Henan Luoyang Orthopedic Hospital (Henan Provincial Orthopedic Hospital), Zhengzhou 450000, Henan Province, China
- Graduate School, Hunan University of Chinese Medicine, Changsha 410208, Hunan Province, China
| | - Zhi-Qiang Zhao
- Molecular Biology Lab, Henan Luoyang Orthopedic Hospital (Henan Provincial Orthopedic Hospital), Zhengzhou 450000, Henan Province, China
| | - Hong-Jian Liu
- Department of Orthopaedics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Ji-Tian Li
- Molecular Biology Lab, Henan Luoyang Orthopedic Hospital (Henan Provincial Orthopedic Hospital), Zhengzhou 450000, Henan Province, China
- Graduate School, Hunan University of Chinese Medicine, Changsha 410208, Hunan Province, China
- Graduate School, Henan University of Chinese Medicine, Zhengzhou 450046, Henan Province, China.
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Ragni E, Piccolo S, De Luca P, Taiana M, Grieco G, de Girolamo L. Housekeeping Gene Stability in Adipose Mesenchymal Stromal Cells Cultivated in Serum/Xeno-Free Media for Osteoarthritis. Cells 2024; 13:167. [PMID: 38247858 PMCID: PMC10814848 DOI: 10.3390/cells13020167] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Revised: 01/08/2024] [Accepted: 01/13/2024] [Indexed: 01/23/2024] Open
Abstract
Among the available therapeutics for the conservative treatment of osteoarthritis (OA), mesenchymal stromal cells (MSCs)-based products appear to be the most promising. Alongside minimally manipulated cell-based orthobiologics, where MSCs are the engine of the bioactive properties, cell expansion under good manufacturing practice (GMP) settings is actively studied to obtain clinical-grade pure populations able to concentrate the biological activity. One of the main characteristics of GMP protocols is the use of clinical-grade reagents, including the recently released serum-free/xeno-free (SFM/XFM) synthetic media, which differ significantly from the traditional reagents like those based on fetal bovine serum (FBS). As SFM/XFM are still poorly characterized, a main lack is the notion of reliable housekeeping genes (HKGs) for molecular studies, either standalone or in combination with standard conditions. Indeed, the aim of this work was to test the stability of five commonly used HKGs (ACTB, EF1A, GAPDH, RPLP0, and TBP) in adipose-derived MSCs (ASCs) cultivated in two commercially available SFM/XFM and to compare outcomes with those obtained in FBS. Four different applets widely recognized by the scientific community (NormFinder, geNorm, comparative ΔCt method, and BestKeeper) were used and data were merged to obtain a final stability order. The analysis showed that cells cultured in both synthetic media had a similar ranking for HKGs stability (GAPDH being best), albeit divergent from FBS expanded products (EF1A at top). Moreover, it was possible to identify specific HKGs for side by side studies, with EF1A/TBP being the most reliable normalizers for single SFM/XFM vs. FBS cultured cells and TBP the best one for a comprehensive analysis of all samples. In addition, stability of HKGs was donor-dependent. The normalization effect on selected genes coding for factors known to be involved in OA pathology, and whose amount should be carefully considered for the selection of the most appropriate MSC-based treatment, showed how HKGs choice might affect the perceived amount for the different media or donor. Overall, this work confirms the impact of SFM/XFM conditions on HKGs stability performance, which resulted similarly for both synthetic media analyzed in the study.
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Affiliation(s)
| | | | - Paola De Luca
- Laboratorio di Biotecnologie Applicate all’Ortopedia, IRCCS Istituto Ortopedico Galeazzi, Via Cristina Belgioioso 173, 20157 Milano, Italy; (E.R.); (S.P.); (M.T.); (G.G.); (L.d.G.)
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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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Urzì O, Olofsson Bagge R, Crescitelli R. The dark side of foetal bovine serum in extracellular vesicle studies. J Extracell Vesicles 2022; 11:e12271. [PMID: 36214482 PMCID: PMC9549727 DOI: 10.1002/jev2.12271] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/1912] [Revised: 12/12/1912] [Accepted: 12/12/1912] [Indexed: 11/06/2022] Open
Abstract
Extracellular vesicles (EVs) have been shown to be involved in cell-cell communication and to take part in both physiological and pathological processes. Thanks to their exclusive cargo, which includes proteins, lipids, and nucleic acids from the originating cells, they are gaining interest as potential biomarkers of disease. In recent years, their appealing features have been fascinating researchers from all over the world, thus increasing the number of in vitro studies focused on EV release, content, and biological activities. Cultured cell lines are the most-used source of EVs; however, the EVs released in cell cultures are influenced by the cell culture conditions, such as the use of foetal bovine serum (FBS). FBS is the most common supplement for cell culture media, but it is also a source of contaminants, such as exogenous bovine EVs, RNA, and protein aggregates, that can contaminate the cell-derived EVs and influence their cargo composition. The presence of FBS contaminants in cell-derived EV samples is a well-known issue that limits the clinical applications of EVs, thus increasing the need for standardization. In this review, we will discuss the pros and cons of using FBS in cell cultures as a source of EVs, as well as the protocols used to remove contaminants from FBS.
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Affiliation(s)
- Ornella Urzì
- Sahlgrenska Center for Cancer Research and Wallenberg Centre for Molecular and Translational MedicineDepartment of SurgeryInstitute of Clinical SciencesSahlgrenska AcademyUniversity of GothenburgGothenburgSweden
- Department of BiomedicineNeurosciences and Advanced Diagnostics (Bi.N.D)University of PalermoPalermoItaly
| | - Roger Olofsson Bagge
- Sahlgrenska Center for Cancer Research and Wallenberg Centre for Molecular and Translational MedicineDepartment of SurgeryInstitute of Clinical SciencesSahlgrenska AcademyUniversity of GothenburgGothenburgSweden
- Department of SurgerySahlgrenska University HospitalRegion Västra GötalandGothenburgSweden
| | - Rossella Crescitelli
- Sahlgrenska Center for Cancer Research and Wallenberg Centre for Molecular and Translational MedicineDepartment of SurgeryInstitute of Clinical SciencesSahlgrenska AcademyUniversity of GothenburgGothenburgSweden
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Shi MY, Liu L, Yang FY. Strategies to improve the effect of mesenchymal stem cell therapy on inflammatory bowel disease. World J Stem Cells 2022; 14:684-699. [PMID: 36188115 PMCID: PMC9516464 DOI: 10.4252/wjsc.v14.i9.684] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Revised: 07/07/2022] [Accepted: 09/07/2022] [Indexed: 02/07/2023] Open
Abstract
Inflammatory bowel disease (IBD) includes Crohn’s disease and ulcerative colitis and is an idiopathic, chronic inflammatory disease of the colonic mucosa. The occurrence of IBD, causes irreversible damage to the colon and increases the risk of carcinoma. The routine clinical treatment of IBD includes drug treatment, endoscopic treatment and surgery. The vast majority of patients are treated with drugs and biological agents, but the complete cure of IBD is difficult. Mesenchymal stem cells (MSCs) have become a new type of cell therapy for the treatment of IBD due to their immunomodulatory and nutritional functions, which have been confirmed in many clinical trials. This review discusses some potential mechanisms of MSCs in the treatment of IBD, summarizes the experimental results, and provides new insights to enhance the therapeutic effects of MSCs in future applications.
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Affiliation(s)
- Meng-Yue Shi
- School of Medicine, Yangtze University, Jingzhou 434023, Hubei Province, China
| | - Lian Liu
- Department of Pharmacology, Medical School of Yangtze University, Yangtze University, Jingzhou 434023, Hubei Province, China
| | - Fu-Yuan Yang
- Health Science Center, Yangtze University, Jingzhou 434020, Hubei Province, China
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11
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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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12
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Zhang J, Zhai H, Yu P, Shang D, Mo R, Li Z, Wang X, Lu J, Xie Q, Xiang X. Human Umbilical Cord Blood Mononuclear Cells Ameliorate CCl4-Induced Acute Liver Injury in Mice via Inhibiting Inflammatory Responses and Upregulating Peripheral Interleukin-22. Front Pharmacol 2022; 13:924464. [PMID: 35942221 PMCID: PMC9356225 DOI: 10.3389/fphar.2022.924464] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Accepted: 06/21/2022] [Indexed: 11/13/2022] Open
Abstract
Background: Human umbilical cord blood mononuclear cells (hUCBMNCs) show therapeutic effects on many inflammatory diseases. The deterioration of acute liver injury is attributed to excessive inflammatory responses triggered by damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs). Whether hUCBMNCs treatment is a promising strategy for acute liver injury/failure needs to be investigated.Methods: Liver injury mice induced by PAMPs, DAMPs, or DAMPs plus PAMPs were developed. DAMPs included CCl4 (carbon tetrachloride), APAP (acetaminophen), and ConA (Concanavalin A). PAMPs included Klebsiella pneumoniae (K.P.) and Salmonella typhimurium (S. Typhimurium). DAMP plus PAMP-induced liver injury was developed by sequential CCl4 and K.P. administration. hUCBMNCs were injected intravenously.Results: hUCBMNCs significantly prolonged mice survival time in DAMP plus PAMP-induced liver failure but had no benefit in bacteria-infected mice. hUCBMNCs significantly alleviated hepatic necrosis post CCl4/ConA insult. In CCl4-induced acute liver injury, peripheral levels of interleukin (IL)-22 were upregulated and liver regeneration was enhanced after treating with hUCBMNCs at 48h. The levels of p62 and LC3B-II, autophagy markers, were also upregulated in the hUCBMNC-treated group.Conclusion: hUCBMNCs as a kind of cell therapeutic strategy could attenuate acute liver injury in mice, which is executed by enhancing autophagy and regeneration in the liver via inhibiting inflammatory responses and upregulating peripheral IL-22.
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Affiliation(s)
- Jinming Zhang
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Hengben Zhai
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Translational Lab of Liver Diseases, Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Pei Yu
- Department of Orthopedics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Dabao Shang
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Translational Lab of Liver Diseases, Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ruidong Mo
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Translational Lab of Liver Diseases, Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ziqiang Li
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Translational Lab of Liver Diseases, Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiaolin Wang
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Translational Lab of Liver Diseases, Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jie Lu
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Translational Lab of Liver Diseases, Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- *Correspondence: Jie Lu, ; Qing Xie, ; Xiaogang Xiang,
| | - Qing Xie
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Translational Lab of Liver Diseases, Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- *Correspondence: Jie Lu, ; Qing Xie, ; Xiaogang Xiang,
| | - Xiaogang Xiang
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Translational Lab of Liver Diseases, Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- *Correspondence: Jie Lu, ; Qing Xie, ; Xiaogang Xiang,
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13
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Liu C, Xiao K, Xie L. Advances in the Regulation of Macrophage Polarization by Mesenchymal Stem Cells and Implications for ALI/ARDS Treatment. Front Immunol 2022; 13:928134. [PMID: 35880175 PMCID: PMC9307903 DOI: 10.3389/fimmu.2022.928134] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Accepted: 06/16/2022] [Indexed: 12/03/2022] Open
Abstract
Acute lung injury/acute respiratory distress syndrome (ALI/ARDS) is a common condition with high mortality. ALI/ARDS is caused by multiple etiologies, and the main clinical manifestations are progressive dyspnea and intractable hypoxemia. Currently, supportive therapy is the main ALI/ARDS treatment, and there remains a lack of targeted and effective therapeutic strategies. Macrophages are important components of innate immunity. M1 macrophages are pro-inflammatory, while M2 macrophages are anti-inflammatory and promote tissue repair. Mesenchymal stem cells (MSCs) are stem cells with broad application prospects in tissue regeneration due to their multi-directional differentiation potential along with their anti-inflammatory and paracrine properties. MSCs can regulate the balance of M1/M2 macrophage polarization to improve the prognosis of ALI/ARDS. In this paper, we review the mechanisms by which MSCs regulate macrophage polarization and the signaling pathways associated with polarization. This review is expected to provide new targets for the treatment of ALI/ARDS.
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Affiliation(s)
- Chang Liu
- School of Medicine, Nankai University, Tianjin, China
- Center of Pulmonary & Critical Care Medicine, Chinese People’s Liberation Army (PLA) General Hospital, Beijing, China
- Medical School of Chinese People’s Liberation Army (PLA), Beijing, China
| | - Kun Xiao
- Center of Pulmonary & Critical Care Medicine, Chinese People’s Liberation Army (PLA) General Hospital, Beijing, China
- Medical School of Chinese People’s Liberation Army (PLA), Beijing, China
- *Correspondence: Kun Xiao, ; Lixin Xie,
| | - Lixin Xie
- Center of Pulmonary & Critical Care Medicine, Chinese People’s Liberation Army (PLA) General Hospital, Beijing, China
- Medical School of Chinese People’s Liberation Army (PLA), Beijing, China
- *Correspondence: Kun Xiao, ; Lixin Xie,
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14
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Jafari N, Khoradmehr A, Moghiminasr R, Seyed Habashi M. Mesenchymal Stromal/Stem Cells-Derived Exosomes as an Antimicrobial Weapon for Orodental Infections. Front Microbiol 2022; 12:795682. [PMID: 35058912 PMCID: PMC8764367 DOI: 10.3389/fmicb.2021.795682] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Accepted: 12/08/2021] [Indexed: 11/14/2022] Open
Abstract
The oral cavity as the second most various microbial community in the body contains a broad spectrum of microorganisms which are known as the oral microbiome. The oral microbiome includes different types of microbes such as bacteria, fungi, viruses, and protozoa. Numerous factors can affect the equilibrium of the oral microbiome community which can eventually lead to orodental infectious diseases. Periodontitis, dental caries, oral leukoplakia, oral squamous cell carcinoma are some multifactorial infectious diseases in the oral cavity. In defending against infection, the immune system has an essential role. Depending on the speed and specificity of the reaction, immunity is divided into two different types which are named the innate and the adaptive responses but also there is much interaction between them. In these responses, different types of immune cells are present and recent evidence demonstrates that these cell types both within the innate and adaptive immune systems are capable of secreting some extracellular vesicles named exosomes which are involved in the response to infection. Exosomes are 30-150 nm lipid bilayer vesicles that consist of variant molecules, including proteins, lipids, and genetic materials and they have been associated with cell-to-cell communications. However, some kinds of exosomes can be effective on the pathogenicity of various microorganisms and promoting infections, and some other ones have antimicrobial and anti-infective functions in microbial diseases. These discrepancies in performance are due to the origin of the exosome. Exosomes can modulate the innate and specific immune responses of host cells by participating in antigen presentation for activation of immune cells and stimulating the release of inflammatory factors and the expression of immune molecules. Also, mesenchymal stromal/stem cells (MSCs)-derived exosomes participate in immunomodulation by different mechanisms. Ease of expansion and immunotherapeutic capabilities of MSCs, develop their applications in hundreds of clinical trials. Recently, it has been shown that cell-free therapies, like exosome therapies, by having more advantages than previous treatment methods are emerging as a promising strategy for the treatment of several diseases, in particular inflammatory conditions. In orodental infectious disease, exosomes can also play an important role by modulating immunoinflammatory responses. Therefore, MSCs-derived exosomes may have potential therapeutic effects to be a choice for controlling and treatment of orodental infectious diseases.
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Affiliation(s)
- Nazanin Jafari
- Department of Endodontics, School of Dentistry, Bushehr University of Medical Sciences, Bushehr, Iran
| | - Arezoo Khoradmehr
- The Persian Gulf Marine Biotechnology Research Center, The Persian Gulf Biomedical Sciences Research Institute, Bushehr University of Medical Sciences, Bushehr, Iran
| | - Reza Moghiminasr
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Mina Seyed Habashi
- Department of Endodontics, School of Dentistry, Bushehr University of Medical Sciences, Bushehr, Iran
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15
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Park HS, Oh MK, Lee JW, Chae DH, Joo H, Kang JY, An HB, Yu A, Park JH, Yoo HM, Jung HJ, Choi U, Jung JW, Kim IS, Oh IH, Yu KR. Diesel Exhaust Particles Impair Therapeutic Effect of Human Wharton's Jelly-Derived Mesenchymal Stem Cells against Experimental Colitis through ROS/ERK/cFos Signaling Pathway. Int J Stem Cells 2021; 15:203-216. [PMID: 34966003 PMCID: PMC9148831 DOI: 10.15283/ijsc21178] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Revised: 11/10/2021] [Accepted: 11/10/2021] [Indexed: 11/10/2022] Open
Abstract
Background and Objectives Epidemiological investigations have shown positive correlations between increased diesel exhaust particles (DEP) in ambient air and adverse health outcomes. DEP are the major constituent of particulate atmospheric pollution and have been shown to induce proinflammatory responses both in the lung and systemically. Here, we report the effects of DEP exposure on the properties of human Wharton’s jelly-derived mesenchymal stem cells (WJ-MSCs), including stemness, regeneration, and immunomodulation. Methods and Results Non-apoptotic concentrations of DEP (10 μg/ml) inhibited the migration and osteogenic differentiation capacity of WJ-MSCs. Gene expression profiling showed that DEP increased intracellular reactive oxygen species (ROS) and expression of pro-inflammatory and metabolic-process-related genes including cFos. Furthermore, WJ-MSCs cultured with DEP showed impaired suppression of T cell proliferation that was reversed by inhibition of ROS or knockdown of cFos. ERK inhibition assay revealed that DEP-induced ROS regulated cFos through activation of ERK but not NF-κB signaling. Overall, low concentrations of DEP (10 μg/ml) significantly suppressed the stemness and immunomodulatory properties of WJ-MSCs through ROS/ERK/cFos signaling pathways. Furthermore, WJ-MSCs cultured with DEP impaired the therapeutic effect of WJ-MSCs in experimental colitis mice, but was partly reversed by inhibition of ROS. Conclusions Taken together, these results indicate that exposure to DEP enhances the expression of pro-inflammatory cytokines and immune responses through a mechanism involving the ROS/ERK/cFos pathway in WJ-MSCs, and that DEP-induced ROS damage impairs the therapeutic effect of WJ-MSCs in colitis. Our results suggest that modulation of ROS/ERK/cFos signaling pathways in WJ-MSCs might be a novel therapeutic strategy for DEP-induced diseases.
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Affiliation(s)
- Hyun Sung Park
- Department of Biomedicine and Health Sciences, College of Medicine, The Catholic University of Korea, Seoul, Korea.,Department of Medical Life Sciences, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Mi-Kyung Oh
- Department of Agricultural Biotechnology and Research Institute of Agriculture and Life Sciences, Seoul National University, Seoul, Korea.,Bio-MAX Institute, Seoul National University, Seoul, Korea
| | - Joong Won Lee
- Division of Allergy and Respiratory Disease Research, Department of Chronic Disease Convergence Research, Korea National Institute of Health, Cheongju, Korea
| | - Dong-Hoon Chae
- Department of Agricultural Biotechnology and Research Institute of Agriculture and Life Sciences, Seoul National University, Seoul, Korea
| | - Hansol Joo
- Department of Biomedicine and Health Sciences, College of Medicine, The Catholic University of Korea, Seoul, Korea.,Department of Medical Life Sciences, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Ji Yeon Kang
- Department of Biomedicine and Health Sciences, College of Medicine, The Catholic University of Korea, Seoul, Korea.,Department of Medical Life Sciences, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Hye Bin An
- Department of Agricultural Biotechnology and Research Institute of Agriculture and Life Sciences, Seoul National University, Seoul, Korea
| | - Aaron Yu
- Department of Agricultural Biotechnology and Research Institute of Agriculture and Life Sciences, Seoul National University, Seoul, Korea
| | - Jae Han Park
- Department of Agricultural Biotechnology and Research Institute of Agriculture and Life Sciences, Seoul National University, Seoul, Korea
| | - Hee Min Yoo
- Biometrology Group, Korea Research Institute of Standards and Science (KRISS), Daejeon, Korea.,Department of Bio-Analytical Science, University of Science and Technology (UST), Daejeon, Korea
| | - Hyun Jun Jung
- Division of Nephrology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Uimook Choi
- Laboratory of Clinical Immunology and Microbiology, NIAID, NIH, Bethesda, MD, USA
| | - Ji-Won Jung
- Division of Allergy and Respiratory Disease Research, Department of Chronic Disease Convergence Research, Korea National Institute of Health, Cheongju, Korea
| | - In-Sook Kim
- Department of Biomedicine and Health Sciences, College of Medicine, The Catholic University of Korea, Seoul, Korea.,Department of Medical Life Sciences, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Il-Hoan Oh
- Department of Biomedicine and Health Sciences, College of Medicine, The Catholic University of Korea, Seoul, Korea.,Catholic High-Performance Cell Therapy Center & Department of Medical Life Science, College of Medicine, The Catholic University, Seoul, Korea
| | - Kyung-Rok Yu
- Department of Agricultural Biotechnology and Research Institute of Agriculture and Life Sciences, Seoul National University, Seoul, Korea
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16
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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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17
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Lu D, Xu Y, Liu Q, Zhang Q. Mesenchymal Stem Cell-Macrophage Crosstalk and Maintenance of Inflammatory Microenvironment Homeostasis. Front Cell Dev Biol 2021; 9:681171. [PMID: 34249933 PMCID: PMC8267370 DOI: 10.3389/fcell.2021.681171] [Citation(s) in RCA: 79] [Impact Index Per Article: 19.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Accepted: 05/28/2021] [Indexed: 12/13/2022] Open
Abstract
Macrophages are involved in almost every aspect of biological systems and include development, homeostasis and repair. Mesenchymal stem cells (MSCs) have good clinical application prospects due to their ability to regulate adaptive and innate immune cells, particularly macrophages, and they have been used successfully for many immune disorders, including inflammatory bowel disease (IBD), acute lung injury, and wound healing, which have been reported as macrophage-mediated disorders. In the present review, we focus on the interaction between MSCs and macrophages and summarize their methods of interaction and communication, such as cell-to-cell contact, soluble factor secretion, and organelle transfer. In addition, we discuss the roles of MSC-macrophage crosstalk in the development of disease and maintenance of homeostasis of inflammatory microenvironments. Finally, we provide optimal strategies for applications in immune-related disease treatments.
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Affiliation(s)
- Di Lu
- The Biotherapy Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yan Xu
- The Biotherapy Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Qiuli Liu
- The Biotherapy Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Qi Zhang
- The Biotherapy Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
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18
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Extracellular Vesicles from Thapsigargin-Treated Mesenchymal Stem Cells Ameliorated Experimental Colitis via Enhanced Immunomodulatory Properties. Biomedicines 2021; 9:biomedicines9020209. [PMID: 33670708 PMCID: PMC7922639 DOI: 10.3390/biomedicines9020209] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Revised: 02/15/2021] [Accepted: 02/15/2021] [Indexed: 02/08/2023] Open
Abstract
Therapeutic applications of extracellular vesicles (EVs) derived from mesenchymal stem cells (MSCs) have attracted considerable attention because of their immunomodulatory properties against immune-mediated, inflammatory diseases. Here, we demonstrated enhanced immunomodulatory properties of EVs secreted from endoplasmic reticulum (ER) stress inducer thapsigargin (TSG)-primed human Wharton's jelly-derived MSCs (WJ-MSCs). EVs from TSG-primed WJ-MSCs (TSG-EV) showed increased yield and expression of immunomodulatory factors, such as transforming growth factor-β1 (TGFβ), cyclooxygenase-2 (COX2), and especially indoleamine 2,3-dioxygenase (IDO), compared to control EVs. TSG-EV showed a significantly enhanced immunosuppressive effect on human peripheral blood-derived T cell proliferation and Th1 and Th17 differentiation, whereas Treg and M2-type macrophage were enriched compared to a control EV-treated group. Furthermore, TSG-EV substantially mitigated mouse experimental colitis by reducing the inflammatory response and maintaining intestinal barrier integrity. A significant increase of Tregs and M2-type macrophages in colitic colons of a TSG-EV-treated mouse suggests an anti-inflammatory effect of TSG-EV in colitis model, possibly mediated by Treg and macrophage polarization. These data indicate that TSG treatment promoted immunomodulatory properties of EVs from WJ-MSCs, and TSG-EV may provide a new therapeutic approach for treatment of colitis.
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19
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Lee BC, Kang I, Yu KR. Therapeutic Features and Updated Clinical Trials of Mesenchymal Stem Cell (MSC)-Derived Exosomes. J Clin Med 2021; 10:711. [PMID: 33670202 PMCID: PMC7916919 DOI: 10.3390/jcm10040711] [Citation(s) in RCA: 110] [Impact Index Per Article: 27.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Accepted: 02/04/2021] [Indexed: 02/07/2023] Open
Abstract
Identification of the immunomodulatory and regenerative properties of mesenchymal stem cells (MSCs) have made them an attractive alternative therapeutic option for diseases with no effective treatment options. Numerous clinical trials have followed; however, issues such as infusional toxicity and cellular rejection have been reported. To address these problems associated with cell-based therapy, MSC exosome therapy was developed and has shown promising clinical outcomes. MSC exosomes are nanosized vesicles secreted from MSCs and represent a non-cellular therapeutic agent. MSC exosomes retain therapeutic features of the cells from which they originated including genetic material, lipids, and proteins. Similar to MSCs, exosomes can induce cell differentiation, immunoregulation, angiogenesis, and tumor suppression. MSC exosomes have therefore been employed in several experimental models and clinical studies. Here, we review the therapeutic potential of MSC-derived exosomes and summarize currently ongoing clinical trials according to disease type. In addition, we propose several functional enhancement strategies for the effective clinical application of MSC exosome therapy.
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Affiliation(s)
- Byung-Chul Lee
- Translational Stem Cell Biology Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD 20892, USA;
| | - Insung Kang
- Program in Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, MD 20892, USA;
| | - Kyung-Rok Yu
- Department of Agricultural Biotechnology and Research Institute of Agriculture and Life Sciences, Seoul National University, Seoul 08826, Korea
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