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Rybkowska P, Kawalec M, Dymkowska D, Radoszkiewicz K, Zabłocka B, Zabłocki K, Sarnowska A. Activity and function of auxiliary fluxes of glucose metabolism in response to physiological normoxia (5 % O 2) during long-term Adipose-Derived Stem/Stromal cell culture. Eur J Cell Biol 2025; 104:151486. [PMID: 40187000 DOI: 10.1016/j.ejcb.2025.151486] [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: 08/28/2024] [Revised: 03/20/2025] [Accepted: 03/20/2025] [Indexed: 04/07/2025] Open
Abstract
Energy metabolism homeostasis emerges as a dominant element influencing mesenchymal stem/stromal cells' trajectory of development. The predominant glycolysis activity is a primary driver of cell proliferation and maintenance of the high-energetic state. Here, we examined the functions of two crucial auxiliary pathways: the phosphate-pentose pathway (PPP) and fructose-2,6-biphosphate pathway (FBP) to evaluate their impact on the therapeutic potential of Adipose-Derived Stem/Stromal cells (ASCs) during prolonged culture in various oxygen conditions: 5 % O2 - physiological normoxia or 21 % O2 - atmospheric oxygen. Our findings demonstrate that ASCs cultured in 5 % O2 increased the rate of proliferation, migration, and expression of stemness factors, which is prominent during the initial and middle passages. Additionally, ASCs cultured in a 5 % O2 exhibited heightened protection mechanisms against free radicals, increased LDH gene expression, and elevated extracellular acidification rate (ECAR). By estimating the HIF-1α level, we concluded that 5 % oxygen conditions were insufficient to induce a profound hypoxic state in ASCs. However, at the protein level, both the PPP and FBP pathways appeared to be more active in young (2-passage) cells, regardless of oxygen conditions, and their activity diminished over time. Additionally, the chemical suppression of G6PDH by Polydatin and inhibition of PFKFB3 by PFK-158 in ASCs (passage-2) revealed dose- and time-dependent effect on decreasing migratory capabilities of cells. Nevertheless, our work underscores the adaptable nature of ASC metabolism to prevailing external conditions, with the aging of the culture contributing to the decline in glycolysis-associated auxiliary pathways.
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Affiliation(s)
- Paulina Rybkowska
- Translational Platform for Regenerative Medicine, Mossakowski Medical Research Institute, Polish Academy of Sciences, Pawinskiego 5 Street, Warsaw 02-106, Poland.
| | - Maria Kawalec
- Molecular Biology Unit, Mossakowski Medical Research Institute, Polish Academy of Sciences, Pawinskiego 5 Street, Warsaw 02-106, Poland
| | - Dorota Dymkowska
- Laboratory of Cellular Metabolism, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Pasteur 3 Street, Warsaw 02-093, Poland
| | - Klaudia Radoszkiewicz
- Translational Platform for Regenerative Medicine, Mossakowski Medical Research Institute, Polish Academy of Sciences, Pawinskiego 5 Street, Warsaw 02-106, Poland
| | - Barbara Zabłocka
- Molecular Biology Unit, Mossakowski Medical Research Institute, Polish Academy of Sciences, Pawinskiego 5 Street, Warsaw 02-106, Poland
| | - Krzysztof Zabłocki
- Laboratory of Cellular Metabolism, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Pasteur 3 Street, Warsaw 02-093, Poland
| | - Anna Sarnowska
- Translational Platform for Regenerative Medicine, Mossakowski Medical Research Institute, Polish Academy of Sciences, Pawinskiego 5 Street, Warsaw 02-106, Poland.
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Huang QM, Zhuo YQ, Duan ZX, Long YL, Wang JN, Zhang ZH, Fan SY, Huang YM, Deng KY, Xin HB. Long-term hypoxic atmosphere enhances the stemness, immunoregulatory functions, and therapeutic application of human umbilical cord mesenchymal stem cells. Bone Joint Res 2024; 13:764-778. [PMID: 39662502 PMCID: PMC11634399 DOI: 10.1302/2046-3758.1312.bjr-2024-0136.r2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2024] Open
Abstract
Aims Mesenchymal stem cells (MSCs) are usually cultured in a normoxic atmosphere (21%) in vitro, while the oxygen concentrations in human tissues and organs are 1% to 10% when the cells are transplanted in vivo. However, the impact of hypoxia on MSCs has not been deeply studied, especially its translational application. Methods In the present study, we investigated the characterizations of human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) in hypoxic (1%) and normoxic (21%) atmospheres with a long-term culture from primary to 30 generations, respectively. The comparison between both atmospheres systematically analyzed the biological functions of MSCs, mainly including stemness maintenance, immune regulation, and resistance to chondrocyte apoptosis, and studied their joint function and anti-inflammatory effects in osteoarthritis (OA) rats constructed by collagenase II. Results We observed that long-term hypoxic culture surpassed normoxic atmosphere during hUC-MSCs culture in respect of promoting proliferation, anti-tumorigenicity, maintaining normal karyotype and stemness, inhibiting senescence, and improving immunoregulatory function and the role of anti-apoptosis in chondrocytes. Furthermore, we demonstrated that the transplantation of long-term hypoxic hUC-MSCs (Hy-MSCs) had a better therapeutic effect on OA rats compared with the hUC-MSCs cultured in the normoxic atmosphere (No-MSCs) in terms of the improved function and swelling recovery in the joints, and substantially inhibited the secretion of pro-inflammatory factors, which effectively alleviated cartilage damage by reducing the expression of matrix metallopeptidase 13 (MMP-13). Conclusion Our results demonstrate that Hy-MSCs possess immense potential for clinical applications via promoting stemness maintenance and enhancing immunoregulatory function.
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Affiliation(s)
- Qi-Ming Huang
- The National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Nanchang University, Nanchang, China
- College of Life Science, Nanchang University, Nanchang, China
| | - You-Qiong Zhuo
- The National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Nanchang University, Nanchang, China
- School of Food Science and Technology, Nanchang University, Nanchang, China
| | - Zhong-Xin Duan
- Lushan Botanical Garden, Jiangxi Province and Chinese Academy of Sciences, Lushan, China
| | - Yin-lin Long
- The National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Nanchang University, Nanchang, China
| | - Jia-Nan Wang
- The National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Nanchang University, Nanchang, China
| | - Zhou-hang Zhang
- The National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Nanchang University, Nanchang, China
- College of Life Science, Nanchang University, Nanchang, China
| | - Shao-Yong Fan
- Sports Medicine Department, Hongdu Traditional Chinese Medicine Hospital, Nanchang, China
| | - Yong-Ming Huang
- Department of Orthopedic Surgery, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Ke-Yu Deng
- The National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Nanchang University, Nanchang, China
- College of Life Science, Nanchang University, Nanchang, China
| | - Hong-Bo Xin
- The National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Nanchang University, Nanchang, China
- College of Life Science, Nanchang University, Nanchang, China
- School of Food Science and Technology, Nanchang University, Nanchang, China
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Qu T, Sun Y, Zhao J, Liu N, Yang J, Lyu D, Huang W, Zhan W, Li T, Yao Z, Yan R, Zhang H, Hong H, Shi L, Meng X, Yin B. Scoulerine: A natural isoquinoline alkaloid targeting SLC6A3 to treat RCC. Biomed Pharmacother 2024; 180:117524. [PMID: 39395255 DOI: 10.1016/j.biopha.2024.117524] [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: 07/21/2024] [Revised: 09/30/2024] [Accepted: 10/04/2024] [Indexed: 10/14/2024] Open
Abstract
Scoulerine, an isoquinoline alkaloid derived from the corydalis plant, exhibits diverse therapeutic properties against tumors, Alzheimer's disease, and inflammation. This research delves into the pharmacological impact and underlying mechanism of scoulerine on renal cell carcinoma (RCC). Our findings suggest that Scoulerine displays promise as a potential therapeutic agent for RCC, demonstrating notable inhibitory effects in both in vivo and in vitro models. In addition, scoulerine inhibited the viability of 769-P and 786-O cell lines in a time-dependent and dose-dependent manner, and promoted the level of apoptosis associated with B-cell lymphoma-2 associated X protein (Bax). Moreover, the administration of scoulerine resulted in a significant suppression of the mitogen activated protein kinase (MAPK) signaling pathway. Subsequently, utilizing bioinformatics and spatial transcriptomic databases, we identified solute carrier family 6 Member 3 (SLC6A3) as the most promising target of scoulerine. Through experimental validation, we confirmed the functional and therapeutic relevance of SLC6A3 in scoulerine-mediated treatment of RCC. The results of our study indicate a significant affinity between scoulerine and SLC6A3, with competitive inhibition of this interaction leading to a reduction in the inhibitory impact of scoulerine on RCC cell viability. In conclusion, our findings suggest that scoulerine may induce apoptosis in RCC by targeting SLC6A3 and inhibiting the activation of the MAPK signaling pathway, thereby positioning it as a promising natural compound for potential future RCC treatment.
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Affiliation(s)
- Tianrui Qu
- Department of Urology, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, China
| | - Yu Sun
- Department of Urology, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, China
| | - Jingying Zhao
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, China
| | - Nanqi Liu
- Department of Biochemistry and Molecular Biology, School of Life Sciences, China Medical University, Shenyang, Liaoning 110122, China
| | - Jianli Yang
- Department of Laboratory Animals, China Medical University, Shenyang, Liaoning 110122, China
| | - Dantong Lyu
- Department of Biochemistry and Molecular Biology, School of Life Sciences, China Medical University, Shenyang, Liaoning 110122, China
| | - Wenjie Huang
- Department of Biochemistry and Molecular Biology, School of Life Sciences, China Medical University, Shenyang, Liaoning 110122, China
| | - Weizhen Zhan
- Department of Biochemistry and Molecular Biology, School of Life Sciences, China Medical University, Shenyang, Liaoning 110122, China
| | - Tao Li
- Department of Biochemistry and Molecular Biology, School of Life Sciences, China Medical University, Shenyang, Liaoning 110122, China
| | - Zichuan Yao
- Department of Urology, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, China
| | - Rongbo Yan
- Department of Urology, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning 110000, China
| | - Haiyan Zhang
- Department of Geriatrics, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, China
| | - Hong Hong
- Department of Geriatrics, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, China
| | - Liye Shi
- Department of Geriatrics, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, China.
| | - Xin Meng
- Department of Biochemistry and Molecular Biology, School of Life Sciences, China Medical University, Shenyang, Liaoning 110122, China.
| | - Bo Yin
- Department of Urology, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, China.
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Zhang WY, Wen L, Du L, Liu TT, Sun Y, Chen YZ, Lu YX, Cheng XC, Sun HY, Xiao FJ, Wang LS. S-RBD-modified and miR-486-5p-engineered exosomes derived from mesenchymal stem cells suppress ferroptosis and alleviate radiation-induced lung injury and long-term pulmonary fibrosis. J Nanobiotechnology 2024; 22:662. [PMID: 39462403 PMCID: PMC11515248 DOI: 10.1186/s12951-024-02830-9] [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: 05/09/2024] [Accepted: 09/02/2024] [Indexed: 10/29/2024] Open
Abstract
BACKGROUND Radiation-induced lung injury (RILI) is associated with alveolar epithelial cell death and secondary fibrosis in injured lung. Mesenchymal stem cell (MSC)-derived exosomes have regenerative effect against lung injury and the potential to intervene of RILI. However, their intervention efficacy is limited because they lack lung targeting characters and do not carry sufficient specific effectors. SARS-CoV-2 spike glycoprotein (SARS-CoV-2-S-RBD) binds angiotensin-converting enzyme 2 (ACE2) receptor and mediates interaction with host cells. MiR-486-5p is a multifunctional miRNA with angiogenic and antifibrotic potential and acts as an effector in MSC-derived exosomes. Ferroptosis is a form of cell death associated with radiation injury, its roles and mechanisms in RILI remain unclear. In this study, we developed an engineered MSC-derived exosomes with SARS-CoV-2-S-RBD- and miR-486-5p- modification and investigated their intervention effects on RIPF and action mechanisms via suppression of epithelial cell ferroptosis. RESULTS Adenovirus-mediated gene modification led to miR-486-5p overexpression in human umbilical cord MSC exosomes (p < 0.05), thereby constructing miR-486-5p engineered MSC exosomes (miR-486-MSC-Exo). MiR-486-MSC-Exo promoted the proliferation and migration of irradiated mouse lung epithelial (MLE-12) cells in vitro and inhibited RILI in vivo (all p < 0.05). MiR-486-MSC-Exo suppressed ferroptosis in MLE-12 cells, and an in vitro assay revealed that the expression of fibrosis-related genes is up-regulated following ferroptosis (both p < 0.05). MiR-486-MSC-Exo reversed the up-regulated expression of fibrosis-related genes induced by TGF-β1 in vitro and improved pathological fibrosis in RIPF mice in vivo (all p < 0.05). SARS-CoV-2-S-RBD-modified and miR-486-5p-engineered MSC exosomes (miR-486-RBD-MSC-Exo) were also constructed, and the distribution of DiR dye-labeled miR-486-RBD-MSC-Exo in hACE2CKI/CKI Sftpc-Cre+ mice demonstrated long-term retention in the lung (p < 0.05). MiR-486-RBD-MSC-Exo significantly improved the survival rate and pathological changes in hACE2CKI/CKI Sftpc-Cre+ RIPF mice (all p < 0.05). Furthermore, miR-486-MSC-Exo exerted anti-fibrotic effects via targeted SMAD2 inhibition and Akt phosphorylation activation (p < 0.05). CONCLUSIONS Engineered MSC exosomes with SARS-CoV-2-S-RBD- and miR-486-5p-modification were developed. MiR-486-RBD-MSC-Exo suppressed ferroptosis and fibrosis of MLE-12 cells in vitro, and alleviated RILI and long-term RIPF in ACE2 humanized mice in vivo. MiR-486-MSC-Exo exerted anti-fibrotic effects via SMAD2 inhibition and Akt activation. This study provides a potential approach for RIPF intervention.
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Affiliation(s)
- Wei-Yuan Zhang
- Department of Special Medicine, School of Basic Medicine, Qingdao University, Qingdao, 266071, People's Republic of China
- Laboratory of Molecular Diagnosis and Regenerative Medicine, The Affiliated Hospital of Qingdao University, Qingdao, 266000, People's Republic of China
| | - Li Wen
- School of Nursing, Jilin University, Changchun, 130021, Jilin, People's Republic of China
| | - Li Du
- Beijing Institute of Radiation Medicine, Beijing, 100850, People's Republic of China
| | - Ting Ting Liu
- Department of Pulmonary and Critical Care Medicine, The Second Medical Center, National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Beijing, 100853, China
| | - Yang Sun
- Department of Special Medicine, School of Basic Medicine, Qingdao University, Qingdao, 266071, People's Republic of China
- Laboratory of Molecular Diagnosis and Regenerative Medicine, The Affiliated Hospital of Qingdao University, Qingdao, 266000, People's Republic of China
| | - Yi-Zhu Chen
- Beijing Institute of Radiation Medicine, Beijing, 100850, People's Republic of China
| | - Yu-Xin Lu
- Beijing Institute of Radiation Medicine, Beijing, 100850, People's Republic of China
| | - Xiao-Chen Cheng
- Beijing Institute of Radiation Medicine, Beijing, 100850, People's Republic of China
| | - Hui-Yan Sun
- Yanda Medical Research Institute, Hebei Yanda Hospital, Langfang, 065201, China
| | - Feng-Jun Xiao
- Beijing Institute of Radiation Medicine, Beijing, 100850, People's Republic of China.
| | - Li-Sheng Wang
- Department of Special Medicine, School of Basic Medicine, Qingdao University, Qingdao, 266071, People's Republic of China.
- Laboratory of Molecular Diagnosis and Regenerative Medicine, The Affiliated Hospital of Qingdao University, Qingdao, 266000, People's Republic of China.
- School of Nursing, Jilin University, Changchun, 130021, Jilin, People's Republic of China.
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Yasumura Y, Teshima T, Nagashima T, Michishita M, Taira Y, Suzuki R, Matsumoto H. Effective enhancement of the immunomodulatory capacity of canine adipose-derived mesenchymal stromal cells on colitis by priming with colon tissue from mice with colitis. Front Vet Sci 2024; 11:1437648. [PMID: 39176394 PMCID: PMC11338805 DOI: 10.3389/fvets.2024.1437648] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2024] [Accepted: 07/22/2024] [Indexed: 08/24/2024] Open
Abstract
Introduction The therapeutic efficacy of mesenchymal stromal cells (MSCs) in inflammatory bowel disease is not completely known and is not consistent. Priming with inflammatory cytokines has been proposed to adapt MSCs to an inflammatory environment to have them ready to counteract it, but may have undesirable effects on MSCs, such as increased immunogenicity. In this study, we hypothesized that priming MSCs with inflamed intestinal tissue would more effectively enhance their therapeutic effect on intestinal inflammation. Methods The capacity of canine adipose-derived MSCs (cADSCs) primed with colon tissue homogenates from mice with experimentally induced colitis or a combination of tumor necrosis factor-α and interferon-γ to inhibit T-cell proliferation was analyzed, along with their own apoptosis, proliferation, cell surface marker expression, and transcriptome. In addition, colitis mice were treated with the primed cADSCs to assess colitis severity and immune cell profile. Results Priming with cytokines induced apoptosis, decreased cell proliferation, and major histocompatibility complex-II gene expression in cADSCs, but these adverse effects were mild or absent with colitis-tissue priming. cADSCs primed with colitis tissue reduced the severity of colitis via the induction of M2 macrophages and T-regulatory cells and suppression of T-helper (Th)1/Th17-cell responses, and their effects were comparable to those of cytokine-primed cells. Discussion Our results emphasize the importance of the activation of MSCs by the appropriate microenvironment to maximize their therapeutic effect.
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Affiliation(s)
- Yuyo Yasumura
- Laboratory of Veterinary Internal Medicine, School of Veterinary Medicine, Faculty of Veterinary Science, Nippon Veterinary and Life Science University, Musashino, Japan
| | - Takahiro Teshima
- Laboratory of Veterinary Internal Medicine, School of Veterinary Medicine, Faculty of Veterinary Science, Nippon Veterinary and Life Science University, Musashino, Japan
- Research Center for Animal Life Science, Nippon Veterinary and Life Science University, Musashino, Japan
| | - Tomokazu Nagashima
- Laboratory of Veterinary Pathology, School of Veterinary Medicine, Faculty of Veterinary Science, Nippon Veterinary and Life Science University, Musashino, Japan
| | - Masaki Michishita
- Laboratory of Veterinary Pathology, School of Veterinary Medicine, Faculty of Veterinary Science, Nippon Veterinary and Life Science University, Musashino, Japan
| | - Yoshiaki Taira
- Laboratory of Veterinary Internal Medicine, School of Veterinary Medicine, Faculty of Veterinary Science, Nippon Veterinary and Life Science University, Musashino, Japan
| | - Ryohei Suzuki
- Laboratory of Veterinary Internal Medicine, School of Veterinary Medicine, Faculty of Veterinary Science, Nippon Veterinary and Life Science University, Musashino, Japan
| | - Hirotaka Matsumoto
- Laboratory of Veterinary Internal Medicine, School of Veterinary Medicine, Faculty of Veterinary Science, Nippon Veterinary and Life Science University, Musashino, Japan
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Cao Z, Kong F, Ding J, Chen C, He F, Deng W. Promoting Alzheimer's disease research and therapy with stem cell technology. Stem Cell Res Ther 2024; 15:136. [PMID: 38715083 PMCID: PMC11077895 DOI: 10.1186/s13287-024-03737-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2023] [Accepted: 04/17/2024] [Indexed: 05/12/2024] Open
Abstract
BACKGROUND Alzheimer's disease (AD) is a prevalent form of dementia leading to memory loss, reduced cognitive and linguistic abilities, and decreased self-care. Current AD treatments aim to relieve symptoms and slow disease progression, but a cure is elusive due to limited understanding of the underlying disease mechanisms. MAIN CONTENT Stem cell technology has the potential to revolutionize AD research. With the ability to self-renew and differentiate into various cell types, stem cells are valuable tools for disease modeling, drug screening, and cell therapy. Recent advances have broadened our understanding beyond the deposition of amyloidβ (Aβ) or tau proteins in AD to encompass risk genes, immune system disorders, and neuron-glia mis-communication, relying heavily on stem cell-derived disease models. These stem cell-based models (e.g., organoids and microfluidic chips) simulate in vivo pathological processes with extraordinary spatial and temporal resolution. Stem cell technologies have the potential to alleviate AD pathology through various pathways, including immunomodulation, replacement of damaged neurons, and neurotrophic support. In recent years, transplantation of glial cells like oligodendrocytes and the infusion of exosomes have become hot research topics. CONCLUSION Although stem cell-based models and therapies for AD face several challenges, such as extended culture time and low differentiation efficiency, they still show considerable potential for AD treatment and are likely to become preferred tools for AD research.
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Affiliation(s)
- Zimeng Cao
- School of Pharmaceutical Sciences, Shenzhen Campus of Sun Yat-Sen University, Shenzhen, 518107, China
| | - Fanshu Kong
- School of Pharmaceutical Sciences, Shenzhen Campus of Sun Yat-Sen University, Shenzhen, 518107, China
| | - Jiaqi Ding
- School of Pharmaceutical Sciences, Shenzhen Campus of Sun Yat-Sen University, Shenzhen, 518107, China
| | - Chunxia Chen
- School of Pharmaceutical Sciences, Shenzhen Campus of Sun Yat-Sen University, Shenzhen, 518107, China.
| | - Fumei He
- School of Pharmaceutical Sciences, Shenzhen Campus of Sun Yat-Sen University, Shenzhen, 518107, China.
- School of Pharmaceutical Sciences, Dali University, Dali, 671000, China.
| | - Wenbin Deng
- School of Pharmaceutical Sciences, Shenzhen Campus of Sun Yat-Sen University, Shenzhen, 518107, China.
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Miceli V. Use of priming strategies to advance the clinical application of mesenchymal stromal/stem cell-based therapy. World J Stem Cells 2024; 16:7-18. [PMID: 38292438 PMCID: PMC10824041 DOI: 10.4252/wjsc.v16.i1.7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2023] [Revised: 12/18/2023] [Accepted: 12/28/2023] [Indexed: 01/22/2024] Open
Abstract
Mesenchymal stromal/stem cells (MSCs) have garnered significant attention in the field of regenerative medicine due to their remarkable therapeutic potential. MSCs play a pivotal role in maintaining tissue homeostasis and possess diverse functions in tissue repair and recovery in various organs. These cells are characterized by easy accessibility, few ethical concerns, and adaptability to in vitro cultures, making them a valuable resource for cell therapy in several clinical conditions. Over the years, it has been shown that the true therapeutic power of MSCs lies not in cell engraftment and replacement but in their ability to produce critical paracrine factors, including cytokines, growth factors, and exosomes (EXOs), which modulate the tissue microenvironment and facilitate repair and regeneration processes. Consequently, MSC-derived products, such as conditioned media and EXOs, are now being extensively evaluated for their potential medical applications, offering advantages over the long-term use of whole MSCs. However, the efficacy of MSC-based treatments varies in clinical trials due to both intrinsic differences resulting from the choice of diverse cell sources and non-standardized production methods. To address these concerns and to enhance MSC therapeutic potential, researchers have explored many priming strategies, including exposure to inflammatory molecules, hypoxic conditions, and three-dimensional culture techniques. These approaches have optimized MSC secretion of functional factors, empowering them with enhanced immunomodulatory, angiogenic, and regenerative properties tailored to specific medical conditions. In fact, various priming strategies show promise in the treatment of numerous diseases, from immune-related disorders to acute injuries and cancer. Currently, in order to exploit the full therapeutic potential of MSC therapy, the most important challenge is to optimize the modulation of MSCs to obtain adapted cell therapy for specific clinical disorders. In other words, to unlock the complete potential of MSCs in regenerative medicine, it is crucial to identify the most suitable tissue source and develop in vitro manipulation protocols specific to the type of disease being treated.
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Affiliation(s)
- Vitale Miceli
- Department of Research, Istituto Mediterraneo per i Trapianti e Terapie ad alta Specializzazione, Palermo 90127, Italy.
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Kahrizi MS, Mousavi E, Khosravi A, Rahnama S, Salehi A, Nasrabadi N, Ebrahimzadeh F, Jamali S. Recent advances in pre-conditioned mesenchymal stem/stromal cell (MSCs) therapy in organ failure; a comprehensive review of preclinical studies. Stem Cell Res Ther 2023; 14:155. [PMID: 37287066 DOI: 10.1186/s13287-023-03374-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Accepted: 05/10/2023] [Indexed: 06/09/2023] Open
Abstract
Mesenchymal stem/stromal cells (MSCs)-based therapy brings the reassuring capability to regenerative medicine through their self-renewal and multilineage potency. Also, they secret a diversity of mediators, which are complicated in moderation of deregulated immune responses, and yielding angiogenesis in vivo. Nonetheless, MSCs may lose biological performance after procurement and prolonged expansion in vitro. Also, following transplantation and migration to target tissue, they encounter a harsh milieu accompanied by death signals because of the lack of proper tensegrity structure between the cells and matrix. Accordingly, pre-conditioning of MSCs is strongly suggested to upgrade their performances in vivo, leading to more favored transplantation efficacy in regenerative medicine. Indeed, MSCs ex vivo pre-conditioning by hypoxia, inflammatory stimulus, or other factors/conditions may stimulate their survival, proliferation, migration, exosome secretion, and pro-angiogenic and anti-inflammatory characteristics in vivo. In this review, we deliver an overview of the pre-conditioning methods that are considered a strategy for improving the therapeutic efficacy of MSCs in organ failures, in particular, renal, heart, lung, and liver.
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Affiliation(s)
| | - Elnaz Mousavi
- Department of Endodontics, School of Dentistry, Guilan University of Medical Sciences, Rasht, Iran
| | - Armin Khosravi
- Department of Periodontics, Dental School, Islamic Azad University, Isfahan (Khorasgan) Branch, Isfahan, Iran
| | - Sara Rahnama
- Department of Pediatric Dentistry, School of Dentistry, Semnan University of Medical Sciences, Semnan, Iran
| | - Ali Salehi
- Department of Oral and Maxillofacial Radiology, School of Dentistry, Islamic Azad University, Isfahan (Khorasgan) Branch, Isfahan, Iran
| | - Navid Nasrabadi
- Department of Endodontics, School of Dentistry, Birjand University of Medical Sciences, Birjand, Iran
| | - Farnoosh Ebrahimzadeh
- Department of Internal Medicine, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
| | - Samira Jamali
- Department of Endodontics, Stomatological Hospital, College of Stomatology, Xi'an Jiaotong University, Shaanxi, People's Republic of China.
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Miceli V, Zito G, Bulati M, Gallo A, Busà R, Iannolo G, Conaldi PG. Different priming strategies improve distinct therapeutic capabilities of mesenchymal stromal/stem cells: Potential implications for their clinical use. World J Stem Cells 2023; 15:400-420. [PMID: 37342218 PMCID: PMC10277962 DOI: 10.4252/wjsc.v15.i5.400] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2023] [Revised: 03/07/2023] [Accepted: 04/17/2023] [Indexed: 05/26/2023] Open
Abstract
Mesenchymal stromal/stem cells (MSCs) have shown significant therapeutic potential, and have therefore been extensively investigated in preclinical studies of regenerative medicine. However, while MSCs have been shown to be safe as a cellular treatment, they have usually been therapeutically ineffective in human diseases. In fact, in many clinical trials it has been shown that MSCs have moderate or poor efficacy. This inefficacy appears to be ascribable primarily to the heterogeneity of MSCs. Recently, specific priming strategies have been used to improve the therapeutic properties of MSCs. In this review, we explore the literature on the principal priming approaches used to enhance the preclinical inefficacy of MSCs. We found that different priming strategies have been used to direct the therapeutic effects of MSCs toward specific pathological processes. Particularly, while hypoxic priming can be used primarily for the treatment of acute diseases, inflammatory cytokines can be used mainly to prime MSCs in order to treat chronic immune-related disorders. The shift in approach from regeneration to inflammation implies, in MSCs, a shift in the production of functional factors that stimulate regenerative or anti-inflammatory pathways. The opportunity to fine-tune the therapeutic properties of MSCs through different priming strategies could conceivably pave the way for optimizing their therapeutic potential.
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Affiliation(s)
- Vitale Miceli
- Department of Research, IRCCS ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad alta Specializzazione), Palermo 90127, Italy
| | - Giovanni Zito
- Department of Research, IRCCS ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad alta Specializzazione), Palermo 90127, Italy
| | - Matteo Bulati
- Department of Research, IRCCS ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad alta Specializzazione), Palermo 90127, Italy
| | - Alessia Gallo
- Department of Research, IRCCS ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad alta Specializzazione), Palermo 90127, Italy
| | - Rosalia Busà
- Department of Research, IRCCS ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad alta Specializzazione), Palermo 90127, Italy
| | - Gioacchin Iannolo
- Department of Research, IRCCS ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad alta Specializzazione), Palermo 90127, Italy
| | - Pier Giulio Conaldi
- Department of Research, IRCCS ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad alta Specializzazione), Palermo 90127, Italy
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10
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Lopes-Pacheco M, Rocco PRM. Functional enhancement strategies to potentiate the therapeutic properties of mesenchymal stromal cells for respiratory diseases. Front Pharmacol 2023; 14:1067422. [PMID: 37007034 PMCID: PMC10062457 DOI: 10.3389/fphar.2023.1067422] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Accepted: 03/06/2023] [Indexed: 03/18/2023] Open
Abstract
Respiratory diseases remain a major health concern worldwide because they subject patients to considerable financial and psychosocial burdens and result in a high rate of morbidity and mortality. Although significant progress has been made in understanding the underlying pathologic mechanisms of severe respiratory diseases, most therapies are supportive, aiming to mitigate symptoms and slow down their progressive course but cannot improve lung function or reverse tissue remodeling. Mesenchymal stromal cells (MSCs) are at the forefront of the regenerative medicine field due to their unique biomedical potential in promoting immunomodulation, anti-inflammatory, anti-apoptotic and antimicrobial activities, and tissue repair in various experimental models. However, despite several years of preclinical research on MSCs, therapeutic outcomes have fallen far short in early-stage clinical trials for respiratory diseases. This limited efficacy has been associated with several factors, such as reduced MSC homing, survival, and infusion in the late course of lung disease. Accordingly, genetic engineering and preconditioning methods have emerged as functional enhancement strategies to potentiate the therapeutic actions of MSCs and thus achieve better clinical outcomes. This narrative review describes various strategies that have been investigated in the experimental setting to functionally potentiate the therapeutic properties of MSCs for respiratory diseases. These include changes in culture conditions, exposure of MSCs to inflammatory environments, pharmacological agents or other substances, and genetic manipulation for enhanced and sustained expression of genes of interest. Future directions and challenges in efficiently translating MSC research into clinical practice are discussed.
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Affiliation(s)
- Miquéias Lopes-Pacheco
- Biosystems & Integrative Sciences Institute, Faculty of Sciences, University of Lisbon, Lisbon, Portugal
- *Correspondence: Miquéias Lopes-Pacheco, ; Patricia R. M. Rocco,
| | - Patricia R. M. Rocco
- Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
- *Correspondence: Miquéias Lopes-Pacheco, ; Patricia R. M. Rocco,
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11
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Jerkic M, Szaszi K, Laffey JG, Rotstein O, Zhang H. Key Role of Mesenchymal Stromal Cell Interaction with Macrophages in Promoting Repair of Lung Injury. Int J Mol Sci 2023; 24:ijms24043376. [PMID: 36834784 PMCID: PMC9965074 DOI: 10.3390/ijms24043376] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2023] [Revised: 01/30/2023] [Accepted: 02/04/2023] [Indexed: 02/11/2023] Open
Abstract
Lung macrophages (Mφs) are essential for pulmonary innate immunity and host defense due to their dynamic polarization and phenotype shifts. Mesenchymal stromal cells (MSCs) have secretory, immunomodulatory, and tissue-reparative properties and have shown promise in acute and chronic inflammatory lung diseases and in COVID-19. Many beneficial effects of MSCs are mediated through their interaction with resident alveolar and pulmonary interstitial Mφs. Bidirectional MSC-Mφ communication is achieved through direct contact, soluble factor secretion/activation, and organelle transfer. The lung microenvironment facilitates MSC secretion of factors that result in Mφ polarization towards an immunosuppressive M2-like phenotype for the restoration of tissue homeostasis. M2-like Mφ in turn can affect the MSC immune regulatory function in MSC engraftment and tissue reparatory effects. This review article highlights the mechanisms of crosstalk between MSCs and Mφs and the potential role of their interaction in lung repair in inflammatory lung diseases.
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Affiliation(s)
- Mirjana Jerkic
- The Keenan Research Centre for Biomedical Science of St. Michael’s Hospital, Unity Health Toronto, University of Toronto, Toronto, ON M5B 1T8, Canada
- Correspondence:
| | - Katalin Szaszi
- The Keenan Research Centre for Biomedical Science of St. Michael’s Hospital, Unity Health Toronto, University of Toronto, Toronto, ON M5B 1T8, Canada
- Department of Surgery, University of Toronto, Toronto, ON M5T 1P5, Canada
| | - John G. Laffey
- The Keenan Research Centre for Biomedical Science of St. Michael’s Hospital, Unity Health Toronto, University of Toronto, Toronto, ON M5B 1T8, Canada
- Anaesthesia and Intensive Care Medicine, School of Medicine, University of Galway, H91 TK33 Galway, Ireland
| | - Ori Rotstein
- The Keenan Research Centre for Biomedical Science of St. Michael’s Hospital, Unity Health Toronto, University of Toronto, Toronto, ON M5B 1T8, Canada
- Department of Surgery, University of Toronto, Toronto, ON M5T 1P5, Canada
| | - Haibo Zhang
- The Keenan Research Centre for Biomedical Science of St. Michael’s Hospital, Unity Health Toronto, University of Toronto, Toronto, ON M5B 1T8, Canada
- Department of Anesthesiology and Pain Medicine, Interdepartmental Division of Critical Care Medicine and Department of Physiology, University of Toronto, Toronto, ON M5G 1E2, Canada
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12
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Sabe SA, Xu CM, Potz BA, Malhotra A, Sabra M, Harris DD, Broadwin M, Abid MR, Sellke FW. Comparative Analysis of Normoxia- and Hypoxia-Modified Extracellular Vesicle Therapy in Function, Perfusion, and Collateralization in Chronically Ischemic Myocardium. Int J Mol Sci 2023; 24:2076. [PMID: 36768399 PMCID: PMC9916784 DOI: 10.3390/ijms24032076] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2022] [Revised: 01/17/2023] [Accepted: 01/17/2023] [Indexed: 01/21/2023] Open
Abstract
We have previously shown that normoxia serum-starved extracellular vesicle (EV) therapy improves myocardial function, perfusion, and angiogenesis in a swine model of chronic myocardial ischemia. Hypoxia-modified EVs have increased abundance of anti-oxidant, pro-angiogenic, and pro-survival proteins. The purpose of this study is to investigate the differential effects of normoxia serum-starved EVs and hypoxia-modified EVs on myocardial function, perfusion, and microvascular density in chronically ischemic myocardium. Yorkshire swine underwent placement of an ameroid constrictor to the left circumflex artery to induce chronic myocardial ischemia. Two weeks later, the pigs underwent intramyocardial injection of either normoxia serum-starved EVs (NOR, n = 10) or hypoxia-modified EVs (HYP, n = 7). Five weeks later, pigs were euthanized, and ischemic myocardium was harvested. Hypoxia EV treatment was associated with improved contractility compared to NOR, as well as improved capillary density, without changes in arteriolar density. There were trends towards improved perfusion at rest and during pacing in the HYP group compared to NOR. Ischemic myocardium in the HYP group had increased pro-angiogenic Akt and ERK signaling and decreased expression of anti-angiogenic markers compared to the NOR group. In the setting of chronic myocardial ischemia, hypoxia-modified EVs may enhance contractility, capillary density, and angiogenic signaling pathways compared to normoxia serum-starved EVs.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Frank W. Sellke
- Division of Cardiothoracic Surgery, Department of Surgery, Cardiovascular Research Center, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI 02903, USA
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13
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Cheng C, Wan H, Cong P, Huang X, Wu T, He M, Zhang Q, Xiong L, Tian L. Targeting neuroinflammation as a preventive and therapeutic approach for perioperative neurocognitive disorders. J Neuroinflammation 2022; 19:297. [PMID: 36503642 PMCID: PMC9743533 DOI: 10.1186/s12974-022-02656-y] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2022] [Accepted: 11/23/2022] [Indexed: 12/14/2022] Open
Abstract
Perioperative neurocognitive disorders (PND) is a common postoperative complication associated with regional or general anesthesia and surgery. Growing evidence in both patient and animal models of PND suggested that neuroinflammation plays a critical role in the development and progression of this problem, therefore, mounting efforts have been made to develop novel therapeutic approaches for PND by targeting specific factors or steps alongside the neuroinflammation. Multiple studies have shown that perioperative anti-neuroinflammatory strategies via administering pharmacologic agents or performing nonpharmacologic approaches exert benefits in the prevention and management of PND, although more clinical evidence is urgently needed to testify or confirm these results. Furthermore, long-term effects and outcomes with respect to cognitive functions and side effects are needed to be observed. In this review, we discuss recent preclinical and clinical studies published within a decade as potential preventive and therapeutic approaches targeting neuroinflammation for PND.
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Affiliation(s)
- Chun Cheng
- Shanghai Key Laboratory of Anesthesiology and Brain Functional Modulation, Shanghai, 200434 China ,grid.24516.340000000123704535Translational Research Institute of Brain and Brain-Like Intelligence, Shanghai Fourth People’s Hospital, School of Medicine, Tongji University, Shanghai, 200434 China ,grid.24516.340000000123704535Clinical Research Center for Anesthesiology and Perioperative Medicine, Tongji University, Shanghai, 200434 China
| | - Hanxi Wan
- Shanghai Key Laboratory of Anesthesiology and Brain Functional Modulation, Shanghai, 200434 China ,grid.24516.340000000123704535Translational Research Institute of Brain and Brain-Like Intelligence, Shanghai Fourth People’s Hospital, School of Medicine, Tongji University, Shanghai, 200434 China ,grid.24516.340000000123704535Clinical Research Center for Anesthesiology and Perioperative Medicine, Tongji University, Shanghai, 200434 China
| | - Peilin Cong
- Shanghai Key Laboratory of Anesthesiology and Brain Functional Modulation, Shanghai, 200434 China ,grid.24516.340000000123704535Translational Research Institute of Brain and Brain-Like Intelligence, Shanghai Fourth People’s Hospital, School of Medicine, Tongji University, Shanghai, 200434 China ,grid.24516.340000000123704535Clinical Research Center for Anesthesiology and Perioperative Medicine, Tongji University, Shanghai, 200434 China
| | - Xinwei Huang
- Shanghai Key Laboratory of Anesthesiology and Brain Functional Modulation, Shanghai, 200434 China ,grid.24516.340000000123704535Translational Research Institute of Brain and Brain-Like Intelligence, Shanghai Fourth People’s Hospital, School of Medicine, Tongji University, Shanghai, 200434 China ,grid.24516.340000000123704535Clinical Research Center for Anesthesiology and Perioperative Medicine, Tongji University, Shanghai, 200434 China
| | - Tingmei Wu
- Shanghai Key Laboratory of Anesthesiology and Brain Functional Modulation, Shanghai, 200434 China ,grid.24516.340000000123704535Translational Research Institute of Brain and Brain-Like Intelligence, Shanghai Fourth People’s Hospital, School of Medicine, Tongji University, Shanghai, 200434 China ,grid.24516.340000000123704535Clinical Research Center for Anesthesiology and Perioperative Medicine, Tongji University, Shanghai, 200434 China
| | - Mengfan He
- Shanghai Key Laboratory of Anesthesiology and Brain Functional Modulation, Shanghai, 200434 China ,grid.24516.340000000123704535Translational Research Institute of Brain and Brain-Like Intelligence, Shanghai Fourth People’s Hospital, School of Medicine, Tongji University, Shanghai, 200434 China ,grid.24516.340000000123704535Clinical Research Center for Anesthesiology and Perioperative Medicine, Tongji University, Shanghai, 200434 China
| | - Qian Zhang
- Shanghai Key Laboratory of Anesthesiology and Brain Functional Modulation, Shanghai, 200434 China ,grid.24516.340000000123704535Translational Research Institute of Brain and Brain-Like Intelligence, Shanghai Fourth People’s Hospital, School of Medicine, Tongji University, Shanghai, 200434 China ,grid.24516.340000000123704535Clinical Research Center for Anesthesiology and Perioperative Medicine, Tongji University, Shanghai, 200434 China
| | - Lize Xiong
- Shanghai Key Laboratory of Anesthesiology and Brain Functional Modulation, Shanghai, 200434 China ,grid.24516.340000000123704535Translational Research Institute of Brain and Brain-Like Intelligence, Shanghai Fourth People’s Hospital, School of Medicine, Tongji University, Shanghai, 200434 China ,grid.24516.340000000123704535Clinical Research Center for Anesthesiology and Perioperative Medicine, Tongji University, Shanghai, 200434 China
| | - Li Tian
- Shanghai Key Laboratory of Anesthesiology and Brain Functional Modulation, Shanghai, 200434 China ,grid.24516.340000000123704535Translational Research Institute of Brain and Brain-Like Intelligence, Shanghai Fourth People’s Hospital, School of Medicine, Tongji University, Shanghai, 200434 China ,grid.24516.340000000123704535Clinical Research Center for Anesthesiology and Perioperative Medicine, Tongji University, Shanghai, 200434 China
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14
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Hoang VT, Nguyen HP, Nguyen VN, Hoang DM, Nguyen TST, Nguyen Thanh L. “Adipose-derived mesenchymal stem cell therapy for the management of female sexual dysfunction: Literature reviews and study design of a clinical trial”. Front Cell Dev Biol 2022; 10:956274. [PMID: 36247008 PMCID: PMC9554747 DOI: 10.3389/fcell.2022.956274] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Accepted: 07/29/2022] [Indexed: 11/25/2022] Open
Abstract
Hormone imbalance and female sexual dysfunction immensely affect perimenopausal female health and quality of life. Hormone therapy can improve female hormone deficiency, but long-term use increases the risk of cardiovascular diseases and cancer. Therefore, it is necessary to develop a novel effective treatment to achieve long-term improvement in female general and sexual health. This study reviewed factors affecting syndromes of female sexual dysfunction and its current therapy options. Next, the authors introduced research data on mesenchymal stromal cell/mesenchymal stem cell (MSC) therapy to treat female reproductive diseases, including Asherman’s syndrome, premature ovarian failure/primary ovarian insufficiency, and vaginal atrophy. Among adult tissue-derived MSCs, adipose tissue-derived stem cells (ASCs) have emerged as the most potent therapeutic cell therapy due to their abundant presence in the stromal vascular fraction of fat, high proliferation capacity, superior immunomodulation, and strong secretion profile of regenerative factors. Potential mechanisms and side effects of ASCs for the treatment of female sexual dysfunction will be discussed. Our phase I clinical trial has demonstrated the safety of autologous ASC therapy for women and men with sexual hormone deficiency. We designed the first randomized controlled crossover phase II trial to investigate the safety and efficacy of autologous ASCs to treat female sexual dysfunction in perimenopausal women. Here, we introduce the rationale, trial design, and methodology of this clinical study. Because aging and metabolic diseases negatively impact the bioactivity of adult-derived MSCs, this study will use ASCs cultured in physiological oxygen tension (5%) to cope with these challenges. A total of 130 perimenopausal women with sexual dysfunction will receive two intravenous infusions of autologous ASCs in a crossover design. The aims of the proposed study are to evaluate 1) the safety of cell infusion based on the frequency and severity of adverse events/serious adverse events during infusion and follow-up and 2) improvements in female sexual function assessed by the Female Sexual Function Index (FSFI), the Utian Quality of Life Scale (UQOL), and the levels of follicle-stimulating hormone (FSH) and estradiol. In addition, cellular aging biomarkers, including plasminogen activator inhibitor-1 (PAI-1), p16 and p21 expression in T cells and the inflammatory cytokine profile, will also be characterized. Overall, this study will provide essential insights into the effects and potential mechanisms of ASC therapy for perimenopausal women with sexual dysfunction. It also suggests direction and design strategies for future research.
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Affiliation(s)
- Van T. Hoang
- Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Health Care System, Hanoi, Vietnam
| | - Hoang-Phuong Nguyen
- Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Health Care System, Hanoi, Vietnam
| | - Viet Nhan Nguyen
- Vinmec International Hospital—Times City, Vinmec Health Care System, Hanoi, Vietnam
- College of Health Science, Vin University, Vinhomes Ocean Park, Hanoi, Vietnam
| | - Duc M. Hoang
- Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Health Care System, Hanoi, Vietnam
| | - Tan-Sinh Thi Nguyen
- Vinmec International Hospital—Times City, Vinmec Health Care System, Hanoi, Vietnam
| | - Liem Nguyen Thanh
- Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Health Care System, Hanoi, Vietnam
- Vinmec International Hospital—Times City, Vinmec Health Care System, Hanoi, Vietnam
- College of Health Science, Vin University, Vinhomes Ocean Park, Hanoi, Vietnam
- *Correspondence: Liem Nguyen Thanh,
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15
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Sarsenova M, Kim Y, Raziyeva K, Kazybay B, Ogay V, Saparov A. Recent advances to enhance the immunomodulatory potential of mesenchymal stem cells. Front Immunol 2022; 13:1010399. [PMID: 36211399 PMCID: PMC9537745 DOI: 10.3389/fimmu.2022.1010399] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Accepted: 09/07/2022] [Indexed: 11/19/2022] Open
Abstract
Considering the unique therapeutic potential of mesenchymal stem cells (MSCs), including their immunosuppressive and immunomodulatory properties as well as their ability to improve tissue regeneration, these cells have attracted the attention of scientists and clinicians for the treatment of different inflammatory and immune system mediated disorders. However, various clinical trials using MSCs for the therapeutic purpose are conflicting and differ from the results of promising preclinical studies. This inconsistency is caused by several factors such as poor migration and homing capacities, low survival rate, low level of proliferation and differentiation, and donor-dependent variation of the cells. Enhancement and retention of persistent therapeutic effects of the cells remain a challenge to overcome in MSC-based therapy. In this review, we summarized various approaches to enhance the clinical outcomes of MSC-based therapy as well as revised current and future perspectives for the creation of cellular products with improved potential for diverse clinical applications.
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Affiliation(s)
- Madina Sarsenova
- Department of Medicine, School of Medicine, Nazarbayev University, Nur-Sultan, Kazakhstan
| | - Yevgeniy Kim
- Department of Medicine, School of Medicine, Nazarbayev University, Nur-Sultan, Kazakhstan
| | - Kamila Raziyeva
- Department of Medicine, School of Medicine, Nazarbayev University, Nur-Sultan, Kazakhstan
| | - Bexultan Kazybay
- Department of Medicine, School of Medicine, Nazarbayev University, Nur-Sultan, Kazakhstan
| | - Vyacheslav Ogay
- Laboratory of Stem Cells, National Center for Biotechnology, Nur-Sultan, Kazakhstan
| | - Arman Saparov
- Department of Medicine, School of Medicine, Nazarbayev University, Nur-Sultan, Kazakhstan
- *Correspondence: Arman Saparov,
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16
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Zhou W, Li L, Tao J, Ma C, Xie Y, Ding L, Hou S, Zhang Z, Xue D, Luo J, Zhu Y. Autophagy inhibition restores CD200 expression under IL-1β microenvironment in placental mesenchymal stem cells of fetal origin and improves its pulmonary fibrosis therapeutic potential. Mol Immunol 2022; 151:29-40. [PMID: 36075140 DOI: 10.1016/j.molimm.2022.08.014] [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: 04/12/2022] [Revised: 08/02/2022] [Accepted: 08/21/2022] [Indexed: 11/25/2022]
Abstract
BACKGROUND Mesenchymal stem cells (MSCs) are promising remedies for various inflammatory disease including pulmonary fibrosis (PF). However, the properties of MSCs in PF pathological microenvironment remain unclear. In this study, the efficacy of autophagy in placental mesenchymal stem cells of fetal origin (fPMSCs) in either IL-1β treatment or BLM induced pulmonary fibrosis mice model was examined. METHODS The characteristic of fPMSCs was identified by morphological observation, flow cytometry and differentiation potential. In vitro experiments, fPMSCs were stimulated with IL-1β, to mimic inflammatory microenvironment of pulmonary fibrosis. The immunosuppressive properties and autophagic function in fPMSCs treated with IL-1β were evaluated by both macrophage cells THP-1 activation and the expression of CD200 situation, autophagy marker and MAPK signaling pathway. The in vivo anti-fibrotic activity of fPMSCs interfering autophagy was evaluated by using BLM induced pulmonary fibrosis mice model. RESULTS fPMSCs belonged to CD73+CD90+CD105+/CD14- CD34-CD45-HLA-DR- cells, and capable differentiation to adipogenic, osteogenic and chondrogenic cells. In addition, immunoinhibitory activity of fPMSCs for macrophage was restrained by IL-1β treatment in CD200 dependent manner. Suppression of autophagy by sh-Atg5 lentivirus increased the expression of CD200 and ratio of CD200 positive fPMSCs, and enhanced fPMSCs immunosuppression for THP-1 activation. Mechanistically, IL-1β induced autophagy regulated by p38 signaling cascade. In vivo, autophagy inhibition induced by Atg5 knockdown in fPMSCs resulted in strengthening antifibrotic effects on PF mice model. CONCLUSIONS Collectively, autophagy derived from inflammatory microenvironment hampered the immunoinhibitory properties of MSCs. Based on this, adjustment of autophagy may be a valid approach to facilitate their immunomodulatory and anti-fibrotic efficacy.
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Affiliation(s)
- Wei Zhou
- School of Clinical Medicine, Ningxia Medical University, Yinchuan, Ningxia 750004, China
| | - Li Li
- The Center of Laboratory Medicine, General Hospital of Ningxia Medical University, Yinchuan, Ningxia 750004, China
| | - Jin Tao
- Human Stem Cell Institute, General Hospital of Ningxia Medical University, Yinchuan, Ningxia 750004, China
| | - Cunxiang Ma
- School of Clinical Medicine, Ningxia Medical University, Yinchuan, Ningxia 750004, China
| | - Yawei Xie
- School of Clinical Medicine, Ningxia Medical University, Yinchuan, Ningxia 750004, China
| | - Lu Ding
- Surgical Laboratory, General Hospital of Ningxia Medical University, Yinchuan, Ningxia 750004, China
| | - Shaozhang Hou
- School of Basic Medicine, Ningxia Medical University, Yinchuan, Ningxia 750004, China
| | - Zaiqi Zhang
- School of Clinical Medicine, Ningxia Medical University, Yinchuan, Ningxia 750004, China
| | - Di Xue
- Ningxia Key Laboratory of Clinical and Pathogenic Microbiology, Yinchuan, Ningxia 750004, China
| | - Jia Luo
- Ningxia Key Laboratory of Clinical and Pathogenic Microbiology, Yinchuan, Ningxia 750004, China.
| | - Yongzhao Zhu
- Surgical Laboratory, General Hospital of Ningxia Medical University, Yinchuan, Ningxia 750004, China.
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17
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Pan L, Huang Z, Li G, Zhan Q, Zheng W, Chen L, Zhang X. A novel and feasible mouse model of modified inoculation method by subcutaneous EMT6 cells injection for subclinical breast cancer. JOURNAL OF RADIATION RESEARCH AND APPLIED SCIENCES 2022. [DOI: 10.1016/j.jrras.2022.07.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/16/2022]
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18
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Wang Y, Chang L, Zhu G, Li G, Kong Q, Lv L, Wang Q, Tian C, Li Y, Zhu X, Pan X. Mechanism of thymus rejuvenation in elderly macaques. Rejuvenation Res 2022; 25:223-232. [PMID: 35876435 DOI: 10.1089/rej.2022.0013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Senile thymus atrophy is an important factor leading to decreased immune function. Repairing the atrophic thymus tissue structure, rebuilding immune function, and replenishing the number of exogenous stem cells may be effective methods. In this study, BMSCs (Bone Marrow Mesenchymal Stem Cells, BMSCs) were intravenously infused into elderly macaques. We found that thymus area was substantially increased, some thymus tissue regeneration was observed, the degree of thymus tissue fibrosis decreased, collagen fibre deposition decreased, cortical and medulla structures emerge gradually, the number of apoptotic cells decreased significantly, inhibit the expression of apoptosis-related proteins. Bone marrow mesenchymal cells inhibit the expression of genes related to aging. By sequencing the mRNA transcriptome in thymus tissue, the expression pattern of the tissue transcriptome tended to be similar to the thymus expression pattern in young macaques compared with the old group, reverse aging-related proteins. Based on the results, an intravenous infusion designed to increase the number of stem cells in the body effectively repairs the structure of the thymus and rebuilds immune function.
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Affiliation(s)
| | | | - Gaohong Zhu
- The First Affiliated Hospital of Kunming Medical University, Kunming, China;
| | - Gonghua Li
- Kunming Institute of Zoology Chinese Academy of Sciences, Kunming, Yunnan, China;
| | - Qingpeng Kong
- Kunming Institute of Zoology Chinese Academy of Sciences, Kunming, Yunnan, China;
| | - Longbao Lv
- Kunming Institute of Zoology Chinese Academy of Sciences, Kunming, Yunnan, China;
| | | | | | - Ye Li
- 920th hospital, Kunming, China;
| | - Xiangqing Zhu
- 920th hospital , Basic Medical Laboratory, Kunming, China;
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19
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Alagesan S, Brady J, Byrnes D, Fandiño J, Masterson C, McCarthy S, Laffey J, O’Toole D. Enhancement strategies for mesenchymal stem cells and related therapies. Stem Cell Res Ther 2022; 13:75. [PMID: 35189962 PMCID: PMC8860135 DOI: 10.1186/s13287-022-02747-w] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Accepted: 02/05/2022] [Indexed: 12/14/2022] Open
Abstract
Cell therapy, particularly mesenchymal stem/stromal (MSC) therapy, has been investigated for a wide variety of disease indications, particularly those with inflammatory pathologies. However, recently it has become evident that the MSC is far from a panacea. In this review we will look at current and future strategies that might overcome limitations in efficacy. Many of these take their inspiration from stem cell niche and the mechanism of MSC action in response to the injury microenvironment, or from previous gene therapy work which can now benefit from the added longevity and targeting ability of a live cell vector. We will also explore the nascent field of extracellular vesicle therapy and how we are already seeing enhancement protocols for this exciting new drug. These enhanced MSCs will lead the way in more difficult to treat diseases and restore potency where donors or manufacturing practicalities lead to diminished MSC effect.
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20
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Hypoxia, a dynamic tool to amplify the gingival mesenchymal stem cells potential for neurotrophic factor secretion. Saudi J Biol Sci 2022; 29:3568-3576. [PMID: 35844419 PMCID: PMC9280216 DOI: 10.1016/j.sjbs.2022.02.039] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Revised: 02/05/2022] [Accepted: 02/23/2022] [Indexed: 12/27/2022] Open
Abstract
Gingival mesenchymal stem cells (GMSCs) have significant regenerative potential. Their potential applications range from the treatment of inflammatory diseases, wound healing, and oral disorders. Preconditioning these stem cells can optimize their biological properties. Hypoxia preconditioning of MSCs improves stem cell properties like proliferation, survival, and differentiation potential. This research explored the possible impact of hypoxia on the pluripotent stem cell properties that GMSCs possess. We evaluated the morphology, stemness, neurotrophic factors, and stemness-related genes. We compared the protein levels of secreted neurotrophic factors between normoxic and hypoxic GMSC-conditioned media (GMSC-CM). Results revealed that hypoxic cultured GMSC’s had augmented expression of neurotrophic factors BDNF, GDNF, VEGF, and IGF1 and stemness-related gene NANOG. Hypoxic GMSCs showed decreased expression of the OCT4 gene. In hypoxic GMSC-CM, the neurotrophic factors secretions were significantly higher than normoxic GMSC-CM. Our data demonstrate that culturing of GMSCs in hypoxia enhances the secretion of neurotrophic factors that can lead to neuronal lineage differentiation.
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21
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Sheets K, Overbey J, Ksajikian A, Bovid K, Kenter K, Li Y. The pathophysiology and treatment of musculoskeletal fibrosis. J Cell Biochem 2022; 123:843-851. [DOI: 10.1002/jcb.30217] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Revised: 12/20/2021] [Accepted: 01/07/2022] [Indexed: 12/19/2022]
Affiliation(s)
- Kelsey Sheets
- Department of Orthopaedic Surgery, Homer Stryker MD School of Medicine Western Michigan University Kalamazoo Michigan USA
| | - Juliana Overbey
- BioMedical Engineering, Department of Orthopaedic Surgery, WMed, Homer Stryker MD School of Medicine Western Michigan University Kalamazoo Michigan USA
| | - Andre Ksajikian
- BioMedical Engineering, Department of Orthopaedic Surgery, WMed, Homer Stryker MD School of Medicine Western Michigan University Kalamazoo Michigan USA
| | - Karen Bovid
- Department of Orthopaedic Surgery, Homer Stryker MD School of Medicine Western Michigan University Kalamazoo Michigan USA
| | - Keith Kenter
- Department of Orthopaedic Surgery, Homer Stryker MD School of Medicine Western Michigan University Kalamazoo Michigan USA
| | - Yong Li
- Department of Orthopaedic Surgery, Homer Stryker MD School of Medicine Western Michigan University Kalamazoo Michigan USA
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22
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Therapeutic Effects of Hypoxic and Pro-Inflammatory Priming of Mesenchymal Stem Cell-Derived Extracellular Vesicles in Inflammatory Arthritis. Int J Mol Sci 2021; 23:ijms23010126. [PMID: 35008555 PMCID: PMC8745583 DOI: 10.3390/ijms23010126] [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: 11/27/2021] [Revised: 12/19/2021] [Accepted: 12/20/2021] [Indexed: 12/12/2022] Open
Abstract
Mesenchymal stem cells (MSCs) immunomodulate inflammatory responses through paracrine signalling, including via secretion of extracellular vesicles (EVs) in the cell secretome. We evaluated the therapeutic potential of MSCs-derived small EVs in an antigen-induced model of arthritis (AIA). EVs isolated from MSCs cultured normoxically (21% O2, 5% CO2), hypoxically (2% O2, 5% CO2) or with a pro-inflammatory cytokine cocktail were applied into the AIA model. Disease pathology was assessed post-arthritis induction through swelling and histopathological analysis of synovial joint structure. Activated CD4+ T cells from healthy mice were cultured with EVs or MSCs to assess deactivation capabilities prior to application of standard EVs in vivo to assess T cell polarisation within the immune response to AIA. All EVs treatments reduced knee-joint swelling whilst only normoxic and pro-inflammatory primed EVs improved histopathological outcomes. In vitro culture with EVs did not achieve T cell deactivation. Polarisation towards CD4+ helper cells expressing IL17a (Th17) was reduced when normoxic and hypoxic EV treatments were applied in vitro. Normoxic EVs applied into the AIA model reduced Th17 polarisation and improved Regulatory T cell (Treg):Th17 homeostatic balance. Normoxic EVs present the optimal strategy for broad therapeutic benefit. EVs present an effective novel technology with the potential for cell-free therapeutic translation.
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23
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Li DY, Li RF, Sun DX, Pu DD, Zhang YH. Mesenchymal stem cell therapy in pulmonary fibrosis: a meta-analysis of preclinical studies. Stem Cell Res Ther 2021; 12:461. [PMID: 34407861 PMCID: PMC8371890 DOI: 10.1186/s13287-021-02496-2] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Accepted: 07/05/2021] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Pulmonary fibrosis (PF) is a devastating disease characterized by remodeling of lung architecture and abnormal deposition of fibroblasts in parenchymal tissue and ultimately results in respiratory failure and death. Preclinical studies suggest that mesenchymal stem cell (MSC) administration may be a safe and promising option in treating PF. The objective of our meta-analysis is to assess the efficacy of MSC therapy in preclinical models of PF. METHODS We performed a comprehensive literature search in PubMed, EMBASE, Web of Science, and Cochrane Library databases from inception to March 17, 2021. Studies that assessed the efficacy of MSC therapy to animals with PF were included. The SYRCLE bias risk tool was employed to evaluate the bias of included studies. The primary outcomes included survival rate and pulmonary fibrosis scores. Meta-analysis was conducted via Cochrane Collaboration Review Manager (version 5.4) and Stata 14.0 statistical software. RESULTS A total of 1120 articles were reviewed, of which 24 articles met inclusion criteria. Of these, 12 studies evaluated the survival rate and 20 studies evaluated pulmonary fibrosis scores. Compared to the control group, MSC therapy was associated with an improvement in survival rate (odds ratios (OR) 3.10, 95% confidence interval (CI) 2.06 to 4.67, P < 0.001, I2 = 0%) and a significant reduction in pulmonary fibrosis scores (weighted mean difference (WMD) 2.05, 95% CI -2.58 to -1.51, P < 0.001, I2 = 90%). CONCLUSIONS MSC therapy is a safe and effective method that can significantly improve the survival and pulmonary fibrosis of PF animals. These results provide an important basis for future translational clinical studies.
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Affiliation(s)
- Deng-Yuan Li
- Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, 650500, People's Republic of China.,The Affiliated Hospital of Kunming University of Science and Technology, Kunming, 650500, People's Republic of China.,Department of Pulmonary and Critical Care Medicine, The First People's Hospital of Yunnan Province, Kunming, 650022, People's Republic of China
| | - Ru-Fang Li
- The Affiliated Hospital of Kunming University of Science and Technology, Kunming, 650500, People's Republic of China.,Department of Pulmonary and Critical Care Medicine, The First People's Hospital of Yunnan Province, Kunming, 650022, People's Republic of China
| | - Dan-Xiong Sun
- The Affiliated Hospital of Kunming University of Science and Technology, Kunming, 650500, People's Republic of China.,Department of Pulmonary and Critical Care Medicine, The First People's Hospital of Yunnan Province, Kunming, 650022, People's Republic of China
| | - Dan-Dan Pu
- The Affiliated Hospital of Kunming University of Science and Technology, Kunming, 650500, People's Republic of China.,Department of Pulmonary and Critical Care Medicine, The First People's Hospital of Yunnan Province, Kunming, 650022, People's Republic of China
| | - Yun-Hui Zhang
- Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, 650500, People's Republic of China. .,The Affiliated Hospital of Kunming University of Science and Technology, Kunming, 650500, People's Republic of China. .,Department of Pulmonary and Critical Care Medicine, The First People's Hospital of Yunnan Province, Kunming, 650022, People's Republic of China.
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24
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Denu RA, Hematti P. Optimization of oxidative stress for mesenchymal stromal/stem cell engraftment, function and longevity. Free Radic Biol Med 2021; 167:193-200. [PMID: 33677063 DOI: 10.1016/j.freeradbiomed.2021.02.042] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Revised: 02/24/2021] [Accepted: 02/26/2021] [Indexed: 12/18/2022]
Abstract
Mesenchymal stromal/stem cells (MSCs) are multipotent cells that possess great potential as a cellular therapeutic based on their ability to differentiate to different lineages and to modulate immune responses. However, their potential is limited by their low tissue abundance, and thus the need for robust ex vivo expansion prior to their application. This creates its own issues, namely replicative senescence, which could lead to reduced MSC functionality and negatively impact their engraftment. Ex vivo expansion and MSC aging are associated with greater oxidative stress. Therefore, there is great need to identify strategies to reduce oxidative stress in MSCs. This review summarizes the achievements made to date in addressing oxidative stress in MSCs and speculates about interesting avenues of future investigation to solve this critical problem.
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Affiliation(s)
- Ryan A Denu
- Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
| | - Peiman Hematti
- Departments of Medicine, Pediatrics, Surgery and Biomedical Engineering, Carbone Cancer Center, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA
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25
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Karbasiafshar C, Sellke FW, Abid MR. Mesenchymal stem cell-derived extracellular vesicles in the failing heart: past, present, and future. Am J Physiol Heart Circ Physiol 2021; 320:H1999-H2010. [PMID: 33861149 PMCID: PMC8163643 DOI: 10.1152/ajpheart.00951.2020] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Revised: 03/29/2021] [Accepted: 04/09/2021] [Indexed: 12/20/2022]
Abstract
Cardiovascular disease (CVD) is the leading cause of death globally. Current treatment options include lifestyle changes, medication, and surgical intervention. However, many patients are unsuitable candidates for surgeries due to comorbidities, diffuse coronary artery disease, or advanced stages of heart failure. The search for new treatment options has recently transitioned from cell-based therapies to stem-cell-derived extracellular vesicles (EVs). A number of challenges remain in the EV field, including the effect of comorbidities, characterization, and delivery. However, recent revolutionary developments and insight into the potential of personalizing EV contents by bioengineering methods to alter specific signaling pathways in the ischemic myocardium hold promise. Here, we discuss the past limitations of cell-based therapies and recent EV studies involving in vivo, in vitro, and omics, and future challenges and opportunities in EV-based treatments in CVD.
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Affiliation(s)
| | - Frank W Sellke
- Cardiovascular Research Center, Rhode Island Hospital, Providence, Rhode Island
- Department of Surgery, Warren Alpert Medical School of Brown University, Providence, Rhode Island
| | - M Ruhul Abid
- Cardiovascular Research Center, Rhode Island Hospital, Providence, Rhode Island
- Department of Surgery, Warren Alpert Medical School of Brown University, Providence, Rhode Island
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26
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Noronha NC, Mizukami A, Orellana MD, Oliveira MC, Covas DT, Swiech K, Malmegrim KC. Hypoxia priming improves in vitro angiogenic properties of umbilical cord derived-mesenchymal stromal cells expanded in stirred-tank bioreactor. Biochem Eng J 2021. [DOI: 10.1016/j.bej.2021.107949] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
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27
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Niu S, Zhang Y. Applications and therapeutic mechanisms of action of mesenchymal stem cells in radiation-induced lung injury. Stem Cell Res Ther 2021; 12:212. [PMID: 33766127 PMCID: PMC7993004 DOI: 10.1186/s13287-021-02279-9] [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: 10/13/2020] [Accepted: 03/10/2021] [Indexed: 12/28/2022] Open
Abstract
Radiation-induced lung injury (RILI) is one of the most common complications associated with radiotherapy, characterized by early-stage radiation pneumonia and subsequent radiation pulmonary fibrosis. However, effective therapeutic strategies for RILI are currently lacking. Recently, an increasing number of studies reported that mesenchymal stem cells (MSCs) can enhance the regeneration of damaged tissue, modulate the inflammatory response, reduce the levels of fibrotic cytokines and reactive oxygen species, and inhibit epithelial-mesenchymal transformation. Interestingly, MSCs can also exert immunosuppressive effects, which highlights a new potential therapeutic activity of MSCs for managing RILI. Here, we reviewed the potential applications and therapeutic mechanisms of action of MSCs in RILI, which will represent a good compendium of information for researchers in this field.
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Affiliation(s)
- Shiying Niu
- Institute of Basic Medicine, The First Affiliated Hospital of Shandong First Medical University, Jinan, 250062, Shandong, China.,Department of Experimental Pathology, Institute of Basic Medicine, Shandong First Medical University (Shandong Academy of Medical Sciences), Jinan, 250062, Shandong, China
| | - Yueying Zhang
- Institute of Basic Medicine, The First Affiliated Hospital of Shandong First Medical University, Jinan, 250062, Shandong, China. .,Department of Experimental Pathology, Institute of Basic Medicine, Shandong First Medical University (Shandong Academy of Medical Sciences), Jinan, 250062, Shandong, China.
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28
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Yang S, Liu P, Jiang Y, Wang Z, Dai H, Wang C. Therapeutic Applications of Mesenchymal Stem Cells in Idiopathic Pulmonary Fibrosis. Front Cell Dev Biol 2021; 9:639657. [PMID: 33768094 PMCID: PMC7985078 DOI: 10.3389/fcell.2021.639657] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Accepted: 02/15/2021] [Indexed: 12/17/2022] Open
Abstract
Idiopathic pulmonary fibrosis (IPF) is an interstitial disease of unknown etiology characterized by progressive pulmonary fibrosis. Pirfenidone and nintedanib are the only drugs that can prolong the time to disease progression, slow down the decline in lung function, and prolong survival. However, they do not offer a cure and are associated with tolerability issues. The pluripotency of mesenchymal stem cells (MSCs) and their ability to regulate immunity, inhibit inflammation, and promote epithelial tissue repair highlight the promise of MSC therapy for treating interstitial lung disease. However, optimal protocols are lacking for multi-parameter selection in MSC therapy. This review summarizes preclinical studies on MSC transplantation for the treatment of interstitial lung disease and clinical studies with known results. An analysis of relevant factors for the optimization of treatment plans is presented, including MSCs with different sources, administration routes and timing, dosages, frequencies, and pretreatments with MSCs. This review proposes an optimized plan for guiding the design of future clinical research to identify therapeutic options for this complex disease.
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Affiliation(s)
- Shengnan Yang
- Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing, China.,National Center for Respiratory Medicine, Beijing, China.,Institute of Respiratory Medicine, Chinese Academy of Medical Sciences, Beijing, China.,National Clinical Research Center for Respiratory Diseases, Beijing, China.,WHO Collaborating Centre for Tobacco Cessation and Respiratory Diseases Prevention, Beijing, China.,Harbin Medical University, Harbin, China
| | - Peipei Liu
- Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing, China.,Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yale Jiang
- School of Medicine, Tsinghua University, Beijing, China
| | - Zai Wang
- Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, China
| | - Huaping Dai
- Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing, China.,National Center for Respiratory Medicine, Beijing, China.,Institute of Respiratory Medicine, Chinese Academy of Medical Sciences, Beijing, China.,National Clinical Research Center for Respiratory Diseases, Beijing, China.,WHO Collaborating Centre for Tobacco Cessation and Respiratory Diseases Prevention, Beijing, China
| | - Chen Wang
- Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing, China.,National Center for Respiratory Medicine, Beijing, China.,Institute of Respiratory Medicine, Chinese Academy of Medical Sciences, Beijing, China.,National Clinical Research Center for Respiratory Diseases, Beijing, China.,WHO Collaborating Centre for Tobacco Cessation and Respiratory Diseases Prevention, Beijing, China.,Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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29
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Samal JRK, Rangasami VK, Samanta S, Varghese OP, Oommen OP. Discrepancies on the Role of Oxygen Gradient and Culture Condition on Mesenchymal Stem Cell Fate. Adv Healthc Mater 2021; 10:e2002058. [PMID: 33533187 PMCID: PMC11469238 DOI: 10.1002/adhm.202002058] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2020] [Revised: 01/19/2021] [Indexed: 12/11/2022]
Abstract
Over the past few years, mesenchymal stem (or stromal) cells (MSCs) have garnered enormous interest due to their therapeutic value especially for their multilineage differentiation potential leading to regenerative medicine applications. MSCs undergo physiological changes upon in vitro expansion resulting in expression of different receptors, thereby inducing high variabilities in therapeutic efficacy. Therefore, understanding the biochemical cues that influence the native local signals on differentiation or proliferation of these cells is very important. There have been several reports that in vitro culture of MSCs in low oxygen gradient (or hypoxic conditions) upregulates the stemness markers and promotes cell proliferation in an undifferentiated state, as hypoxia mimics the conditions the progenitor cells experience within the tissue. However, different studies report different oxygen gradients and culture conditions causing ambiguity in their interpretation of the results. In this progress report, it is aimed to summarize recent studies in the field with specific focus on conflicting results reported during the application of hypoxic conditions for improving the proliferation or differentiation of MSCs. Further, it is tried to decipher the factors that can affect characteristics of MSC under hypoxia and suggest a few techniques that could be combined with hypoxic cell culture to better recapitulate the MSC tissue niche.
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Affiliation(s)
- Jay R. K. Samal
- Department of Instructive Biomaterial EngineeringMERLN Institute for Technology‐Inspired Regenerative MedicineMaastricht UniversityMaastricht6229 ERThe Netherlands
| | - Vignesh K. Rangasami
- Bioengineering and Nanomedicine GroupFaculty of Medicine and Health TechnologiesTampere UniversityTampere33720Finland
| | - Sumanta Samanta
- Bioengineering and Nanomedicine GroupFaculty of Medicine and Health TechnologiesTampere UniversityTampere33720Finland
| | - Oommen P. Varghese
- Translational Chemical Biology LaboratoryDepartment of Chemistry, Polymer ChemistryÅngström LaboratoryUppsala UniversityUppsala751 21Sweden
| | - Oommen P. Oommen
- Bioengineering and Nanomedicine GroupFaculty of Medicine and Health TechnologiesTampere UniversityTampere33720Finland
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30
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Yan W, Diao S, Fan Z. The role and mechanism of mitochondrial functions and energy metabolism in the function regulation of the mesenchymal stem cells. Stem Cell Res Ther 2021; 12:140. [PMID: 33597020 PMCID: PMC7890860 DOI: 10.1186/s13287-021-02194-z] [Citation(s) in RCA: 76] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Accepted: 01/26/2021] [Indexed: 12/14/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are multipotent cells that show self-renewal, multi-directional differentiation, and paracrine and immune regulation. As a result of these properties, the MSCs have great clinical application prospects, especially in the regeneration of injured tissues, functional reconstruction, and cell therapy. However, the transplanted MSCs are prone to ageing and apoptosis and have a difficult to control direction differentiation. Therefore, it is necessary to effectively regulate the functions of the MSCs to promote their desired effects. In recent years, it has been found that mitochondria, the main organelles responsible for energy metabolism and adenosine triphosphate production in cells, play a key role in regulating different functions of the MSCs through various mechanisms. Thus, mitochondria could act as effective targets for regulating and promoting the functions of the MSCs. In this review, we discuss the research status and current understanding of the role and mechanism of mitochondrial energy metabolism, morphology, transfer modes, and dynamics on MSC functions.
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Affiliation(s)
- Wanhao Yan
- Laboratory of Molecular Signaling and Stem Cells Therapy, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Capital Medical University School of Stomatology, Beijing, 100050, China.,Research Unit of Tooth Development and Regeneration, Chinese Academy of Medical Sciences, Beijing, China
| | - Shu Diao
- Department of Pediatric dentistry, Capital Medical University School of Stomatology, Beijing, 100050, China
| | - Zhipeng Fan
- Laboratory of Molecular Signaling and Stem Cells Therapy, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Capital Medical University School of Stomatology, Beijing, 100050, China. .,Research Unit of Tooth Development and Regeneration, Chinese Academy of Medical Sciences, Beijing, China.
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31
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Challenges and advances in clinical applications of mesenchymal stromal cells. J Hematol Oncol 2021; 14:24. [PMID: 33579329 PMCID: PMC7880217 DOI: 10.1186/s13045-021-01037-x] [Citation(s) in RCA: 360] [Impact Index Per Article: 90.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Accepted: 01/26/2021] [Indexed: 12/12/2022] Open
Abstract
Mesenchymal stromal cells (MSCs), also known as mesenchymal stem cells, have been intensely investigated for clinical applications within the last decades. However, the majority of registered clinical trials applying MSC therapy for diverse human diseases have fallen short of expectations, despite the encouraging pre-clinical outcomes in varied animal disease models. This can be attributable to inconsistent criteria for MSCs identity across studies and their inherited heterogeneity. Nowadays, with the emergence of advanced biological techniques and substantial improvements in bio-engineered materials, strategies have been developed to overcome clinical challenges in MSC application. Here in this review, we will discuss the major challenges of MSC therapies in clinical application, the factors impacting the diversity of MSCs, the potential approaches that modify MSC products with the highest therapeutic potential, and finally the usage of MSCs for COVID-19 pandemic disease.
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32
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Graceffa V. Therapeutic Potential of Reactive Oxygen Species: State of the Art and Recent Advances. SLAS Technol 2020; 26:140-158. [PMID: 33345675 DOI: 10.1177/2472630320977450] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
In the last decade, several studies have proven that when at low concentration reactive oxygen species (ROS) show an adaptive beneficial effect and posited the idea that they can be utilized as inexpensive and convenient inducers of tissue regeneration. On the other hand, the recent discovery that cancer cells are more sensitive to oxidative damage paved the way for their use in the selective killing of tumor cells, and sensors to monitor ROS production during cancer treatment are under extensive investigation. Nevertheless, although ROS-activated signaling pathways are well established, less is known about the mechanisms underlying the switch from an anabolic to a cytotoxic response. Furthermore, a high variability in biological response is observed between different modalities of administration, cell types, donor ages, eventual concomitant diseases, and external microenvironment. On the other hand, available preclinical studies are scarce, whereas the quest for the most suitable systems for in vivo delivery is still elusive. Furthermore, new strategies to control the temporal pattern of ROS release need to be developed, if considering their tumorigenic potential. This review initially discusses ROS mechanisms of action and their potential application in stem cell biology, tissue engineering, and cancer therapy. It then outlines the state of art of ROS-based drugs and identifies challenges faced in translating ROS research into clinical practice.
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Affiliation(s)
- Valeria Graceffa
- Cellular Health and Toxicology Research Group (CHAT), Institute of Technology Sligo, Bellanode, Sligo, Ireland.,Department of Life Sciences, Institute of Technology Sligo, Bellanode, Sligo, Ireland
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33
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Obrador E, Salvador R, Villaescusa JI, Soriano JM, Estrela JM, Montoro A. Radioprotection and Radiomitigation: From the Bench to Clinical Practice. Biomedicines 2020; 8:E461. [PMID: 33142986 PMCID: PMC7692399 DOI: 10.3390/biomedicines8110461] [Citation(s) in RCA: 70] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2020] [Revised: 10/27/2020] [Accepted: 10/29/2020] [Indexed: 02/07/2023] Open
Abstract
The development of protective agents against harmful radiations has been a subject of investigation for decades. However, effective (ideal) radioprotectors and radiomitigators remain an unsolved problem. Because ionizing radiation-induced cellular damage is primarily attributed to free radicals, radical scavengers are promising as potential radioprotectors. Early development of such agents focused on thiol synthetic compounds, e.g., amifostine (2-(3-aminopropylamino) ethylsulfanylphosphonic acid), approved as a radioprotector by the Food and Drug Administration (FDA, USA) but for limited clinical indications and not for nonclinical uses. To date, no new chemical entity has been approved by the FDA as a radiation countermeasure for acute radiation syndrome (ARS). All FDA-approved radiation countermeasures (filgrastim, a recombinant DNA form of the naturally occurring granulocyte colony-stimulating factor, G-CSF; pegfilgrastim, a PEGylated form of the recombinant human G-CSF; sargramostim, a recombinant granulocyte macrophage colony-stimulating factor, GM-CSF) are classified as radiomitigators. No radioprotector that can be administered prior to exposure has been approved for ARS. This differentiates radioprotectors (reduce direct damage caused by radiation) and radiomitigators (minimize toxicity even after radiation has been delivered). Molecules under development with the aim of reaching clinical practice and other nonclinical applications are discussed. Assays to evaluate the biological effects of ionizing radiations are also analyzed.
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Affiliation(s)
- Elena Obrador
- Department of Physiology, Faculty of Medicine and Odontology, University of Valencia, 46010 Valencia, Spain; (E.O.); (R.S.); (J.M.E.)
| | - Rosario Salvador
- Department of Physiology, Faculty of Medicine and Odontology, University of Valencia, 46010 Valencia, Spain; (E.O.); (R.S.); (J.M.E.)
| | - Juan I. Villaescusa
- Service of Radiological Protection, Clinical Area of Medical Image, La Fe University Hospital, 46026 Valencia, Spain;
- Biomedical Imaging Research Group GIBI230, Health Research Institute (IISLaFe), La Fe University Hospital, 46026 Valencia, Spain
| | - José M. Soriano
- Food & Health Lab, Institute of Materials Science, University of Valencia, 46980 Valencia, Spain;
- Joint Research Unit in Endocrinology, Nutrition and Clinical Dietetics, University of Valencia-Health Research Institute IISLaFe, 46026 Valencia, Spain
| | - José M. Estrela
- Department of Physiology, Faculty of Medicine and Odontology, University of Valencia, 46010 Valencia, Spain; (E.O.); (R.S.); (J.M.E.)
| | - Alegría Montoro
- Service of Radiological Protection, Clinical Area of Medical Image, La Fe University Hospital, 46026 Valencia, Spain;
- Biomedical Imaging Research Group GIBI230, Health Research Institute (IISLaFe), La Fe University Hospital, 46026 Valencia, Spain
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34
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Khodamoradi E, Hoseini-Ghahfarokhi M, Amini P, Motevaseli E, Shabeeb D, Musa AE, Najafi M, Farhood B. Targets for protection and mitigation of radiation injury. Cell Mol Life Sci 2020; 77:3129-3159. [PMID: 32072238 PMCID: PMC11104832 DOI: 10.1007/s00018-020-03479-x] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2019] [Revised: 02/04/2020] [Accepted: 02/07/2020] [Indexed: 02/06/2023]
Abstract
Protection of normal tissues against toxic effects of ionizing radiation is a critical issue in clinical and environmental radiobiology. Investigations in recent decades have suggested potential targets that are involved in the protection against radiation-induced damages to normal tissues and can be proposed for mitigation of radiation injury. Emerging evidences have been shown to be in contrast to an old dogma in radiation biology; a major amount of reactive oxygen species (ROS) production and cell toxicity occur during some hours to years after exposure to ionizing radiation. This can be attributed to upregulation of inflammatory and fibrosis mediators, epigenetic changes and disruption of the normal metabolism of oxygen. In the current review, we explain the cellular and molecular changes following exposure of normal tissues to ionizing radiation. Furthermore, we review potential targets that can be proposed for protection and mitigation of radiation toxicity.
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Affiliation(s)
- Ehsan Khodamoradi
- Radiology and Nuclear Medicine Department, School of Paramedical Sciences, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Mojtaba Hoseini-Ghahfarokhi
- Radiology and Nuclear Medicine Department, School of Paramedical Sciences, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Peyman Amini
- Department of Radiology, Faculty of Paramedical, Tehran University of Medical Sciences, Tehran, Iran
| | - Elahe Motevaseli
- Department of Molecular Medicine, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Dheyauldeen Shabeeb
- Department of Physiology, College of Medicine, University of Misan, Misan, Iraq
- Misan Radiotherapy Center, Misan, Iraq
| | - Ahmed Eleojo Musa
- Department of Medical Physics, Tehran University of Medical Sciences (International Campus), Tehran, Iran
| | - Masoud Najafi
- Radiology and Nuclear Medicine Department, School of Paramedical Sciences, Kermanshah University of Medical Sciences, Kermanshah, Iran.
| | - Bagher Farhood
- Department of Medical Physics and Radiology, Faculty of Paramedical Sciences, Kashan University of Medical Sciences, Kashan, Iran.
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35
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Umbilical Cord-Derived Mesenchymal Stem Cells Are Able to Use bFGF Treatment and Represent a Superb Tool for Immunosuppressive Clinical Applications. Int J Mol Sci 2020; 21:ijms21155366. [PMID: 32731615 PMCID: PMC7432622 DOI: 10.3390/ijms21155366] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Revised: 07/15/2020] [Accepted: 07/22/2020] [Indexed: 12/17/2022] Open
Abstract
Mesenchymal stem cells (MSCs) have become a promising tool in cellular therapy for restoring immune system haemostasis; however, the success of clinical trials has been impaired by the lack of standardized manufacturing processes. This study aims to determine the suitability of source tissues and culture media for the production of MSC-based advanced therapy medicinal products (ATMPs) and to define parameters to extend the set of release criteria. MSCs were isolated from umbilical cord (UC), bone marrow and lipoaspirate and expanded in three different culture media. MSC phenotype, proliferation capacity and immunosuppressive parameters were evaluated in normal MSCs compared to primed MSCs treated with cytokines mimicking an inflammatory environment. Compared to bone marrow and lipoaspirate, UC-derived MSCs (UC-MSCs) showed the highest proliferative capacity, which was further enhanced by media supplemented with bFGF, while the cells maintained their immunosuppressive characteristics. Moreover, UC-MSCs expanded in the bFGF-enriched medium were the least sensitive to undesirable priming-induced changes in the MSC phenotype. Surface markers and secreted factors were identified to reflect the cell response to inflammatory priming and to be variable among MSCs from different source tissues. This study demonstrates that UC is a favorable cell source for manufacturing MSC-based ATMPs for immunosuppressive applications. UC-MSCs are able to use the bFGF-enriched medium for higher cell yields without the impairment of immunosuppressive parameters and undesirable phenotype changes after inflammatory preconditioning of MSCs before transplantation. Additionally, immunosuppressive parameters were identified to help finding predictors of clinically efficient MSCs in the following clinical trials.
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Huang Y, Tan F, Zhuo Y, Liu J, He J, Duan D, Lu M, Hu Z. Hypoxia-preconditioned olfactory mucosa mesenchymal stem cells abolish cerebral ischemia/reperfusion-induced pyroptosis and apoptotic death of microglial cells by activating HIF-1α. Aging (Albany NY) 2020; 12:10931-10950. [PMID: 32507769 PMCID: PMC7346036 DOI: 10.18632/aging.103307] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2020] [Accepted: 03/30/2020] [Indexed: 04/11/2023]
Abstract
Microglial cells are the first line immune cells that initiate inflammatory responses following cerebral ischemia/reperfusion(I/R) injury. Microglial cells are also associated with a novel subtype of pro-inflammatory programmed cell death known as pyroptosis. Research has been directed at developing treatments that modulate inflammatory responses and protect against cell death caused by cerebral I/R. Key among such treatments include mesenchymal stem cell (MSC) therapy. A unique type of MSC termed olfactory mucosa mesenchymal stem cell (OM-MSC) confers neuroprotection by promoting the secretion of paracrine factors, and neuroprotection. This study investigated whether hypoxic OM-MSCs could inhibit microglial cell death upon I/R insult in vitro. A traditional oxygen-glucose deprivation/reperfusion (OGD/R) model, analogous to I/R, was established. Results showed that OGD/R induced apoptosis and pyroptosis in microglial cells while hypoxia in OM-MSCs significantly attenuated these effects. Moreover, the effects of OM-MSCs were mediated by Hypoxia-inducible factor 1-alpha (HIF-1α). Taken together, these findings reveal that hypoxia-preconditioned OM-MSC inhibits pyroptotic and apoptotic death of microglial cell in response to cerebral ischemia/reperfusion insult by activating HIF-1α in vitro.
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Affiliation(s)
- Yan Huang
- Key Laboratory of Protein Chemistry and Developmental Biology of Ministry of Education, College of Life Sciences, Hunan Normal University, Changsha 410081, Hunan, P.R. China
- Department of Neurosurgery, Second Affiliated Hospital of Hunan Normal University, Changsha 410003, Hunan, P.R. China
- Hunan Provincial Key Laboratory of Neurorestoration, Second Affiliated Hospital of Hunan Normal University, Changsha 410003, Hunan, P.R. China
| | - Fengbo Tan
- Department of Gastrointestinal Surgery, Xiangya Hospital, Central South University, Changsha 410008, Hunan, P.R. China
| | - Yi Zhuo
- Key Laboratory of Protein Chemistry and Developmental Biology of Ministry of Education, College of Life Sciences, Hunan Normal University, Changsha 410081, Hunan, P.R. China
- Department of Neurosurgery, Second Affiliated Hospital of Hunan Normal University, Changsha 410003, Hunan, P.R. China
- Hunan Provincial Key Laboratory of Neurorestoration, Second Affiliated Hospital of Hunan Normal University, Changsha 410003, Hunan, P.R. China
| | - Jianyang Liu
- Department of Neurology, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan, P.R. China
| | - Jialin He
- Department of Neurology, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan, P.R. China
| | - Da Duan
- Department of Neurosurgery, Second Affiliated Hospital of Hunan Normal University, Changsha 410003, Hunan, P.R. China
- Hunan Provincial Key Laboratory of Neurorestoration, Second Affiliated Hospital of Hunan Normal University, Changsha 410003, Hunan, P.R. China
| | - Ming Lu
- Key Laboratory of Protein Chemistry and Developmental Biology of Ministry of Education, College of Life Sciences, Hunan Normal University, Changsha 410081, Hunan, P.R. China
- Department of Neurosurgery, Second Affiliated Hospital of Hunan Normal University, Changsha 410003, Hunan, P.R. China
- Hunan Provincial Key Laboratory of Neurorestoration, Second Affiliated Hospital of Hunan Normal University, Changsha 410003, Hunan, P.R. China
| | - Zhiping Hu
- Department of Neurology, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan, P.R. China
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Budgude P, Kale V, Vaidya A. Mesenchymal stromal cell‐derived extracellular vesicles as cell‐free biologics for the ex vivo expansion of hematopoietic stem cells. Cell Biol Int 2020; 44:1078-1102. [DOI: 10.1002/cbin.11313] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2019] [Accepted: 01/31/2020] [Indexed: 12/11/2022]
Affiliation(s)
- Pallavi Budgude
- Symbiosis Centre for Stem Cell ResearchSymbiosis International (Deemed University) Pune 412115 India
| | - Vaijayanti Kale
- Symbiosis Centre for Stem Cell ResearchSymbiosis International (Deemed University) Pune 412115 India
| | - Anuradha Vaidya
- Symbiosis Centre for Stem Cell ResearchSymbiosis International (Deemed University) Pune 412115 India
- Symbiosis School of Biological SciencesSymbiosis International (Deemed University) Pune 412115 India
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Huh JW, Tanksley J, Chino J, Willett CG, Dewhirst MW. Long-term Consequences of Pelvic Irradiation: Toxicities, Challenges, and Therapeutic Opportunities with Pharmacologic Mitigators. Clin Cancer Res 2020; 26:3079-3090. [PMID: 32098770 DOI: 10.1158/1078-0432.ccr-19-2744] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2019] [Revised: 01/17/2020] [Accepted: 02/21/2020] [Indexed: 11/16/2022]
Abstract
A percentage of long-term cancer survivors who receive pelvic irradiation will develop treatment-related late effects, collectively termed pelvic radiation disease. Thus, there is a need to prevent or ameliorate treatment-related late effects in these patients. Modern radiotherapy methods can preferentially protect normal tissues from radiation toxicities to permit higher doses to targets. However, concerns about chronic small bowel toxicity, for example, still constrain the prescription dose. This provides strong rationale for considering adding pharmacologic mitigators. Implementation of modern targeted radiotherapy methods enables delivery of focused radiation to target volumes, while minimizing dose to normal tissues. In prostate cancer, these technical advances enabled safe radiation dose escalation and better local tumor control without increasing normal tissue complications. In other pelvic diseases, these new radiotherapy methods have not resulted in the low probability of normal tissue damage achieved with prostate radiotherapy. The persistence of toxicity provides rationale for pharmacologic mitigators. Several new agents could be readily tested in clinical trials because they are being or have been studied in human patients already. Although there are promising preclinical data supporting mitigators, no clinically proven options to treat or prevent pelvic radiation disease currently exist. This review highlights therapeutic options for prevention and/or treatment of pelvic radiation disease, using pharmacologic mitigators. Successful development of mitigators would reduce the number of survivors who suffer from these devastating consequences of pelvic radiotherapy. It is important to note that pharmacologic mitigators to ameliorate pelvic radiation disease may be applicable to other irradiated sites in which chronic toxicity impairs quality of life.
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Affiliation(s)
- Jung Wook Huh
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
- Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina
| | - Jarred Tanksley
- Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina
| | - Junzo Chino
- Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina
| | - Christopher G Willett
- Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina
| | - Mark W Dewhirst
- Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina.
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Najafi M, Farhood B, Mortezaee K, Kharazinejad E, Majidpoor J, Ahadi R. Hypoxia in solid tumors: a key promoter of cancer stem cell (CSC) resistance. J Cancer Res Clin Oncol 2020; 146:19-31. [PMID: 31734836 DOI: 10.1007/s00432-019-03080-1] [Citation(s) in RCA: 95] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2019] [Accepted: 11/08/2019] [Indexed: 12/12/2022]
Abstract
PURPOSE Cancer stem cells (CSCs) are highly tumorigenic cell types that reside within specific areas of tumor microenvironment (TME), and are endowed with self-renewal and resistance properties. Here, we aimed to discuss mechanisms involved in hypoxia-derived CSC resistance and targeting for effective cancer therapy. RESULTS Preferential localization within hypoxic niches would help CSCs develop adaptive mechanisms, mediated through the modification of responses to various stressors and, as a result, show a more aggressive behavior. CONCLUSION Hypoxia, in fact, serves as a multi-tasking strategy to nurture CSCs with this adaptive capacity, complexing targeted therapies.
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Affiliation(s)
- Masoud Najafi
- Radiology and Nuclear Medicine Department, School of Paramedical Sciences, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Bagher Farhood
- Departments of Medical Physics and Radiology, Faculty of Paramedical Sciences, Kashan University of Medical Sciences, Kashan, Iran
| | - Keywan Mortezaee
- Cancer and Immunology Research Center, Kurdistan University of Medical Sciences, Sanandaj, Iran.
- Department of Anatomy, School of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran.
| | - Ebrahim Kharazinejad
- Department of Anatomy, Faculty of Medicine, Abadan University of Medical Sciences, Abadan, Iran
| | - Jamal Majidpoor
- Department of Anatomy, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Reza Ahadi
- Department of Anatomy, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
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Rockel JS, Rabani R, Viswanathan S. Anti-fibrotic mechanisms of exogenously-expanded mesenchymal stromal cells for fibrotic diseases. Semin Cell Dev Biol 2019; 101:87-103. [PMID: 31757583 DOI: 10.1016/j.semcdb.2019.10.014] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2019] [Revised: 10/11/2019] [Accepted: 10/30/2019] [Indexed: 12/17/2022]
Abstract
Most chronic diseases involving inflammation have a fibrotic component that involves remodeling and excess accumulation of extracellular matrix components. Left unchecked, fibrosis leads to organ failure and death. Mesenchymal stromal cells (MSCs) are emerging as a potent cell-based therapy for a wide spectrum of fibrotic conditions due to their immunomodulatory, anti-inflammatory and anti-fibrotic properties. This review provides an overview of known mechanisms by which MSCs mediate their anti-fibrotic actions and in relation to animal models of pulmonary, liver, renal and cardiac fibrosis. Recent MSC clinical trials results in liver, lung, skin, kidney and hearts are discussed and next steps for future MSC-based therapies including pre-activated or genetically-modified cells, or extracellular vesicles are also considered.
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Affiliation(s)
- Jason S Rockel
- Arthritis Program, University Health Network, Toronto, ON, Canada; Division of Genetics and Development, Krembil Research Institute, University Health Network, Toronto, ON, Canada.
| | - Razieh Rabani
- Arthritis Program, University Health Network, Toronto, ON, Canada; Division of Genetics and Development, Krembil Research Institute, University Health Network, Toronto, ON, Canada
| | - Sowmya Viswanathan
- Arthritis Program, University Health Network, Toronto, ON, Canada; Division of Genetics and Development, Krembil Research Institute, University Health Network, Toronto, ON, Canada; Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Canada; Division of Hematology, Department of Medicine, University of Toronto, Toronto, Canada
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Afsar CU, Uysal P. HIF-1α Levels in patients receiving chemoradiotherapy for locally advanced non-small cell lung carcinoma. ACTA ACUST UNITED AC 2019; 65:1295-1299. [PMID: 31721962 DOI: 10.1590/1806-9282.65.10.1295] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2019] [Accepted: 03/31/2019] [Indexed: 12/13/2022]
Abstract
AIM To examine the relationship between treatment response and hypoxia-inducible factor-1 alpha (HIF-1α) levels in patients with locally advanced non-small cell lung cancer (NSCLC) who received chemoradiotherapy (CRT). METHODS Eighty patients with NSCLC were included in the study and treated at Acibadem Mehmet Ali Aydınlar University Medical Faculty. HIF-1 α levels were measured before and after CRT by the enzyme-linked immunosorbent assay (ELISA) method. RESULTS Patients' stages were as follows; stage IIIA (65%) and stage IIIB (35%). Squamous histology was 45%, adenocarcinoma was 44%, and others were 11%. Chemotherapy and radiotherapy were given concurrently to 80 patients. Forty-five (56%) patients received cisplatin-based chemotherapy, and 35 (44%) received carboplatin-based chemotherapy. Serum HIF-1α levels (42.90 ± 10.55 pg/mL) after CRT were significantly lower than the pretreatment levels (63.10 ± 10.22 pg/mL, p<0.001) in patients with locally advanced NSCLC. CONCLUSION The results of this study revealed that serum HIF-1α levels decreased after CRT. Decrease of HIF-1α levels after the initiation of CRT may be useful for predicting the efficacy of CRT.
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Affiliation(s)
- Cigdem Usul Afsar
- . Acıbadem Mehmet Ali Aydınlar University Medical Faculty, Bakirkoy Acıbadem Hospital, Department of Internal Medicine and Medical Oncology, Istanbul, Turkey
| | - Pelin Uysal
- . Acıbadem Mehmet Ali Aydınlar University Medical Faculty, Atakent Acıbadem Hospital, Department of Pulmonary Medicine, Istanbul, Turkey
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Jiang Y, Gao H, Yuan H, Xu H, Tian M, Du G, Xie W. Amelioration of postoperative cognitive dysfunction in mice by mesenchymal stem cell-conditioned medium treatments is associated with reduced inflammation, oxidative stress and increased BDNF expression in brain tissues. Neurosci Lett 2019; 709:134372. [DOI: 10.1016/j.neulet.2019.134372] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2019] [Revised: 06/21/2019] [Accepted: 07/05/2019] [Indexed: 12/22/2022]
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Noronha NDC, Mizukami A, Caliári-Oliveira C, Cominal JG, Rocha JLM, Covas DT, Swiech K, Malmegrim KCR. Priming approaches to improve the efficacy of mesenchymal stromal cell-based therapies. Stem Cell Res Ther 2019; 10:131. [PMID: 31046833 PMCID: PMC6498654 DOI: 10.1186/s13287-019-1224-y] [Citation(s) in RCA: 374] [Impact Index Per Article: 62.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Multipotent mesenchymal stromal cells (MSC) have been widely explored for cell-based therapy of immune-mediated, inflammatory, and degenerative diseases, due to their immunosuppressive, immunomodulatory, and regenerative potentials. Preclinical studies and clinical trials have demonstrated promising therapeutic results although these have been somewhat limited. Aspects such as low in vivo MSC survival in inhospitable disease microenvironments, requirements for ex vivo cell overexpansion prior to infusions, intrinsic differences between MSC and different sources and donors, variability of culturing protocols, and potency assays to evaluate MSC products have been described as limitations in the field. In recent years, priming approaches to empower MSC have been investigated, thereby generating cellular products with improved potential for different clinical applications. Herein, we review the current priming approaches that aim to increase MSC therapeutic efficacy. Priming with cytokines and growth factors, hypoxia, pharmacological drugs, biomaterials, and different culture conditions, as well as other diverse molecules, are revised from current and future perspectives.
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Affiliation(s)
- Nádia de Cássia Noronha
- Center for Cell-based Therapy, Regional Blood Center of Ribeirão Preto, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil.,Graduate Program on Bioscience and Biotechnology, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil
| | - Amanda Mizukami
- Center for Cell-based Therapy, Regional Blood Center of Ribeirão Preto, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
| | | | - Juçara Gastaldi Cominal
- Center for Cell-based Therapy, Regional Blood Center of Ribeirão Preto, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil.,Graduate Program on Bioscience and Biotechnology, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil
| | - José Lucas M Rocha
- Center for Cell-based Therapy, Regional Blood Center of Ribeirão Preto, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil.,Graduate Program on Basic and Applied Immunology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
| | - Dimas Tadeu Covas
- Center for Cell-based Therapy, Regional Blood Center of Ribeirão Preto, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
| | - Kamilla Swiech
- Center for Cell-based Therapy, Regional Blood Center of Ribeirão Preto, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil.,Department of Pharmaceutical Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil
| | - Kelen C R Malmegrim
- Center for Cell-based Therapy, Regional Blood Center of Ribeirão Preto, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil. .,Department of Clinical, Toxicological and Bromatological Analysis, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Avenida do Café, s/n°, Ribeirão Preto, SP, 14010-903, Brazil.
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Ariyanti AD, Zhang J, Marcelina O, Nugrahaningrum DA, Wang G, Kasim V, Wu S. Salidroside-Pretreated Mesenchymal Stem Cells Enhance Diabetic Wound Healing by Promoting Paracrine Function and Survival of Mesenchymal Stem Cells Under Hyperglycemia. Stem Cells Transl Med 2019; 8:404-414. [PMID: 30624028 PMCID: PMC6431607 DOI: 10.1002/sctm.18-0143] [Citation(s) in RCA: 51] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2018] [Accepted: 12/03/2018] [Indexed: 12/12/2022] Open
Abstract
Systemic abnormalities cause several complications in diabetes patients. Impaired wound healing is a serious complication that leads to severe foot ulcer and amputation. Mesenchymal stem cells (MSCs) have been considered a promising strategy for promoting wound healing due to their paracrine function. However, their poor survival after transplantation limits their therapeutic effect and applications. Salidroside, a glucopyranoside, has been reported to exert cytoprotective effects. Our previous study revealed that salidroside could promote the paracrine function of skeletal muscle cells. However, whether salidroside could improve MSCs survival under hyperglycemic condition and, subsequently, promote wound healing in diabetic model mice remains unknown. Here, we found that salidroside pretreatment effectively reversed the hyperglycemia-induced suppression of the expression of crucial wound healing factors in MSCs, such as heme oxygenase-1 (HO-1), fibroblast growth factor 2 (FGF2), and hepatocyte growth factor (HGF). Salidroside pretreatment also suppressed the hyperglycemia-induced intracellular reactive oxygen species (ROS) levels in MSCs, thereby lowering the apoptosis rate and enhancing MSCs survival rate. Furthermore, salidroside improved the MSCs migration potential that was impaired under hyperglycemia. in vivo experiments revealed that salidroside pretreatment prior to transplantation significantly enhanced the effect of MSCs in promoting wound closure in diabetic mice. Collectively, our results suggest that pretreatment with salidroside could be an effective strategy to enhance the survival rate and the therapeutic effect of MSCs. Thus, our article suggested a novel, potential MSC-based strategy for diabetic wound healing. Stem Cells Translational Medicine 2019;8:404-414.
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Affiliation(s)
- Agnes Dwi Ariyanti
- The Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, People's Republic of China.,State and Local Joint Engineering Laboratory for Vascular Implants, College of Bioengineering, Chongqing University, Chongqing, People's Republic of China
| | - Jianqi Zhang
- The Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, People's Republic of China.,State and Local Joint Engineering Laboratory for Vascular Implants, College of Bioengineering, Chongqing University, Chongqing, People's Republic of China
| | - Olivia Marcelina
- The Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, People's Republic of China.,State and Local Joint Engineering Laboratory for Vascular Implants, College of Bioengineering, Chongqing University, Chongqing, People's Republic of China
| | - Dyah Ari Nugrahaningrum
- The Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, People's Republic of China.,State and Local Joint Engineering Laboratory for Vascular Implants, College of Bioengineering, Chongqing University, Chongqing, People's Republic of China
| | - Guixue Wang
- The Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, People's Republic of China.,State and Local Joint Engineering Laboratory for Vascular Implants, College of Bioengineering, Chongqing University, Chongqing, People's Republic of China
| | - Vivi Kasim
- The Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, People's Republic of China.,State and Local Joint Engineering Laboratory for Vascular Implants, College of Bioengineering, Chongqing University, Chongqing, People's Republic of China.,The 111 Project Laboratory of Biomechanics and Tissue Repair, College of Bioengineering, Chongqing University, Chongqing, People's Republic of China
| | - Shourong Wu
- The Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, People's Republic of China.,State and Local Joint Engineering Laboratory for Vascular Implants, College of Bioengineering, Chongqing University, Chongqing, People's Republic of China.,The 111 Project Laboratory of Biomechanics and Tissue Repair, College of Bioengineering, Chongqing University, Chongqing, People's Republic of China
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Hu C, Zhao L, Peng C, Li L. Regulation of the mitochondrial reactive oxygen species: Strategies to control mesenchymal stem cell fates ex vivo and in vivo. J Cell Mol Med 2018; 22:5196-5207. [PMID: 30160351 PMCID: PMC6201215 DOI: 10.1111/jcmm.13835] [Citation(s) in RCA: 52] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2018] [Accepted: 07/11/2018] [Indexed: 12/18/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are broadly used in cell‐based regenerative medicine because of their self‐renewal and multilineage potencies in vitro and in vivo. To ensure sufficient amounts of MSCs for therapeutic purposes, cells are generally cultured in vitro for long‐term expansion or specific terminal differentiation until cell transplantation. Although physiologically up‐regulated reactive oxygen species (ROS) production is essential for maintenance of stem cell activities, abnormally high levels of ROS can harm MSCs both in vitro and in vivo. Overall, additional elucidation of the mechanisms by which physiological and pathological ROS are generated is necessary to better direct MSC fates and improve their therapeutic effects by controlling external ROS levels. In this review, we focus on the currently revealed ROS generation mechanisms and the regulatory routes for controlling their rates of proliferation, survival, senescence, apoptosis, and differentiation. A promising strategy in future regenerative medicine involves regulating ROS generation via various means to augment the therapeutic efficacy of MSCs, thus improving the prognosis of patients with terminal diseases.
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Affiliation(s)
- Chenxia Hu
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, School of Medicine, First Affiliated Hospital, Zhejiang University, Hangzhou, Zhejiang, China
| | - Lingfei Zhao
- Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.,Key Laboratory of Kidney Disease Prevention and Control Technology, Zhejiang Province, Institute of Nephrology, Zhejiang University, Hangzhou, Zhejiang, China
| | - Conggao Peng
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, School of Medicine, First Affiliated Hospital, Zhejiang University, Hangzhou, Zhejiang, China
| | - Lanjuan Li
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, School of Medicine, First Affiliated Hospital, Zhejiang University, Hangzhou, Zhejiang, China
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Gupta N, Nizet V. Stabilization of Hypoxia-Inducible Factor-1 Alpha Augments the Therapeutic Capacity of Bone Marrow-Derived Mesenchymal Stem Cells in Experimental Pneumonia. Front Med (Lausanne) 2018; 5:131. [PMID: 29780805 PMCID: PMC5945808 DOI: 10.3389/fmed.2018.00131] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2018] [Accepted: 04/19/2018] [Indexed: 12/21/2022] Open
Abstract
Bone marrow-derived mesenchymal stem cells (MSCs) have therapeutic effects in experimental models of lung injury. Hypoxia-inducible factor-1 alpha (HIF-1α) is a transcriptional regulator that influences cellular metabolism, energetics, and survival under hypoxic conditions. The current study investigated the effects of stabilizing HIF-1α on the therapeutic capacity of MSCs in an experimental mouse model of bacterial pneumonia. HIF-1α stabilization was achieved by the small molecule prolyl-hydroxlase inhibitor, AKB-4924 (Aerpio Therapeutics, Inc.), which blocks the pathway for HIF-1α degradation in the proteosome. In vitro, pre-treatment with AKB-4924 increased HIF-1α levels in MSCs, reduced the kinetics of their cell death when exposed to cytotoxic stimuli, and increased their antibacterial capacity. In vivo, AKB-4924 enhanced MSC therapeutic capacity in experimental pneumonia as quantified by a sustainable survival benefit, greater bacterial clearance from the lung, decreased lung injury, and reduced inflammatory indices. These results suggest that HIF-1α stabilization in MSCs, achieved ex vivo, may represent a promising approach to augment the therapeutic benefit of these cells in severe pneumonia complicated by acute lung injury.
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Affiliation(s)
- Naveen Gupta
- Division of Pulmonary and Critical Care, Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, CA, United States.,Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, United States
| | - Victor Nizet
- Division of Host-Microbe Systems and Therapeutics, Department of Pediatrics, School of Medicine, University of California, San Diego, La Jolla, CA, United States.,Skaggs School of Pharmacy and Pharmaceutical Sciences, School of Medicine, University of California, San Diego, La Jolla, CA, United States
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Wang Y, Ma WQ, Zhu Y, Han XQ, Liu N. Exosomes Derived From Mesenchymal Stromal Cells Pretreated With Advanced Glycation End Product-Bovine Serum Albumin Inhibit Calcification of Vascular Smooth Muscle Cells. Front Endocrinol (Lausanne) 2018; 9:524. [PMID: 30298051 PMCID: PMC6160580 DOI: 10.3389/fendo.2018.00524] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2018] [Accepted: 08/21/2018] [Indexed: 12/19/2022] Open
Abstract
Background: The osteogenic differentiation of vascular smooth muscle cell (VSMCs) is important for the development of vascular calcification (VC), particularly in diabetes. Exosomes derived from Mesenchymal Stromal Cells (MSCs) are effective against cardiovascular diseases, yet their role in VC remains unclear. Advanced glycation end products (AGEs) inhibit bone marrow stromal cell osteogenesis by targeting osteogenesis-associated genes. Thus, we investigated the role of exosomes derived from MSCs pretreated with AGEs-BSA in VC and its potential mechanisms. Methods: Primary VSMCs and MSCs were isolated from the aorta and bone marrow of Sprague-Dawley rats, respectively. VSMCs were cultured with AGEs-BSA to induce osteogenic differentiation. Exosomes were harvested from MSCs by ultracentrifugation. MSCs and VSMCs were cocultured in Transwells, and exosomes were added to VSMC culture medium to assess their effects on osteogenic differentiation. Double luciferase reporter assay was applied to confirm that miR-146a directly targets the 3' UTR of the thioredoxin-interacting protein (TXNIP) gene. Results: Pretreatment of VSMCs with AGEs-BSA increased the expression of thioredoxin-interacting protein (TXNIP) by inhibiting that of miR-146a, resulting in enhanced ROS production and VSMC calcification. By contrast, the expression of miR-146a in MSCs was increased by AGEs-BSA treatment. Thus, miR-146a was transferred from AGEs-BSA-pretreated or miR-146a-transfected MSCs to VSMCs via exosomes. After coculture with miR-146a-containing exosomes, the AGEs-BSA-mediated increase in VSMC calcification was diminished, accompanied by decreased TXNIP expression and ROS production. Furthermore, TXNIP overexpression counteracted the anti-calcification effects of MSC-derived miR-146a-containing exosomes. In addition, TXNIP was identified as a target gene of miR-146a, and the results of double luciferase reporter assay confirmed that TXNIP was the direct target gene of miR-146a. Conclusions: Exosomes secreted by MSCs pretreated with AGEs-BSA contained a high level of miR-146a, which was transferred to VSMCs and inhibited AGEs-BSA-induced calcification in a TXNIP-dependent manner. Thus, miR-146a-containing exosomes may be a potential therapeutic target for VC.
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