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1
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Tian RC, Zhang RY, Ma CF. Rejuvenation of Bone Marrow Mesenchymal Stem Cells: Mechanisms and Their Application in Senile Osteoporosis Treatment. Biomolecules 2025; 15:276. [PMID: 40001580 PMCID: PMC11853522 DOI: 10.3390/biom15020276] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2024] [Revised: 02/01/2025] [Accepted: 02/10/2025] [Indexed: 02/27/2025] Open
Abstract
Bone marrow mesenchymal stromal cells (BM-MSCs) are multipotent cells present in bone marrow; they play a crucial role in the process of bone formation. Cellular senescence is defined as a stable state of cell cycle arrest that impairs the functioning of cells. Research has shown that aging triggers a state of senescence in BM-MSCs, leading to a reduced capacity for osteogenic differentiation and the accumulation of senescent cells, which can accelerate the onset of various diseases. Therefore, it is essential to explore mechanisms and strategies for the rejuvenation of senescent BM-MSCs. Senile osteoporosis (SOP) is a metabolic bone disease characterized by reduced bone formation. The senescence of BM-MSCs is considered one of the most important factors in the occurrence and development of SOP. Therefore, the rejuvenation of BM-MSCs for the treatment of SOP represents a promising strategy. This work provides a summary of the functional alterations observed in senescent BM-MSCs and a systematic review of the mechanisms that facilitate the rejuvenation of senescent BM-MSCs. Additionally, we analyze the progress in and the limitations associated with the application of rejuvenated senescent BM-MSCs to treat SOP, with the aim of providing new insights for the prevention and treatment of SOP.
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Affiliation(s)
- Rui-Chuan Tian
- Department of Stomatology, Air Force Medical Center, The Fourth Military Medical University, Beijing 100142, China;
- Graduate School, China Medical University, Shenyang 110002, China
| | - Ru-Ya Zhang
- Department of Emergency and Oral Medicine, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, Shenyang 110002, China;
| | - Chu-Fan Ma
- Department of Stomatology, Air Force Medical Center, The Fourth Military Medical University, Beijing 100142, China;
- Graduate School, China Medical University, Shenyang 110002, China
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2
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Zhao L, Zhao BH, Ruze A, Li QL, Deng AX, Gao XM. Distinct roles of MIF in the pathogenesis of ischemic heart disease. Cytokine Growth Factor Rev 2024; 80:121-137. [PMID: 39438226 DOI: 10.1016/j.cytogfr.2024.10.005] [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: 08/28/2024] [Revised: 10/10/2024] [Accepted: 10/10/2024] [Indexed: 10/25/2024]
Abstract
The role of macrophage migration inhibitory factor (MIF) as a multifunctional cytokine in immunomodulation and inflammatory response is increasingly appreciated. Ischemic heart disease (IHD), the leading cause of global mortality, remains a focal point of research owing to its intricate pathophysiology. MIF has been identified as a critical player in IHD, where it exerts distinct roles. On one hand, MIF plays a protective role by enhancing energy metabolism through activation of AMPK, resisting oxidative stress, inhibiting activation of the JNK pathway, and maintaining intracellular calcium ion homeostasis. Additionally, MIF exerts protective effects through mesenchymal stem cells and exosomes. On the other hand, MIF can assume a pro-inflammatory role, which contributes to the exacerbation of IHD's development and progression. Furthermore, MIF levels significantly increase in IHD patients, and its genetic polymorphisms are positively correlated with prevalence and severity. These findings position MIF as a potential biomarker and therapeutic target in the management of IHD. This review summarizes the structure, source, signaling pathways and biological functions of MIF and focuses on its roles and clinical characteristics in IHD. The genetic variants of MIF associated with IHD is also discussed, providing more understandings of its complex interplay in the disease's pathology.
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Affiliation(s)
- Ling Zhao
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Department of Cardiology, First Affiliated Hospital, Clinical Medical Research Institute of Xinjiang Medical University, Urumqi, China; Xinjiang Key Laboratory of Medical Animal Model Research, Urumqi, China
| | - Bang-Hao Zhao
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Department of Cardiology, First Affiliated Hospital, Clinical Medical Research Institute of Xinjiang Medical University, Urumqi, China; Xinjiang Key Laboratory of Medical Animal Model Research, Urumqi, China
| | - Amanguli Ruze
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Department of Cardiology, First Affiliated Hospital, Clinical Medical Research Institute of Xinjiang Medical University, Urumqi, China; Xinjiang Key Laboratory of Medical Animal Model Research, Urumqi, China
| | - Qiu-Lin Li
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Department of Cardiology, First Affiliated Hospital, Clinical Medical Research Institute of Xinjiang Medical University, Urumqi, China; Xinjiang Key Laboratory of Medical Animal Model Research, Urumqi, China
| | - An-Xia Deng
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Department of Cardiology, First Affiliated Hospital, Clinical Medical Research Institute of Xinjiang Medical University, Urumqi, China; Xinjiang Key Laboratory of Medical Animal Model Research, Urumqi, China
| | - Xiao-Ming Gao
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Department of Cardiology, First Affiliated Hospital, Clinical Medical Research Institute of Xinjiang Medical University, Urumqi, China; Xinjiang Key Laboratory of Medical Animal Model Research, Urumqi, China; Xinjiang Key Laboratory of Cardiovascular Disease, Urumqi, China.
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Fu Z, Li Q, Jiang P, Song X, Yang J, Chen G, Gong X, Yang L. Macrophage migration inhibitory factor reversed senescent phenotype in human chondrocytes in vitro. Mol Biol Rep 2024; 51:154. [PMID: 38245877 DOI: 10.1007/s11033-023-09101-0] [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: 09/26/2023] [Accepted: 12/04/2023] [Indexed: 01/23/2024]
Abstract
BACKGROUND The senescence of chondrocytes, which is closely linked to the development of osteoarthritis (OA), has been found to be influenced by the inflammatory environment of joint cavity. However, there remains a lack of comprehensive understanding regarding the specific mechanisms through which cytokine impacts chondrocytes senescence. PURPOSE To investigate the effects of MIF on the chondrocytes senescence and explore the underlying mechanism. METHODS Human cytokine array and ELISA were used for the level of MIF in synovium fluid. CCK-8 was used for chondrocytes viability. IF, WB, SA-β-gal staining and flow cytometry were used for the chondrogenic, apoptotic and senescent phenotype of chondrocytes. RESULTS The level of MIF was significantly increased in OA patients. MIF significantly reversed the senescent phenotype induced by LPS pretreatment in human chondrocytes. MIF significantly enhanced the expression of Col II, SOX9, and ACAN in LPS pre-treated human chondrocytes. Furthermore, MIF significantly inhibited the apoptosis of LPS-induced senescent chondrocytes. CONCLUSION Increased level of MIF in osteoarthritic joint cavity might effectively suppress the senescent phenotype and simultaneously improve the chondrogenic phenotype in chondrocytes, the underlying mechanism was likely to be independent of apoptosis.
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Affiliation(s)
- Zhenlan Fu
- Center for Joint Surgery, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing, 400038, China
| | - Qingqing Li
- Key Laboratory of Biorheological Science and Technology, Ministry of Education College of Bioengineering, Chongqing University, Chongqing, 400044, China
| | - Peiyao Jiang
- Center for Joint Surgery, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing, 400038, China
| | - Xiongbo Song
- Center for Joint Surgery, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing, 400038, China
| | - Junjun Yang
- Key Laboratory of Biorheological Science and Technology, Ministry of Education College of Bioengineering, Chongqing University, Chongqing, 400044, China
| | - Guangxing Chen
- Center for Joint Surgery, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing, 400038, China.
| | - Xiaoyuan Gong
- Center for Joint Surgery, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing, 400038, China.
| | - Liu Yang
- Center for Joint Surgery, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing, 400038, China.
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Rasouli M, Naeimzadeh Y, Hashemi N, Hosseinzadeh S. Age-Related Alterations in Mesenchymal Stem Cell Function: Understanding Mechanisms and Seeking Opportunities to Bypass the Cellular Aging. Curr Stem Cell Res Ther 2024; 19:15-32. [PMID: 36642876 DOI: 10.2174/1574888x18666230113144016] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Revised: 10/28/2022] [Accepted: 11/23/2022] [Indexed: 01/17/2023]
Abstract
Undoubtedly, mesenchymal stem cells (MSCs) are the most common cell therapy candidates in clinical research and therapy. They not only exert considerable therapeutic effects to alleviate inflammation and promote regeneration, but also show low-immunogenicity properties, which ensure their safety following allogeneic transplantation. Thanks to the necessity of providing a sufficient number of MSCs to achieve clinically efficient outcomes, prolonged in vitro cultivation is indisputable. However, either following long-term in vitro expansion or aging in elderly individuals, MSCs face cellular senescence. Senescent MSCs undergo an impairment in their function and therapeutic capacities and secrete degenerative factors which negatively affect young MSCs. To this end, designing novel investigations to further elucidate cellular senescence and to pave the way toward finding new strategies to reverse senescence is highly demanded. In this review, we will concisely discuss current progress on the detailed mechanisms of MSC senescence and various inflicted changes following aging in MSC. We will also shed light on the examined strategies underlying monitoring and reversing senescence in MSCs to bypass the comprised therapeutic efficacy of the senescent MSCs.
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Affiliation(s)
- Mehdi Rasouli
- Department of Tissue Engineering and Applied Cell Science, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Yasaman Naeimzadeh
- Department of Molecular Medicine, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Nader Hashemi
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Simzar Hosseinzadeh
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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5
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Rovere M, Reverberi D, Arnaldi P, Palamà MEF, Gentili C. Spheroid size influences cellular senescence and angiogenic potential of mesenchymal stromal cell-derived soluble factors and extracellular vesicles. Front Bioeng Biotechnol 2023; 11:1297644. [PMID: 38162179 PMCID: PMC10756914 DOI: 10.3389/fbioe.2023.1297644] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Accepted: 11/23/2023] [Indexed: 01/03/2024] Open
Abstract
Introduction: The secretome of mesenchymal stromal cells (MSCs) serves as an innovative tool employed in the regenerative medicine approach. In this particular context, three-dimensional (3D) culture systems are widely utilized to better replicate in vivo conditions and facilitate prolonged cell maintenance during culture. The use of spheroids enables the preservation of the classical phenotypical characteristics of MSCs. However, the distinct microenvironment within the spheroid may impact the secretome, thereby enhancing the angiogenic properties of adult MSCs that typically possess a reduced angiogenic potential compared to MSCs derived from perinatal tissues due to the hypoxia created in the internal region of the spheroid. Methods: In this study, large spheroids (2,600 cells, ∼300 μm diameter) and small spheroids (1,000 cells, ∼200 μm diameter) were used to examine the role of spheroid diameter in the generation of nutrients and oxygen gradients, cellular senescence, and the angiogenic potential of secreted factors and extracellular vesicles (EVs). Results: In this study, we demonstrate that large spheroids showed increased senescence and a secretome enriched in pro-angiogenic factors, as well as pro-inflammatory and anti-angiogenic cytokines, while small spheroids exhibited decreased senescence and a secretome enriched in pro-angiogenic molecules. We also demonstrated that 3D culture led to a higher secretion of EVs with classical phenotypic characteristics. Soluble factors and EVs from small spheroids exhibited higher angiogenic potential in a human umbilical vein endothelial cell (HUVEC) angiogenic assay. Discussion: These findings highlighted the necessity of choosing the appropriate culture system for obtaining soluble factors and EVs for specific therapeutic applications.
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Affiliation(s)
- Matteo Rovere
- Department of Experimental Medicine, University of Genoa, Genoa, Italy
| | | | - Pietro Arnaldi
- Department of Experimental Medicine, University of Genoa, Genoa, Italy
| | | | - Chiara Gentili
- Department of Experimental Medicine, University of Genoa, Genoa, Italy
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6
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Lagger C, Ursu E, Equey A, Avelar RA, Pisco AO, Tacutu R, de Magalhães JP. scDiffCom: a tool for differential analysis of cell-cell interactions provides a mouse atlas of aging changes in intercellular communication. NATURE AGING 2023; 3:1446-1461. [PMID: 37919434 PMCID: PMC10645595 DOI: 10.1038/s43587-023-00514-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Accepted: 09/27/2023] [Indexed: 11/04/2023]
Abstract
Dysregulation of intercellular communication is a hallmark of aging. To better quantify and explore changes in intercellular communication, we present scDiffCom and scAgeCom. scDiffCom is an R package, relying on approximately 5,000 curated ligand-receptor interactions, that performs differential intercellular communication analysis between two conditions from single-cell transcriptomics data. Built upon scDiffCom, scAgeCom is an atlas of age-related cell-cell communication changes covering 23 mouse tissues from 58 single-cell RNA sequencing datasets from Tabula Muris Senis and the Calico murine aging cell atlas. It offers a comprehensive resource of tissue-specific and sex-specific aging dysregulations and highlights age-related intercellular communication changes widespread across the whole body, such as the upregulation of immune system processes and inflammation, the downregulation of developmental processes, angiogenesis and extracellular matrix organization and the deregulation of lipid metabolism. Our analysis emphasizes the relevance of the specific ligands, receptors and cell types regulating these processes. The atlas is available online ( https://scagecom.org ).
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Affiliation(s)
- Cyril Lagger
- Integrative Genomics of Ageing Group, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, UK
- Altos Labs, San Diego, CA, USA
| | - Eugen Ursu
- Systems Biology of Aging Group, Institute of Biochemistry of the Romanian Academy, Bucharest, Romania
| | - Anaïs Equey
- Department of Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Roberto A Avelar
- Integrative Genomics of Ageing Group, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, UK
| | - Angela Oliveira Pisco
- Chan Zuckerberg Biohub, San Francisco, CA, USA
- Insitro, Inc., South San Francisco, USA
| | - Robi Tacutu
- Systems Biology of Aging Group, Institute of Biochemistry of the Romanian Academy, Bucharest, Romania
| | - João Pedro de Magalhães
- Integrative Genomics of Ageing Group, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, UK.
- Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK.
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7
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Jiang X, Li W, Ge L, Lu M. Mesenchymal Stem Cell Senescence during Aging:From Mechanisms to Rejuvenation Strategies. Aging Dis 2023; 14:1651-1676. [PMID: 37196126 PMCID: PMC10529739 DOI: 10.14336/ad.2023.0208] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Accepted: 02/08/2023] [Indexed: 05/19/2023] Open
Abstract
In cell transplantation therapy, mesenchymal stem cells(MSCs)are ideal seed cells due to their easy acquisition and cultivation, strong regenerative capacity, multi-directional differentiation abilities, and immunomodulatory effects. Autologous MSCs are better applicable compared with allogeneic MSCs in clinical practice. The elderly are the main population for cell transplantation therapy, but as donor aging, MSCs in the tissue show aging-related changes. When the number of generations of in vitro expansion is increased, MSCs will also exhibit replicative senescence. The quantity and quality of MSCs decline during aging, which limits the efficacy of autologous MSCs transplantation therapy. In this review, we examine the changes in MSC senescence as a result of aging, discuss the progress of research on mechanisms and signalling pathways of MSC senescence, and discuss possible rejuvenation strategies of aged MSCs to combat senescence and enhance the health and therapeutic potential of MSCs.
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Affiliation(s)
- Xinchen Jiang
- The National & Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha, China.
- Hunan provincical key laboratory of Neurorestoratology, the Second Affiliated Hospital, Hunan Normal University, Changsha, China.
| | - Wenshui Li
- The National & Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha, China.
- Hunan provincical key laboratory of Neurorestoratology, the Second Affiliated Hospital, Hunan Normal University, Changsha, China.
| | - Lite Ge
- The National & Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha, China.
- Hunan provincical key laboratory of Neurorestoratology, the Second Affiliated Hospital, Hunan Normal University, Changsha, China.
- Department of Neurology, Second Xiangya Hospital, Central South University, Changsha, 410011, China, Changsha
| | - Ming Lu
- The National & Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha, China.
- Hunan provincical key laboratory of Neurorestoratology, the Second Affiliated Hospital, Hunan Normal University, Changsha, China.
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8
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Yang X, Wang Y, Rovella V, Candi E, Jia W, Bernassola F, Bove P, Piacentini M, Scimeca M, Sica G, Tisone G, Mauriello A, Wei L, Melino G, Shi Y. Aged mesenchymal stem cells and inflammation: from pathology to potential therapeutic strategies. Biol Direct 2023; 18:40. [PMID: 37464416 PMCID: PMC10353240 DOI: 10.1186/s13062-023-00394-6] [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: 06/17/2023] [Accepted: 06/27/2023] [Indexed: 07/20/2023] Open
Abstract
Natural ageing of organisms and corresponding age-related diseases result mainly from stem cell ageing and "inflammaging". Mesenchymal stem cells (MSCs) exhibit very high immune-regulating capacity and are promising candidates for immune-related disease treatment. However, the effect of MSC application is not satisfactory for some patients, especially in elderly individuals. With ageing, MSCs undergo many changes, including altered cell population reduction and differentiation ability, reduced migratory and homing capacity and, most important, defective immunosuppression. It is necessary to explore the relationship between the "inflammaging" and aged MSCs to prevent age-related diseases and increase the therapeutic effects of MSCs. In this review, we discuss changes in naturally ageing MSCs mainly from an inflammation perspective and propose some ideas for rejuvenating aged MSCs in future treatments.
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Affiliation(s)
- Xue Yang
- Department of Experimental Medicine, TOR, University of Rome Tor Vergata, Rome, 00133 Italy
- The Third Affiliated Hospital of Soochow University, Institutes for Translational Medicine, State Key Laboratory of Radiation Medicine and Protection, Medical College of Soochow University, Suzhou, Jiangsu China
| | - Ying Wang
- The Third Affiliated Hospital of Soochow University, Institutes for Translational Medicine, State Key Laboratory of Radiation Medicine and Protection, Medical College of Soochow University, Suzhou, Jiangsu China
| | - Valentina Rovella
- Department of Experimental Medicine, TOR, University of Rome Tor Vergata, Rome, 00133 Italy
| | - Eleonora Candi
- Department of Experimental Medicine, TOR, University of Rome Tor Vergata, Rome, 00133 Italy
| | - Wei Jia
- Center for Translational Medicine, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Sixth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200233 China
- School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong China
| | - Francesca Bernassola
- Department of Experimental Medicine, TOR, University of Rome Tor Vergata, Rome, 00133 Italy
| | - Pierluigi Bove
- Department of Experimental Medicine, TOR, University of Rome Tor Vergata, Rome, 00133 Italy
| | - Mauro Piacentini
- Department of Experimental Medicine, TOR, University of Rome Tor Vergata, Rome, 00133 Italy
| | - Manuel Scimeca
- Department of Experimental Medicine, TOR, University of Rome Tor Vergata, Rome, 00133 Italy
| | - Giuseppe Sica
- Department of Experimental Medicine, TOR, University of Rome Tor Vergata, Rome, 00133 Italy
| | - Giuseppe Tisone
- Department of Experimental Medicine, TOR, University of Rome Tor Vergata, Rome, 00133 Italy
| | - Alessandro Mauriello
- Department of Experimental Medicine, TOR, University of Rome Tor Vergata, Rome, 00133 Italy
| | - Lixin Wei
- Department of Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Naval Medical University, Shanghai, 200438 China
| | - Gerry Melino
- Department of Experimental Medicine, TOR, University of Rome Tor Vergata, Rome, 00133 Italy
| | - Yufang Shi
- The Third Affiliated Hospital of Soochow University, Institutes for Translational Medicine, State Key Laboratory of Radiation Medicine and Protection, Medical College of Soochow University, Suzhou, Jiangsu China
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9
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Maiese K. Cellular Metabolism: A Fundamental Component of Degeneration in the Nervous System. Biomolecules 2023; 13:816. [PMID: 37238686 PMCID: PMC10216724 DOI: 10.3390/biom13050816] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2023] [Revised: 05/05/2023] [Accepted: 05/10/2023] [Indexed: 05/28/2023] Open
Abstract
It is estimated that, at minimum, 500 million individuals suffer from cellular metabolic dysfunction, such as diabetes mellitus (DM), throughout the world. Even more concerning is the knowledge that metabolic disease is intimately tied to neurodegenerative disorders, affecting both the central and peripheral nervous systems as well as leading to dementia, the seventh leading cause of death. New and innovative therapeutic strategies that address cellular metabolism, apoptosis, autophagy, and pyroptosis, the mechanistic target of rapamycin (mTOR), AMP activated protein kinase (AMPK), growth factor signaling with erythropoietin (EPO), and risk factors such as the apolipoprotein E (APOE-ε4) gene and coronavirus disease 2019 (COVID-19) can offer valuable insights for the clinical care and treatment of neurodegenerative disorders impacted by cellular metabolic disease. Critical insight into and modulation of these complex pathways are required since mTOR signaling pathways, such as AMPK activation, can improve memory retention in Alzheimer's disease (AD) and DM, promote healthy aging, facilitate clearance of β-amyloid (Aß) and tau in the brain, and control inflammation, but also may lead to cognitive loss and long-COVID syndrome through mechanisms that can include oxidative stress, mitochondrial dysfunction, cytokine release, and APOE-ε4 if pathways such as autophagy and other mechanisms of programmed cell death are left unchecked.
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Affiliation(s)
- Kenneth Maiese
- Cellular and Molecular Signaling, New York, NY 10022, USA
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10
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Wang L, Yang J, Tan W, Guo Y, Li J, Duan C, Wei G, Chou M. Macrophage migration inhibitory factor MtMIF3 prevents the premature aging of Medicago truncatula nodules. PLANT, CELL & ENVIRONMENT 2023; 46:1004-1017. [PMID: 36515398 DOI: 10.1111/pce.14515] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Revised: 12/01/2022] [Accepted: 12/09/2022] [Indexed: 06/17/2023]
Abstract
Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine involved in immune response in animals. However, the role of MIFs in plants such as Medicago truncatula, particularly in symbiotic nitrogen fixation, remains unclear. An investigation of M. truncatula-Sinorhizobium meliloti symbiosis revealed that MtMIF3 was mainly expressed in the nitrogen-fixing zone of the nodules. Silencing MtMIF3 using RNA interference (Ri) technology resulted in increased nodule numbers but higher levels of bacteroid degradation in the infected cells of the nitrogen-fixing zone, suggesting that premature aging was induced in MtMIF3-Ri nodules. In agreement with this conclusion, the activities of nitrogenase, superoxide dismutase and catalase were lower than those in controls, but cysteine proteinase activity was increased in nodulated roots at 28 days postinoculation. In contrast, the overexpression of MtMIF3 inhibited nodule senescence. MtMIF3 is localized in the plasma membrane, nucleus, and cytoplasm, where it interacts with methionine sulfoxide reductase B (MsrB), which is also localized in the chloroplasts of tobacco leaf cells. Taken together, these results suggest that MtMIF3 prevents premature nodule aging and protects against oxidation by interacting with MtMsrB.
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Affiliation(s)
- Li Wang
- State Key Laboratory of Crop Stress Biology in Arid Areas, Shaanxi Key Laboratory of Agricultural and Environmental Microbiology, College of Life Sciences, Northwest A&F University, Yangling, Shaanxi, People's Republic of China
| | - Jieyu Yang
- State Key Laboratory of Crop Stress Biology in Arid Areas, Shaanxi Key Laboratory of Agricultural and Environmental Microbiology, College of Life Sciences, Northwest A&F University, Yangling, Shaanxi, People's Republic of China
| | - Wenjun Tan
- State Key Laboratory of Crop Stress Biology in Arid Areas, Shaanxi Key Laboratory of Agricultural and Environmental Microbiology, College of Life Sciences, Northwest A&F University, Yangling, Shaanxi, People's Republic of China
| | - Yile Guo
- State Key Laboratory of Crop Stress Biology in Arid Areas, Shaanxi Key Laboratory of Agricultural and Environmental Microbiology, College of Life Sciences, Northwest A&F University, Yangling, Shaanxi, People's Republic of China
| | - Jiaqi Li
- State Key Laboratory of Crop Stress Biology in Arid Areas, Shaanxi Key Laboratory of Agricultural and Environmental Microbiology, College of Life Sciences, Northwest A&F University, Yangling, Shaanxi, People's Republic of China
| | - Chuntao Duan
- State Key Laboratory of Crop Stress Biology in Arid Areas, Shaanxi Key Laboratory of Agricultural and Environmental Microbiology, College of Life Sciences, Northwest A&F University, Yangling, Shaanxi, People's Republic of China
| | - Gehong Wei
- State Key Laboratory of Crop Stress Biology in Arid Areas, Shaanxi Key Laboratory of Agricultural and Environmental Microbiology, College of Life Sciences, Northwest A&F University, Yangling, Shaanxi, People's Republic of China
| | - Minxia Chou
- State Key Laboratory of Crop Stress Biology in Arid Areas, Shaanxi Key Laboratory of Agricultural and Environmental Microbiology, College of Life Sciences, Northwest A&F University, Yangling, Shaanxi, People's Republic of China
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11
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Shi X, Wu Y, Ni H, Li M, Qi B, Xu Y. Macrophage migration inhibitory factor (MIF) inhibitor iSO-1 promotes staphylococcal protein A-induced osteogenic differentiation by inhibiting NF-κB signaling pathway. Int Immunopharmacol 2023; 115:109600. [PMID: 36577150 DOI: 10.1016/j.intimp.2022.109600] [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: 10/04/2022] [Revised: 12/02/2022] [Accepted: 12/12/2022] [Indexed: 12/27/2022]
Abstract
BACKGROUND Osteomyelitis is among the most difficult to treat diseases in the field of orthopedics, and there is a lack of effective treatment modalities. Exploring the mechanisms of its development is beneficial for finding molecular targets for treatment. Increasing evidence suggests that macrophage migration inhibitory factor (MIF), as a proinflammatory mediator, is not only involved in various pathophysiological processes of inflammation but also plays an important role in osteogenic differentiation, while its specific regulatory mechanism in osteomyelitis remains unclear. METHODS In the present study, staphylococcal protein A (SPA)-treated rat bone marrow mesenchymal stem cells (rBMSCs) were used to construct cell models of osteomyelitis. Rat and cell models of osteomyelitis were used to validate the expression levels of MIF, and to further explore the regulatory mechanisms of the MIF inhibitor methyl ester of (S, R)-3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid (iSO-1) and MIF knockdown on cell model of osteomyelitis toward osteogenic differentiation. RESULTS We found that the expression level of MIF was upregulated in rat and cell models of osteomyelitis and subsequently demonstrated by the GSE30119 dataset that the expression level of MIF was also significantly upregulated in patients with osteomyelitis. Furthermore, SPA promotes MIF expression in rBMSCs while inhibiting the expression of osteogenic-related genes such as Runt-related transcription factor 2 (RUNX2), osteocalcin (OCN), osteopontin (OPN) and collagen type-1 (COL-1) through activation of the nuclear factor kappa-B (NF-κB) pathway. In vivo, we further demonstrated that local injection of iSO-1 significantly increased the osteogenic activity in rat model of osteomyelitis. Importantly, we also demonstrated that MIF knockdown and the MIF inhibitor iSO-1 reversed the SPA-mediated inhibition of osteogenic differentiation of rBMSCs by inhibiting the activation of the NF-κB pathway, as evidenced by the upregulation of osteogenic-related gene expression and enhanced bone mineralization. CONCLUSION ISO-1 and MIF knockdown can reverse the SPA-mediated inhibition of osteogenic differentiation in the rBMSCs model of osteomyelitis by inhibiting the NF-κB signaling pathway, providing a potential target for the treatment of osteomyelitis.
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Affiliation(s)
| | - Yipeng Wu
- Department of Orthopedic Surgery, 920th Hospital of Joint Logistics Support Force, Kunming, China
| | - Haonan Ni
- Kunming Medical University, Kunming, China
| | - Mingjun Li
- Kunming Medical University, Kunming, China
| | | | - Yongqing Xu
- Department of Orthopedic Surgery, 920th Hospital of Joint Logistics Support Force, Kunming, China.
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12
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Maiese K. The Metabolic Basis for Nervous System Dysfunction in Alzheimer's Disease, Parkinson's Disease, and Huntington's Disease. Curr Neurovasc Res 2023; 20:314-333. [PMID: 37488757 PMCID: PMC10528135 DOI: 10.2174/1567202620666230721122957] [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: 05/04/2023] [Revised: 06/10/2023] [Accepted: 06/19/2023] [Indexed: 07/26/2023]
Abstract
Disorders of metabolism affect multiple systems throughout the body but may have the greatest impact on both central and peripheral nervous systems. Currently available treatments and behavior changes for disorders that include diabetes mellitus (DM) and nervous system diseases are limited and cannot reverse the disease burden. Greater access to healthcare and a longer lifespan have led to an increased prevalence of metabolic and neurodegenerative disorders. In light of these challenges, innovative studies into the underlying disease pathways offer new treatment perspectives for Alzheimer's Disease, Parkinson's Disease, and Huntington's Disease. Metabolic disorders are intimately tied to neurodegenerative diseases and can lead to debilitating outcomes, such as multi-nervous system disease, susceptibility to viral pathogens, and long-term cognitive disability. Novel strategies that can robustly address metabolic disease and neurodegenerative disorders involve a careful consideration of cellular metabolism, programmed cell death pathways, the mechanistic target of rapamycin (mTOR) and its associated pathways of mTOR Complex 1 (mTORC1), mTOR Complex 2 (mTORC2), AMP-activated protein kinase (AMPK), growth factor signaling, and underlying risk factors such as the apolipoprotein E (APOE-ε4) gene. Yet, these complex pathways necessitate comprehensive understanding to achieve clinical outcomes that target disease susceptibility, onset, and progression.
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Affiliation(s)
- Kenneth Maiese
- Cellular and Molecular Signaling, New York, New York 10022
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13
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Al-Azab M, Safi M, Idiiatullina E, Al-Shaebi F, Zaky MY. Aging of mesenchymal stem cell: machinery, markers, and strategies of fighting. Cell Mol Biol Lett 2022; 27:69. [PMID: 35986247 PMCID: PMC9388978 DOI: 10.1186/s11658-022-00366-0] [Citation(s) in RCA: 62] [Impact Index Per Article: 20.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Accepted: 07/18/2022] [Indexed: 02/08/2023] Open
Abstract
Human mesenchymal stem cells (MSCs) are primary multipotent cells capable of differentiating into osteocytes, chondrocytes, and adipocytes when stimulated under appropriate conditions. The role of MSCs in tissue homeostasis, aging-related diseases, and cellular therapy is clinically suggested. As aging is a universal problem that has large socioeconomic effects, an improved understanding of the concepts of aging can direct public policies that reduce its adverse impacts on the healthcare system and humanity. Several studies of aging have been carried out over several years to understand the phenomenon and different factors affecting human aging. A reduced ability of adult stem cell populations to reproduce and regenerate is one of the main contributors to the human aging process. In this context, MSCs senescence is a major challenge in front of cellular therapy advancement. Many factors, ranging from genetic and metabolic pathways to extrinsic factors through various cellular signaling pathways, are involved in regulating the mechanism of MSC senescence. To better understand and reverse cellular senescence, this review highlights the underlying mechanisms and signs of MSC cellular senescence, and discusses the strategies to combat aging and cellular senescence.
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14
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Mabotuwana NS, Rech L, Lim J, Hardy SA, Murtha LA, Rainer PP, Boyle AJ. Paracrine Factors Released by Stem Cells of Mesenchymal Origin and their Effects in Cardiovascular Disease: A Systematic Review of Pre-clinical Studies. Stem Cell Rev Rep 2022; 18:2606-2628. [PMID: 35896860 PMCID: PMC9622561 DOI: 10.1007/s12015-022-10429-6] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/12/2022] [Indexed: 11/30/2022]
Abstract
Mesenchymal stem cell (MSC) therapy has gained significant traction in the context of cardiovascular repair, and have been proposed to exert their regenerative effects via the secretion of paracrine factors. In this systematic review, we examined the literature and consolidated available evidence for the "paracrine hypothesis". Two Ovid SP databases were searched using a strategy encompassing paracrine mediated MSC therapy in the context of ischemic heart disease. This yielded 86 articles which met the selection criteria for inclusion in this study. We found that the MSCs utilized in these articles were primarily derived from bone marrow, cardiac tissue, and adipose tissue. We identified 234 individual protective factors across these studies, including VEGF, HGF, and FGF2; which are proposed to exert their effects in a paracrine manner. The data collated in this systematic review identifies secreted paracrine factors that could decrease apoptosis, and increase angiogenesis, cell proliferation, and cell viability. These included studies have also demonstrated that the administration of MSCs and indirectly, their secreted factors can reduce infarct size, and improve left ventricular ejection fraction, contractility, compliance, and vessel density. Furthering our understanding of the way these factors mediate repair could lead to the identification of therapeutic targets for cardiac regeneration.
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Affiliation(s)
- Nishani S Mabotuwana
- College of Health, Medicine and Wellbeing, The University of Newcastle, Newcastle, NSW, Australia
- Hunter Medical Research Institute, Lot 1, Kookaburra Circuit, Newcastle, NSW, 2305, Australia
- Department of Internal Medicine, Division of Cardiology, Medical University of Graz, Graz, Austria
| | - Lavinia Rech
- Department of Internal Medicine, Division of Cardiology, Medical University of Graz, Graz, Austria
- Department of Cardiac Surgery, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA
| | - Joyce Lim
- College of Health, Medicine and Wellbeing, The University of Newcastle, Newcastle, NSW, Australia
- Hunter Medical Research Institute, Lot 1, Kookaburra Circuit, Newcastle, NSW, 2305, Australia
- Department of Cardiovascular Medicine, John Hunter Hospital, Newcastle, NSW, Australia
| | - Sean A Hardy
- College of Health, Medicine and Wellbeing, The University of Newcastle, Newcastle, NSW, Australia
- Hunter Medical Research Institute, Lot 1, Kookaburra Circuit, Newcastle, NSW, 2305, Australia
- Department of Internal Medicine, Division of Cardiology, Medical University of Graz, Graz, Austria
| | - Lucy A Murtha
- College of Health, Medicine and Wellbeing, The University of Newcastle, Newcastle, NSW, Australia
- Hunter Medical Research Institute, Lot 1, Kookaburra Circuit, Newcastle, NSW, 2305, Australia
| | - Peter P Rainer
- Department of Internal Medicine, Division of Cardiology, Medical University of Graz, Graz, Austria
- BioTechMed Graz, Graz, Austria
| | - Andrew J Boyle
- College of Health, Medicine and Wellbeing, The University of Newcastle, Newcastle, NSW, Australia.
- Hunter Medical Research Institute, Lot 1, Kookaburra Circuit, Newcastle, NSW, 2305, Australia.
- Department of Cardiovascular Medicine, John Hunter Hospital, Newcastle, NSW, Australia.
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15
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Calls A, Torres‐Espin A, Tormo M, Martínez‐Escardó L, Bonet N, Casals F, Navarro X, Yuste VJ, Udina E, Bruna J. A transient inflammatory response contributes to oxaliplatin neurotoxicity in mice. Ann Clin Transl Neurol 2022; 9:1985-1998. [PMID: 36369764 PMCID: PMC9735376 DOI: 10.1002/acn3.51691] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Revised: 10/14/2022] [Accepted: 10/16/2022] [Indexed: 11/13/2022] Open
Abstract
OBJECTIVES Peripheral neuropathy is a relevant dose-limiting adverse event that can affect up to 90% of oncologic patients with colorectal cancer receiving oxaliplatin treatment. The severity of neurotoxicity often leads to dose reduction or even premature cessation of chemotherapy. Unfortunately, the limited knowledge about the molecular mechanisms related to oxaliplatin neurotoxicity leads to a lack of effective treatments to prevent the development of this clinical condition. In this context, the present work aimed to determine the exact molecular mechanisms involved in the development of oxaliplatin neurotoxicity in a murine model to try to find new therapeutical targets. METHODS By single-cell RNA sequencing (scRNA-seq), we studied the transcriptomic profile of sensory neurons and satellite glial cells (SGC) of the Dorsal Root Ganglia (DRG) from a well-characterized mouse model of oxaliplatin neurotoxicity. RESULTS Analysis of scRNA-seq data pointed to modulation of inflammatory processes in response to oxaliplatin treatment. In this line, we observed increased levels of NF-kB p65 protein, pro-inflammatory cytokines, and immune cell infiltration in DRGs and peripheral nerves of oxaliplatin-treated mice, which was accompanied by mechanical allodynia and decrease in sensory nerve amplitudes. INTERPRETATION Our data show that, in addition to the well-described DNA damage, oxaliplatin neurotoxicity is related to an exacerbated pro-inflammatory response in DRG and peripheral nerves, and open new insights in the development of anti-inflammatory strategies as a treatment for preventing peripheral neuropathy induced by oxaliplatin.
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Affiliation(s)
- Aina Calls
- Department of Cell Biology, Physiology, and Immunology, Institute of NeuroscienceUniversitat Autònoma de BarcelonaBellaterraSpain,Biomedical Research Center Network on Neurodegenerative Diseases (CIBERNED)BellaterraSpain
| | - Abel Torres‐Espin
- Department of Neurological Surgery, Brain and Spinal Injury CenterUniversity of California San FranciscoSan FranciscoCaliforniaUSA
| | - Marc Tormo
- Genomics Core Facility, Departament de Ciències Experimentals i de la SalutUniversitat Pompeu Fabra, Parc de Recerca Biomèdica de BarcelonaBarcelonaSpain,Scientific IT Core Facility, Departament de Ciències Experimentals i de la SalutUniversitat Pompeu Fabra, Parc de Recerca Biomèdica de BarcelonaBarcelonaSpain
| | - Laura Martínez‐Escardó
- Department of Biochemistry, Institute of NeuroscienceUniversitat Autònoma de BarcelonaBellaterraSpain
| | - Núria Bonet
- Genomics Core Facility, Departament de Ciències Experimentals i de la SalutUniversitat Pompeu Fabra, Parc de Recerca Biomèdica de BarcelonaBarcelonaSpain
| | - Ferran Casals
- Genomics Core Facility, Departament de Ciències Experimentals i de la SalutUniversitat Pompeu Fabra, Parc de Recerca Biomèdica de BarcelonaBarcelonaSpain,Departament de Genètica, Microbiologia i Estadística, Facultat de BiologiaUniversitat de BarcelonaBarcelonaSpain
| | - Xavier Navarro
- Department of Cell Biology, Physiology, and Immunology, Institute of NeuroscienceUniversitat Autònoma de BarcelonaBellaterraSpain,Biomedical Research Center Network on Neurodegenerative Diseases (CIBERNED)BellaterraSpain
| | - Víctor J. Yuste
- Department of Biochemistry, Institute of NeuroscienceUniversitat Autònoma de BarcelonaBellaterraSpain
| | - Esther Udina
- Department of Cell Biology, Physiology, and Immunology, Institute of NeuroscienceUniversitat Autònoma de BarcelonaBellaterraSpain,Biomedical Research Center Network on Neurodegenerative Diseases (CIBERNED)BellaterraSpain
| | - Jordi Bruna
- Department of Cell Biology, Physiology, and Immunology, Institute of NeuroscienceUniversitat Autònoma de BarcelonaBellaterraSpain,Biomedical Research Center Network on Neurodegenerative Diseases (CIBERNED)BellaterraSpain,Unit of Neuro‐Oncology, Hospital Universitari de BellvitgeBellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet de LlobregatBarcelonaSpain
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16
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Suresh V, Dash P, Suklabaidya S, Murmu KC, Sasmal PK, Jogdand GM, Parida D, Sethi M, Das B, Mohapatra D, Saha S, Prasad P, Satoskar A, Senapati S. MIF confers survival advantage to pancreatic CAFs by suppressing interferon pathway-induced p53-dependent apoptosis. FASEB J 2022; 36:e22449. [PMID: 35839070 DOI: 10.1096/fj.202101953r] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Revised: 06/22/2022] [Accepted: 06/30/2022] [Indexed: 11/11/2022]
Abstract
The presence of activated pancreatic stellate cells (PSCs) in the pancreatic ductal adenocarcinoma (PDAC) microenvironment plays a significant role in cancer progression. Macrophage migration inhibitory factor (MIF) is overexpressed in PDAC tissues and expressed by both cancer and stromal cells. The pathophysiological role of MIF in PDAC-associated fibroblasts or PSCs is yet to be elucidated. Here we report that the PSCs of mouse or cancer-associated fibroblast cells (CAFs) of human expresses MIF and its receptors, whose expression gets upregulated upon LPS or TNF-α stimulation. In vitro functional experiments showed that MIF significantly conferred a survival advantage to CAFs/PSCs upon growth factor deprivation. Genetic or pharmacological inhibition of MIF also corroborated these findings. Further, co-injection of mouse pancreatic cancer cells with PSCs isolated from Mif-/- or Mif+/+ mice confirmed the pro-survival effect of MIF in PSCs and also demonstrated the pro-tumorigenic role of MIF expressed by CAFs in vivo. Differential gene expression analysis and in vitro mechanistic studies indicated that MIF expressed by activated CAFs/PSCs confers a survival advantage to these cells by suppression of interferon pathway induced p53 dependent apoptosis.
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Affiliation(s)
- Voddu Suresh
- Tumor Microenvironment and Animal Models Lab, Department of Cancer Biology, Institute of Life Sciences, Bhubaneswar, India
- Regional Centre for Biotechnology, Faridabad, India
| | - Pujarini Dash
- Tumor Microenvironment and Animal Models Lab, Department of Cancer Biology, Institute of Life Sciences, Bhubaneswar, India
| | - Sujit Suklabaidya
- Tumor Microenvironment and Animal Models Lab, Department of Cancer Biology, Institute of Life Sciences, Bhubaneswar, India
| | - Krushna Chandra Murmu
- Regional Centre for Biotechnology, Faridabad, India
- Epigenetic and Chromatin Biology Unit, Institute of Life Sciences, Bhubaneswar, India
| | - Prakash K Sasmal
- Department of General Surgery, All India Institute of Medical Sciences, Bhubaneswar, India
| | - Gajendra M Jogdand
- Infectious Disease Biology, Institute of Life Sciences, Bhubaneswar, India
| | - Deepti Parida
- Tumor Microenvironment and Animal Models Lab, Department of Cancer Biology, Institute of Life Sciences, Bhubaneswar, India
- Regional Centre for Biotechnology, Faridabad, India
| | - Manisha Sethi
- Tumor Microenvironment and Animal Models Lab, Department of Cancer Biology, Institute of Life Sciences, Bhubaneswar, India
- Regional Centre for Biotechnology, Faridabad, India
| | - Biswajit Das
- Tumor Microenvironment and Animal Models Lab, Department of Cancer Biology, Institute of Life Sciences, Bhubaneswar, India
| | - Debasish Mohapatra
- Tumor Microenvironment and Animal Models Lab, Department of Cancer Biology, Institute of Life Sciences, Bhubaneswar, India
- Kalinga Institute of Industrial Technology, Bhubaneswar, India
| | - Subha Saha
- Regional Centre for Biotechnology, Faridabad, India
- Epigenetic and Chromatin Biology Unit, Institute of Life Sciences, Bhubaneswar, India
| | - Punit Prasad
- Epigenetic and Chromatin Biology Unit, Institute of Life Sciences, Bhubaneswar, India
| | - Abhay Satoskar
- Department of Microbiology, The Ohio State University, Columbus, Ohio, USA
| | - Shantibhusan Senapati
- Tumor Microenvironment and Animal Models Lab, Department of Cancer Biology, Institute of Life Sciences, Bhubaneswar, India
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17
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Matta A, Nader V, Lebrin M, Gross F, Prats AC, Cussac D, Galinier M, Roncalli J. Pre-Conditioning Methods and Novel Approaches with Mesenchymal Stem Cells Therapy in Cardiovascular Disease. Cells 2022; 11:1620. [PMID: 35626657 PMCID: PMC9140025 DOI: 10.3390/cells11101620] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Revised: 05/08/2022] [Accepted: 05/10/2022] [Indexed: 02/04/2023] Open
Abstract
Transplantation of mesenchymal stem cells (MSCs) in the setting of cardiovascular disease, such as heart failure, cardiomyopathy and ischemic heart disease, has been associated with good clinical outcomes in several trials. A reduction in left ventricular remodeling, myocardial fibrosis and scar size, an improvement in endothelial dysfunction and prolonged cardiomyocytes survival were reported. The regenerative capacity, in addition to the pro-angiogenic, anti-apoptotic and anti-inflammatory effects represent the main target properties of these cells. Herein, we review the different preconditioning methods of MSCs (hypoxia, chemical and pharmacological agents) and the novel approaches (genetically modified MSCs, MSC-derived exosomes and engineered cardiac patches) suggested to optimize the efficacy of MSC therapy.
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Affiliation(s)
- Anthony Matta
- Department of Cardiology, Institute CARDIOMET, University Hospital of Toulouse, 31059 Toulouse, France; (A.M.); (V.N.); (M.L.); (F.G.); (M.G.)
- Faculty of Medicine, Holy Spirit University of Kaslik, Kaslik 446, Lebanon
- Department of Cardiology, Intercommunal Hospital Centre Castres-Mazamet, 81100 Castres, France
| | - Vanessa Nader
- Department of Cardiology, Institute CARDIOMET, University Hospital of Toulouse, 31059 Toulouse, France; (A.M.); (V.N.); (M.L.); (F.G.); (M.G.)
- Faculty of Pharmacy, Lebanese University, Beirut 6573/14, Lebanon
| | - Marine Lebrin
- Department of Cardiology, Institute CARDIOMET, University Hospital of Toulouse, 31059 Toulouse, France; (A.M.); (V.N.); (M.L.); (F.G.); (M.G.)
- CIC-Biotherapies, University Hospital of Toulouse, 31059 Toulouse, France
| | - Fabian Gross
- Department of Cardiology, Institute CARDIOMET, University Hospital of Toulouse, 31059 Toulouse, France; (A.M.); (V.N.); (M.L.); (F.G.); (M.G.)
- CIC-Biotherapies, University Hospital of Toulouse, 31059 Toulouse, France
| | | | - Daniel Cussac
- INSERM I2MC—UMR1297, 31432 Toulouse, France; (A.-C.P.); (D.C.)
| | - Michel Galinier
- Department of Cardiology, Institute CARDIOMET, University Hospital of Toulouse, 31059 Toulouse, France; (A.M.); (V.N.); (M.L.); (F.G.); (M.G.)
| | - Jerome Roncalli
- Department of Cardiology, Institute CARDIOMET, University Hospital of Toulouse, 31059 Toulouse, France; (A.M.); (V.N.); (M.L.); (F.G.); (M.G.)
- CIC-Biotherapies, University Hospital of Toulouse, 31059 Toulouse, France
- INSERM I2MC—UMR1297, 31432 Toulouse, France; (A.-C.P.); (D.C.)
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18
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Liu L, Xu S, Li P, Li L. A novel adipokine WISP1 attenuates lipopolysaccharide-induced cell injury in 3T3-L1 adipocytes by regulating the PI3K/Akt pathway. Obes Res Clin Pract 2022; 16:122-129. [PMID: 35431155 DOI: 10.1016/j.orcp.2022.03.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Revised: 02/07/2022] [Accepted: 03/15/2022] [Indexed: 11/18/2022]
Abstract
BACKGROUND To study the effect of WISP1 on lipopolysaccharide (LPS)-induced cell injury in 3T3-L1 adipocytes. METHOD Lentivirus was transiently transfected into log phase 3T3-L1 adipocytes, which were then treated with LPS at a concentration of 10 μg/mL for 24 h. The cells were divided into the following groups: group A (control, untreated cells); group B (LPS-treated cells); group C (GFP), cells transfected with lentivirus-containing GFP; group D (GFP+LPS), group C treated with LPS;group E (WISP1OE), cells transfected with lentivirus, group F (shNC+LPS), cells transfected with lentivirus-containing nshRNA treated with LPS; group G (shWISP1 +LPS), cells transfected with lentivirus-containing shRNA treated with LPS; group H (WISP1OE+LPS), group E treated with LPS; group I (WISP1OE+LPS+LY294002), group E treated with LPS followed by LY294002 for 24 h. RESULTS WISP1 overexpression notably ameliorated cell apoptosis, accompanied with the increased expression of bcl-2, the decreased expressions of bax and cleaved-caspase-3, and promoted the release of inflammatory factors, such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in LPS-treated 3T3-L1 adipocytes. WISP1 knockdown exhibited the opposite results. In addition, WISP1 stimulated Akt phosphorylation and reduced nuclear translocation of Fork head box protein O3 (FoxO3a) in 3T3-L1 adipocytes treated by LPS. The inhibition of the PI3K/Akt signaling pathway diminished the protective effect of WISP1. CONCLUSION WISP1 prevents 3T3-L1 adipocytes from being injured by LPS by regulating the PI3K/Akt pathway.
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Affiliation(s)
- Lichao Liu
- Department of Endocrinology, The Second Hospital of Dalian Medical University, Dalian 116027, Liaoning, China
| | - Shiting Xu
- Department of Endocrinology, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning, China
| | - Ping Li
- Department of Endocrinology, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning, China.
| | - Ling Li
- Department of Endocrinology, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning, China.
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19
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Weng Z, Wang Y, Ouchi T, Liu H, Qiao X, Wu C, Zhao Z, Li L, Li B. OUP accepted manuscript. Stem Cells Transl Med 2022; 11:356-371. [PMID: 35485439 PMCID: PMC9052415 DOI: 10.1093/stcltm/szac004] [Citation(s) in RCA: 122] [Impact Index Per Article: 40.7] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Accepted: 12/19/2021] [Indexed: 11/14/2022] Open
Affiliation(s)
| | | | - Takehito Ouchi
- Department of Physiology, Tokyo Dental College, Tokyo, Japan
| | - Hanghang Liu
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Oral Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, People’s Republic of China
| | - Xianghe Qiao
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Head and Neck Oncology, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, People’s Republic of China
| | - Chenzhou Wu
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Head and Neck Oncology, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, People’s Republic of China
| | - Zhihe Zhao
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, People’s Republic of China
| | - Longjiang Li
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Head and Neck Oncology, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, People’s Republic of China
| | - Bo Li
- Corresponding author: Bo Li, DDS, PhD, State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, No.14, 3rd Section of Ren Min Nan Rd. Chengdu, Sichuan 610041, People’s Republic of China.
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20
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Tumorigenic Aspects of MSC Senescence-Implication in Cancer Development and Therapy. J Pers Med 2021; 11:jpm11111133. [PMID: 34834485 PMCID: PMC8618265 DOI: 10.3390/jpm11111133] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Revised: 10/28/2021] [Accepted: 10/29/2021] [Indexed: 12/13/2022] Open
Abstract
As an organism ages, many physiological processes change, including the immune system. This process, called immunosenescence, characterized by abnormal activation and imbalance of innate and adaptive immunity, leads to a state of chronic low-grade systemic inflammation, termed inflammaging. Aging and inflammaging are considered to be the root of many diseases of the elderly, as infections, autoimmune and chronic inflammatory diseases, degenerative diseases, and cancer. The role of mesenchymal stromal/stem cells (MSCs) in the inflammaging process and the age-related diseases is not completely established, although numerous features of aging MSCs, including altered immunomodulatory properties, impeded MSC niche supporting functions, and senescent MSC secretory repertoire are consistent with inflammaging development. Although senescence has its physiological function and can represent a mechanism of tumor prevention, in most cases it eventually transforms into a deleterious (para-)inflammatory process that promotes tumor growth. In this review we are going through current literature, trying to explore the role of senescent MSCs in making and/or sustaining a microenvironment permissive to tumor development and to analyze the therapeutic options that could target this process.
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21
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Woods K, Guezguez B. Dynamic Changes of the Bone Marrow Niche: Mesenchymal Stromal Cells and Their Progeny During Aging and Leukemia. Front Cell Dev Biol 2021; 9:714716. [PMID: 34447754 PMCID: PMC8383146 DOI: 10.3389/fcell.2021.714716] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Accepted: 07/22/2021] [Indexed: 12/11/2022] Open
Abstract
Mesenchymal stromal cells (MSCs) are a heterogenous cell population found in a wide range of tissues in the body, known for their nutrient-producing and immunomodulatory functions. In the bone marrow (BM), these MSCs are critical for the regulation of hematopoietic stem cells (HSC) that are responsible for daily blood production and functional immunity throughout an entire organism's lifespan. Alongside other stromal cells, MSCs form a specialized microenvironment BM tissue called "niche" that tightly controls HSC self-renewal and differentiation. In addition, MSCs are crucial players in maintaining bone integrity and supply of hormonal nutrients due to their capacity to differentiate into osteoblasts and adipocytes which also contribute to cellular composition of the BM niche. However, MSCs are known to encompass a large heterogenous cell population that remains elusive and poorly defined. In this review, we focus on deciphering the BM-MSC biology through recent advances in single-cell identification of hierarchical subsets with distinct functionalities and transcriptional profiles. We also discuss the contribution of MSCs and their osteo-adipo progeny in modulating the complex direct cell-to-cell or indirect soluble factors-mediated interactions of the BM HSC niche during homeostasis, aging and myeloid malignancies. Lastly, we examine the therapeutic potential of MSCs for rejuvenation and anti-tumor remedy in clinical settings.
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Affiliation(s)
- Kevin Woods
- German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany
- Department of Hematology and Oncology, University Medical Center Mainz, Mainz, Germany
- German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Borhane Guezguez
- German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany
- Department of Hematology and Oncology, University Medical Center Mainz, Mainz, Germany
- German Cancer Research Center (DKFZ), Heidelberg, Germany
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22
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Hofmann E, Soppert J, Ruhl T, Gousopoulos E, Gerra S, Storti G, Tian Y, Brandhofer M, Schweizer R, Song SY, Lindenblatt N, Pallua N, Bernhagen J, Kim BS. The Role of Macrophage Migration Inhibitory Factor in Adipose-Derived Stem Cells Under Hypoxia. Front Physiol 2021; 12:638448. [PMID: 34366876 PMCID: PMC8334873 DOI: 10.3389/fphys.2021.638448] [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: 12/06/2020] [Accepted: 06/21/2021] [Indexed: 01/04/2023] Open
Abstract
Background: Adipose-derived stem cells (ASCs) are multipotent mesenchymal stem cells characterized by their strong regenerative potential and low oxygen consumption. Macrophage migration inhibitory factor (MIF) is a multifunctional chemokine-like cytokine that is involved in tissue hypoxia. MIF is not only a major immunomodulator but also is highly expressed in adipose tissue such as subcutaneous adipose tissue of chronic non-healing wounds. In the present study, we investigated the effect of hypoxia on MIF in ASCs isolated from healthy versus inflamed adipose tissue. Methods: Human ASCs were harvested from 17 patients (11 healthy adipose tissue samples, six specimens from chronic non-healing wounds). ASCs were treated in a hypoxia chamber at <1% oxygen. ASC viability, MIF secretion as well as expression levels of MIF, its receptor CD74, hypoxia-inducible transcription factor-1α (HIF-1α) and activation of the AKT and ERK signaling pathways were analyzed. The effect of recombinant MIF on the viability of ASCs was determined. Finally, the effect of MIF on the viability and production capacity of ASCs to produce the inflammatory cytokines tumor necrosis factor (TNF), interleukin (IL)-6, and IL-1β was determined upon treatment with recombinant MIF and/or a blocking MIF antibody. Results: Hypoxic treatment inhibited proliferation of ASCs derived from healthy or chronic non-healing wounds. ASCs from healthy adipose tissue samples were characterized by a low degree of MIF secretion during hypoxic challenge. In contrast, in ASCs from adipose tissue samples of chronic non-healing wounds, secretion and expression of MIF and CD74 expression were significantly elevated under hypoxia. This was accompanied by enhanced ERK signaling, while AKT signaling was not altered. Recombinant MIF did stimulate HIF-1α expression under hypoxia as well as AKT and ERK phosphorylation, while no effect on ASC viability was observed. Recombinant MIF significantly reduced the secretion of IL-1β under hypoxia and normoxia, and neutralizing MIF-antibodies diminished TNF-α and IL-1β release in hypoxic ASCs. Conclusions: Collectively, MIF did not affect the viability of ASCs from neither healthy donor site nor chronic wounds. Our results, however, suggest that MIF has an impact on the wound environment by modulating inflammatory factors such as IL-1β.
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Affiliation(s)
- Elena Hofmann
- Department of Plastic Surgery and Hand Surgery-Burn Center, University Hospital RWTH Aachen, Aachen, Germany.,Institute of Biochemistry and Molecular Cell Biology, University Hospital RWTH Aachen, Aachen, Germany
| | - Josefin Soppert
- Institute of Biochemistry and Molecular Cell Biology, University Hospital RWTH Aachen, Aachen, Germany.,Institute for Molecular Cardiovascular Research, University Hospital RWTH Aachen, Aachen, Germany.,Department of Intensive Care and Intermediate Care, University Hospital RWTH Aachen, Aachen, Germany
| | - Tim Ruhl
- Department of Plastic Surgery and Hand Surgery-Burn Center, University Hospital RWTH Aachen, Aachen, Germany
| | - Epameinondas Gousopoulos
- Department of Plastic Surgery and Hand Surgery, University Hospital of Zürich, Zurich, Switzerland
| | - Simona Gerra
- Chair of Vascular Biology, Institute for Stroke and Dementia Research (ISD), LMU University Hospital, Ludwig Maximilian University of Munich (LMU), Munich, Germany
| | - Gabriele Storti
- Plastic and Reconstructive Surgery, Department of Surgical Sciences, University of Rome "Tor Vergata", Rome, Italy
| | - Yuan Tian
- Chair of Vascular Biology, Institute for Stroke and Dementia Research (ISD), LMU University Hospital, Ludwig Maximilian University of Munich (LMU), Munich, Germany
| | - Markus Brandhofer
- Chair of Vascular Biology, Institute for Stroke and Dementia Research (ISD), LMU University Hospital, Ludwig Maximilian University of Munich (LMU), Munich, Germany
| | - Riccardo Schweizer
- Department of Plastic Surgery and Hand Surgery, University Hospital of Zürich, Zurich, Switzerland
| | - Seung-Yong Song
- Department of Plastic and Reconstructive Surgery, Yonsei University College of Medicine, Seoul, South Korea
| | - Nicole Lindenblatt
- Department of Plastic Surgery and Hand Surgery, University Hospital of Zürich, Zurich, Switzerland
| | - Norbert Pallua
- Department of Plastic Surgery and Hand Surgery-Burn Center, University Hospital RWTH Aachen, Aachen, Germany.,Aesthetic Elite International-Private Clinic, Dusseldorf, Germany
| | - Jürgen Bernhagen
- Institute of Biochemistry and Molecular Cell Biology, University Hospital RWTH Aachen, Aachen, Germany.,Chair of Vascular Biology, Institute for Stroke and Dementia Research (ISD), LMU University Hospital, Ludwig Maximilian University of Munich (LMU), Munich, Germany.,Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
| | - Bong-Sung Kim
- Department of Plastic Surgery and Hand Surgery-Burn Center, University Hospital RWTH Aachen, Aachen, Germany.,Institute of Biochemistry and Molecular Cell Biology, University Hospital RWTH Aachen, Aachen, Germany.,Department of Plastic Surgery and Hand Surgery, University Hospital of Zürich, Zurich, Switzerland
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23
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Network Pharmacology/Metabolomics-Based Validation of AMPK and PI3K/AKT Signaling Pathway as a Central Role of Shengqi Fuzheng Injection Regulation of Mitochondrial Dysfunction in Cancer-Related Fatigue. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:5556212. [PMID: 34326918 PMCID: PMC8302405 DOI: 10.1155/2021/5556212] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Revised: 05/06/2021] [Accepted: 06/12/2021] [Indexed: 12/17/2022]
Abstract
Chinese herbal medicines have multiple targets and properties, and their use in multidisciplinary cancer therapies has consequently received increasing attention. Here, we have investigated the possible active ingredients associated with cancer-related fatigue (CRF) in the Shengqi Fuzheng Injection (SFI). In vitro cell models were used to measure the regulation effects of SFI on CRF. Metabolomic analysis was used to identify the potential genes and pathways in C2C12 mouse myoblasts treated with SFI, and the interaction of compounds and CRF targets was predicted using network pharmacology and molecular docking analyses. The putative pathways were further verified using immuno-blotting assays. The results showed that SFI significantly inhibited muscle cell apoptosis and increased the mitochondrial membrane potential of muscle cells. The network pharmacology analysis results identified 36 candidate compounds, and 244 potential targets were yielded by SFI, and they shared 10 key targets associated with cancer-related fatigue. According to the enrichment analysis and experimental validation, SFI might ameliorate muscle cell mitochondrial function by activating AMPK and inhibiting the PI3K/Akt signaling pathways, and the expression changes of mitochondrial metabolic enzymes MnSOD and apoptosis-associated proteins Bax and Bcl-2 were also triggered. The functions and mechanisms of SFI in anticancer-related fatigue were found here to be at least partly due to the targeting of the AMPK and PI3K/Akt signaling pathways, and this has highlighted new potential applications for network pharmacology when researching Chinese Medicines.
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24
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Zhuang L, Xia W, Chen D, Ye Y, Hu T, Li S, Hou M. Exosomal LncRNA-NEAT1 derived from MIF-treated mesenchymal stem cells protected against doxorubicin-induced cardiac senescence through sponging miR-221-3p. J Nanobiotechnology 2020; 18:157. [PMID: 33129330 PMCID: PMC7603694 DOI: 10.1186/s12951-020-00716-0] [Citation(s) in RCA: 70] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2020] [Accepted: 10/21/2020] [Indexed: 02/07/2023] Open
Abstract
Background The chemotherapy drug doxorubicin (Dox) is widely used for treating a variety of cancers. However, its high cardiotoxicity hampered its clinical use. Exosomes derived from stem cells showed a therapeutic effect against Dox-induced cardiomyopathy (DIC). Previous studies reported that exosomes derived from mesenchymal stem cells (MSCs) pretreated with macrophage migration inhibitory factor (MIF) (exosomeMIF) showed a cardioprotective effect through modulating long noncoding RNAs/microRNAs (lncRNAs/miRs). This study aimed to investigate the role of exosomeMIF in the treatment of DIC. Results Exosomes were isolated from control MSCs (exosome) and MIF-pretreated MSCs (exosomeMIF). Regulatory lncRNAs activated by MIF pretreatment were explored using genomics approaches. Fluorescence-labeled exosomes were tracked in vitro by fluorescence imaging. In vivo and in vitro, miR-221-3p mimic transfection enforced miR-221-3p overexpression, and senescence-associated β-galactosidase assay was applied to test cellular senescence. Exosomal delivering LncRNA-NEAT1 induced therapeutic effect in vivo was confirmed by echocardiography. It demonstrated that exosomesMIF recovered the cardiac function and exerted the anti-senescent effect through LncRNA–NEAT1 transfer against Dox. TargetScan and luciferase assay showed that miR-221-3p targeted the Sirt2 3′-untranslated region. Silencing LncRNA–NEAT1 in MSCs, miR-221-3p overexpression or Sirt2 silencing in cardiomyocytes decreased the exosomeMIF-induced anti-senescent effect against Dox. Conclusions The results indicated exosomeMIF serving as a promising anti-senescent effector against Dox-induced cardiotoxicity through LncRNA–NEAT1 transfer, thus inhibiting miR-221-3p and leading to Sirt2 activation. The study proposed that exosomeMIF might have the potential to serve as a cardioprotective therapeutic agent during cancer chemotherapy.![]()
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Affiliation(s)
- Lei Zhuang
- Department of Hepatobiliary Surgery, First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China
| | - Wenzheng Xia
- Department of Neurosurgery, First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China.,Department of Neurosurgery, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, 200092, China
| | - Didi Chen
- Department of Radiation Oncology, First Affiliated Hospital, Wenzhou Medical University, No. 2 Fuxue Lane, Wenzhou, 325000, People's Republic of China
| | - Yijia Ye
- Department of Radiation Oncology, First Affiliated Hospital, Wenzhou Medical University, No. 2 Fuxue Lane, Wenzhou, 325000, People's Republic of China
| | - Tingting Hu
- Department of Radiation Oncology, First Affiliated Hospital, Wenzhou Medical University, No. 2 Fuxue Lane, Wenzhou, 325000, People's Republic of China
| | - Shiting Li
- Department of Neurosurgery, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, 200092, China.
| | - Meng Hou
- Department of Radiation Oncology, First Affiliated Hospital, Wenzhou Medical University, No. 2 Fuxue Lane, Wenzhou, 325000, People's Republic of China.
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25
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Meng QS, Liu J, Wei L, Fan HM, Zhou XH, Liang XT. Senescent mesenchymal stem/stromal cells and restoring their cellular functions. World J Stem Cells 2020; 12:966-985. [PMID: 33033558 PMCID: PMC7524698 DOI: 10.4252/wjsc.v12.i9.966] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Revised: 06/23/2020] [Accepted: 07/19/2020] [Indexed: 02/06/2023] Open
Abstract
Mesenchymal stem/stromal cells (MSCs) have various properties that make them promising candidates for stem cell-based therapies in clinical settings. These include self-renewal, multilineage differentiation, and immunoregulation. However, recent studies have confirmed that aging is a vital factor that limits their function and therapeutic properties as standardized clinical products. Understanding the features of senescence and exploration of cell rejuvenation methods are necessary to develop effective strategies that can overcome the shortage and instability of MSCs. This review will summarize the current knowledge on characteristics and functional changes of aged MSCs. Additionally, it will highlight cell rejuvenation strategies such as molecular regulation, non-coding RNA modifications, and microenvironment controls that may enhance the therapeutic potential of MSCs in clinical settings.
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Affiliation(s)
- Qing-Shu Meng
- Shanghai Heart Failure Research Center, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China
- Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China
- Institute of Integrated Traditional Chinese and Western Medicine for Cardiovascular Chronic Diseases, Tongji University School of Medicine, Shanghai 200120, China
| | - Jing Liu
- Shanghai Heart Failure Research Center, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China
- Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China
- Institute of Integrated Traditional Chinese and Western Medicine for Cardiovascular Chronic Diseases, Tongji University School of Medicine, Shanghai 200120, China
| | - Lu Wei
- Shanghai Heart Failure Research Center, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China
- Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China
- Institute of Integrated Traditional Chinese and Western Medicine for Cardiovascular Chronic Diseases, Tongji University School of Medicine, Shanghai 200120, China
| | - Hui-Min Fan
- Shanghai Heart Failure Research Center, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China
- Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China
- Institute of Integrated Traditional Chinese and Western Medicine for Cardiovascular Chronic Diseases, Tongji University School of Medicine, Shanghai 200120, China
- Department of Heart Failure, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China
| | - Xiao-Hui Zhou
- Shanghai Heart Failure Research Center, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China
- Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China
- Institute of Integrated Traditional Chinese and Western Medicine for Cardiovascular Chronic Diseases, Tongji University School of Medicine, Shanghai 200120, China
| | - Xiao-Ting Liang
- Shanghai Heart Failure Research Center, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China
- Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China
- Institute of Integrated Traditional Chinese and Western Medicine for Cardiovascular Chronic Diseases, Tongji University School of Medicine, Shanghai 200120, China
- Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200120, China.
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26
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Jiang R, Yang T, Zhang Y, Wang Z, Zhang T. LKB1 Promotes the Transformation of Bone Marrow Mesenchymal Stem Cells into Adipocytes Under Oxidative Stress via AMPK-mTOR Signaling Pathway. J Interferon Cytokine Res 2020; 40:370-376. [PMID: 32634329 DOI: 10.1089/jir.2019.0212] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023] Open
Abstract
Bone marrow mesenchymal stem cells (BM-MSCs) are cells with the potential to differentiate into adipocytes in oxidative stress. In this study, tert-butyl hydroperoxide is used as a stimulator that promotes reactive oxygen species in BM-MSCs. The results demonstrate that knockdown of LKB1 inhibits the transformation of BM-MSCs into adipocytes in the presence of oxidative stress. In addition, β3 adrenergic receptor agonists, a positive stimulatory molecule for the transformation of BM-MSCs into adipocytes, restores the transformation ability of BM-MSCs caused by LKB1-siRNA. As an upstream signal of adenosine monophosphate-activated protein kinase (AMPK), LKB1 activates the AMPK pathway and promotes the expression of PPARγ and CCAAT/enhancer binding proteins (C/EBPα). This indicates that the regulation of LKB1 on BM-MSCs is dependent on the AMPK pathway. Immunofluorescence localization experiments reveal that the LKB1 and AMPK localizations partially overlap, oxidative stress promotes their expression in the cytoplasm. In general, LKB1 promotes the transformation of BM-MSCs to adipocytes by activating AMPK pathway under oxidative stress.
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Affiliation(s)
- Rui Jiang
- Department of Orthopaedic Surgery, Shanghai Gongli Hospital, Shanghai, China
| | - Tieyi Yang
- Department of Orthopaedic Surgery, Shanghai Gongli Hospital, Shanghai, China
| | - Yan Zhang
- Department of Orthopaedic Surgery, Shanghai Gongli Hospital, Shanghai, China
| | - Zhi Wang
- Department of Orthopaedic Surgery, Shanghai Gongli Hospital, Shanghai, China
| | - Tong Zhang
- Department of Dermatology, Central Hospital of Minhang District, Shanghai Minhang Hospital, Fudan University, Shanghai, China
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27
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Li DY, Zhang JY, Chen QJ, Liu F, Zhao Q, Gao XM, Li XM, Yang YN. MIF -173G/C (rs755622) polymorphism modulates coronary artery disease risk: evidence from a systematic meta-analysis. BMC Cardiovasc Disord 2020; 20:300. [PMID: 32560699 PMCID: PMC7304150 DOI: 10.1186/s12872-020-01564-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2019] [Accepted: 06/02/2020] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Coronary artery disease (CAD) remains one of the major causes of death in humans. Genetic testing may allow early detection and prevention of this disease. This study aimed to investigate the association between the macrophage migration inhibitory factor (MIF) -173G/C (rs755622) polymorphism and susceptibility to CAD based on a meta-analysis. METHODS We searched several databases to identify observational case-control studies investigating the association between the MIF -173G > C (rs755622) polymorphism and CAD risk published before July 30, 2019. Data were analyzed using the STATA software. RESULTS Six studies, comprising a total of 1172 CAD cases and 1564 controls evaluated for MIF polymorphisms, were included. The occurrence of CAD was found to be associated with the C allele of the MIF rs755622 SNP in the total population (C/G, OR = 1.489, 95% CI = 1.223-1.813). Further, MIF -173G/C polymorphism was significantly associated with CAD under the allelic model in the Asian (C/G, OR = 1.775, 95% CI = 1.365-2.309) and Caucasian (C/G, OR = 1.288, 95% CI 1.003-1.654) subgroups. The data showed that the risk of CAD was higher in the population carrying the C allele. CONCLUSIONS We found evidence of associations between MIF -173C/G and CAD susceptibility in the Asian and Caucasian populations.
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Affiliation(s)
- De-Yang Li
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Department of Cardiology, First Affiliated Hospital of Xinjiang Medical University, Urumqi, China.,Department one of coronary heart disease, First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830011, China
| | - Jin-Yu Zhang
- Rehabilitation department, First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Qing-Jie Chen
- Department one of coronary heart disease, First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830011, China
| | - Fen Liu
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Department of Cardiology, First Affiliated Hospital of Xinjiang Medical University, Urumqi, China.,Department one of coronary heart disease, First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830011, China
| | - Qian Zhao
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Department of Cardiology, First Affiliated Hospital of Xinjiang Medical University, Urumqi, China.,Department one of coronary heart disease, First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830011, China
| | - Xiao-Ming Gao
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Department of Cardiology, First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Xiao-Mei Li
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Department of Cardiology, First Affiliated Hospital of Xinjiang Medical University, Urumqi, China.,Department one of coronary heart disease, First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830011, China
| | - Yi-Ning Yang
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Department of Cardiology, First Affiliated Hospital of Xinjiang Medical University, Urumqi, China. .,Department one of coronary heart disease, First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830011, China.
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28
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Lynch K, Treacy O, Chen X, Murphy N, Lohan P, Islam MN, Donohoe E, Griffin MD, Watson L, McLoughlin S, O'Malley G, Ryan AE, Ritter T. TGF-β1-Licensed Murine MSCs Show Superior Therapeutic Efficacy in Modulating Corneal Allograft Immune Rejection In Vivo. Mol Ther 2020; 28:2023-2043. [PMID: 32531237 PMCID: PMC7474271 DOI: 10.1016/j.ymthe.2020.05.023] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2019] [Revised: 03/14/2020] [Accepted: 05/26/2020] [Indexed: 12/13/2022] Open
Abstract
Mesenchymal stromal cells (MSCs) are a promising therapeutic option for multiple immune diseases/disorders; however, efficacy of MSC treatments can vary significantly. We present a novel licensing strategy to improve the immunosuppressive capacity of MSCs. Licensing murine MSCs with transforming growth factor-β1 (TGF-β MSCs) significantly improved their ability to modulate both the phenotype and secretome of inflammatory bone marrow-derived macrophages and significantly increased the numbers of regulatory T lymphocytes following co-culture assays. These TGF-β MSC-expanded regulatory T lymphocytes also expressed significantly higher levels of PD-L1 and CD73, indicating enhanced suppressive potential. Detailed analysis of T lymphocyte co-cultures revealed modulation of secreted factors, most notably elevated prostaglandin E2 (PGE2). Furthermore, TGF-β MSCs could significantly prolong rejection-free survival (69.2% acceptance rate compared to 21.4% for unlicensed MSC-treated recipients) in a murine corneal allograft model. Mechanistic studies revealed that (1) therapeutic efficacy of TGF-β MSCs is Smad2/3-dependent, (2) the enhanced immunosuppressive capacity of TGF-β MSCs is contact-dependent, and (3) enhanced secretion of PGE2 (via prostaglandin EP4 [E-type prostanoid 4] receptor) by TGF-β MSCs is the predominant mediator of Treg expansion and T cell activation and is associated with corneal allograft survival. Collectively, we provide compelling evidence for the use of TGF-β1 licensing as an unconventional strategy for enhancing MSC immunosuppressive capacity.
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Affiliation(s)
- Kevin Lynch
- Discipline of Pharmacology and Therapeutics, School of Medicine, College of Medicine, Nursing and Health Sciences, National University of Ireland, Galway, Galway, Ireland; Regenerative Medicine Institute (REMEDI), School of Medicine, College of Medicine, Nursing and Health Sciences, National University of Ireland Galway, Galway, Ireland
| | - Oliver Treacy
- Discipline of Pharmacology and Therapeutics, School of Medicine, College of Medicine, Nursing and Health Sciences, National University of Ireland, Galway, Galway, Ireland; Regenerative Medicine Institute (REMEDI), School of Medicine, College of Medicine, Nursing and Health Sciences, National University of Ireland Galway, Galway, Ireland
| | - Xizhe Chen
- Regenerative Medicine Institute (REMEDI), School of Medicine, College of Medicine, Nursing and Health Sciences, National University of Ireland Galway, Galway, Ireland; CÚRAM, SFI Research Centre for Medical Devices, National University of Ireland Galway, Galway, Ireland
| | - Nick Murphy
- Regenerative Medicine Institute (REMEDI), School of Medicine, College of Medicine, Nursing and Health Sciences, National University of Ireland Galway, Galway, Ireland
| | - Paul Lohan
- Regenerative Medicine Institute (REMEDI), School of Medicine, College of Medicine, Nursing and Health Sciences, National University of Ireland Galway, Galway, Ireland
| | - Md Nahidul Islam
- Regenerative Medicine Institute (REMEDI), School of Medicine, College of Medicine, Nursing and Health Sciences, National University of Ireland Galway, Galway, Ireland
| | - Ellen Donohoe
- Regenerative Medicine Institute (REMEDI), School of Medicine, College of Medicine, Nursing and Health Sciences, National University of Ireland Galway, Galway, Ireland
| | - Matthew D Griffin
- Regenerative Medicine Institute (REMEDI), School of Medicine, College of Medicine, Nursing and Health Sciences, National University of Ireland Galway, Galway, Ireland; CÚRAM, SFI Research Centre for Medical Devices, National University of Ireland Galway, Galway, Ireland
| | - Luke Watson
- Orbsen Therapeutics, National University of Ireland, Galway, Galway, Ireland
| | - Steven McLoughlin
- Regenerative Medicine Institute (REMEDI), School of Medicine, College of Medicine, Nursing and Health Sciences, National University of Ireland Galway, Galway, Ireland
| | - Grace O'Malley
- Discipline of Pharmacology and Therapeutics, School of Medicine, College of Medicine, Nursing and Health Sciences, National University of Ireland, Galway, Galway, Ireland; Regenerative Medicine Institute (REMEDI), School of Medicine, College of Medicine, Nursing and Health Sciences, National University of Ireland Galway, Galway, Ireland
| | - Aideen E Ryan
- Discipline of Pharmacology and Therapeutics, School of Medicine, College of Medicine, Nursing and Health Sciences, National University of Ireland, Galway, Galway, Ireland; Regenerative Medicine Institute (REMEDI), School of Medicine, College of Medicine, Nursing and Health Sciences, National University of Ireland Galway, Galway, Ireland; CÚRAM, SFI Research Centre for Medical Devices, National University of Ireland Galway, Galway, Ireland.
| | - Thomas Ritter
- Regenerative Medicine Institute (REMEDI), School of Medicine, College of Medicine, Nursing and Health Sciences, National University of Ireland Galway, Galway, Ireland; CÚRAM, SFI Research Centre for Medical Devices, National University of Ireland Galway, Galway, Ireland.
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29
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Liu J, Ding Y, Liu Z, Liang X. Senescence in Mesenchymal Stem Cells: Functional Alterations, Molecular Mechanisms, and Rejuvenation Strategies. Front Cell Dev Biol 2020; 8:258. [PMID: 32478063 PMCID: PMC7232554 DOI: 10.3389/fcell.2020.00258] [Citation(s) in RCA: 165] [Impact Index Per Article: 33.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2020] [Accepted: 03/27/2020] [Indexed: 12/12/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are multipotent cells capable of self-renewal and differentiation. There is increasing evidence of the therapeutic value of MSCs in various clinical situations, however, these cells gradually lose their regenerative potential with age, with a concomitant increase in cellular dysfunction. Stem cell aging and replicative exhaustion are considered as hallmarks of aging and functional attrition in organisms. MSCs do not proliferate infinitely but undergo only a limited number of population doublings before becoming senescent. This greatly hinders their clinical application, given that cultures must be expanded to obtain a sufficient number of cells for cell-based therapy. Here, we review the current knowledge of the phenotypic and functional characteristics of senescent MSCs, molecular mechanisms underlying MSCs aging, and strategies to rejuvenate senescent MSCs, which can broaden their range of therapeutic applications.
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Affiliation(s)
- Jing Liu
- Research Center for Translational Medicine, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
- Department of Cardiovascular Surgery, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Yue Ding
- Department of Organ Transplantation, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Zhongmin Liu
- Research Center for Translational Medicine, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
- Department of Cardiovascular Surgery, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Xiaoting Liang
- Research Center for Translational Medicine, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
- Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China
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Yang Z, Liu X, Wang L, Wang T, Chen Y, Teng X, Li J, Shao L, Hui J, Ye W, Shen Z. The protective effects of HMGA2 in the senescence process of bone marrow-derived mesenchymal stromal cells. J Tissue Eng Regen Med 2020; 14:588-599. [PMID: 32068957 DOI: 10.1002/term.3023] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2019] [Revised: 12/25/2019] [Accepted: 02/03/2020] [Indexed: 12/15/2022]
Abstract
Bone marrow-derived mesenchymal stromal cells (MSCs) have been wildly applied to cell-based strategies for tissue engineering and regenerative medicine; however, they have to undergo the senescence process and thus appeared to be less therapeutic effective. HMGA2, a protein belonged to high mobility group A (HMGA) family, exhibits an inverse expression level related to embryonic development and acts as a developmental regulator in stem cell self-renewal progression. Therefore, we performed senescence-associated β-galactosidase (SA-β-gal) staining, transwell assay, to examine the changes of MSCs in different stages and then over-expressed HMGA2 in MSCs by lentivirus transfection. We found the percentage of SA-β-gal staining positive cells in MSCs from 24-month-old Sprague-Dawley (SD) rats (O-MSCs) was significantly higher compared with MSCs from 2-week-old SD rats (Y-MSCs), and the expression levels of P21 and P53, two senescence-related molecules, were also significantly up-regulated in O-MSCs than in Y-MSCs. In contrast, the HMGA2 expression level in O-MSCs was dramatically down-regulated in contrast to Y-MSCs. In additional, the migration ability in O-MSCs was significantly attenuated than in Y-MSCs. After successfully over-expressed HMGA2 in O-MSCs, the percentage of SA-β-gal staining positive cells and the expression levels of P21 and P53 were reduced, and the migration ability was improved compared with O-MSCs without treatment. Further, mRNA sequencing analysis revealed that overexpression of HMGA2 changed the expression of genes related to cell proliferation and senescence, such as Lyz2, Pf4, Rgs2, and Mstn. Knockdown of Rgs2 in HMGA2 overexpression O-MSCs could antagonize the protective effect of HMGA2 in the senescence process of O-MSCs.
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Affiliation(s)
- Ziying Yang
- Department of Cardiovascular Surgery, First Affiliated Hospital & Institute for Cardiovascular Science, Soochow University, Suzhou, China
| | - Xuan Liu
- Department of Cardiovascular Surgery, First Affiliated Hospital & Institute for Cardiovascular Science, Soochow University, Suzhou, China
| | - Longgang Wang
- Department of Cardiovascular Surgery, First Affiliated Hospital & Institute for Cardiovascular Science, Soochow University, Suzhou, China
| | - Tao Wang
- Department of Cardiology, First Affiliated Hospital, Soochow University, Suzhou, China
| | - Yueqiu Chen
- Department of Cardiovascular Surgery, First Affiliated Hospital & Institute for Cardiovascular Science, Soochow University, Suzhou, China
| | - Xiaomei Teng
- Department of Cardiovascular Surgery, First Affiliated Hospital & Institute for Cardiovascular Science, Soochow University, Suzhou, China
| | - Jingjing Li
- Department of Cardiovascular Surgery, First Affiliated Hospital & Institute for Cardiovascular Science, Soochow University, Suzhou, China
| | - Lianbo Shao
- Department of Cardiovascular Surgery, First Affiliated Hospital & Institute for Cardiovascular Science, Soochow University, Suzhou, China
| | - Jie Hui
- Department of Cardiology, First Affiliated Hospital, Soochow University, Suzhou, China
| | - Wenxue Ye
- Department of Cardiovascular Surgery, First Affiliated Hospital & Institute for Cardiovascular Science, Soochow University, Suzhou, China
| | - Zhenya Shen
- Department of Cardiovascular Surgery, First Affiliated Hospital & Institute for Cardiovascular Science, Soochow University, Suzhou, China
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Chen H, Xia W, Hou M. LncRNA-NEAT1 from the competing endogenous RNA network promotes cardioprotective efficacy of mesenchymal stem cell-derived exosomes induced by macrophage migration inhibitory factor via the miR-142-3p/FOXO1 signaling pathway. Stem Cell Res Ther 2020; 11:31. [PMID: 31964409 PMCID: PMC6975066 DOI: 10.1186/s13287-020-1556-7] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2019] [Revised: 12/23/2019] [Accepted: 01/08/2020] [Indexed: 02/06/2023] Open
Abstract
Aims Extracellular vesicles, especially exosomes, have emerged as key mediators of intercellular communication with the potential to improve cardiac function as part of cell-based therapies. We previously demonstrated that the cardioprotective factor, macrophage migration inhibitory factor (MIF), had an optimizing effect on mesenchymal stem cells (MSCs). The aim of this study was to determine the protective function of exosomes derived from MIF-pretreated MSCs in cardiomyocytes and to explore the underlying mechanisms. Methods and results Exosomes were isolated from control MSCs (exosome) and MIF-pretreated MSCs (exosomeMIF), and delivered to cardiomyocytes subjected to H2O2 in vitro. Regulatory long non-coding RNAs (lncRNAs) activated by MIF pretreatment were explored using genomics approaches. ExosomeMIF protected cardiomyocytes from H2O2-induced apoptosis. Mechanistically, we identified lncRNA-NEAT1 as a mediator of exosomeMIF by regulating the expression of miR-142-3p and activating Forkhead class O1 (FOXO1). The cardioprotective effects of exosomeMIF were consistently abrogated by depletion of lncRNA-NEAT1, by overexpression of miR-142-3p, or by FOXO1 silencing. Furthermore, exosomeMIF inhibited H2O2-induced apoptosis through modulating oxidative stress. Conclusions Exosomes obtained from MIF-pretreated MSCs have a protective effect on cardiomyocytes. The lncRNA-NEAT1 functions as an anti-apoptotic molecule via competitive endogenous RNA activity towards miR-142-3p. LncRNA-NEAT1/miR-142-3p/FOXO1 at least partially mediates the cardioprotective roles of exosomeMIF in protecting cardiomyocytes from apoptosis.
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Affiliation(s)
- Hanbin Chen
- Department of Radiation Oncology, First Affiliated Hospital, Wenzhou Medical University, No. 2 Fuxue Lane, Wenzhou, 325000, People's Republic of China
| | - Wenzheng Xia
- Department of Neurosurgery, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Meng Hou
- Department of Radiation Oncology, First Affiliated Hospital, Wenzhou Medical University, No. 2 Fuxue Lane, Wenzhou, 325000, People's Republic of China.
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Liu X, Li X, Zhu W, Zhang Y, Hong Y, Liang X, Fan B, Zhao H, He H, Zhang F. Exosomes from mesenchymal stem cells overexpressing MIF enhance myocardial repair. J Cell Physiol 2020; 235:8010-8022. [PMID: 31960418 DOI: 10.1002/jcp.29456] [Citation(s) in RCA: 72] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2019] [Accepted: 01/06/2020] [Indexed: 12/22/2022]
Abstract
Accumulating evidence has shown that mesenchymal stem cell (MSC)-derived exosomes (exo) mediate cardiac repair following myocardial infarction (MI). Macrophage migration inhibitory factor (MIF), a proinflammatory cytokine, plays a critical role in regulating cell homeostasis. This study aimed to investigate the cardioprotective effects of exo secreted from bone marrow-MSCs (BM-MSCs) overexpressing MIF in a rat model of MI. MIF plasmid was transducted in BM-MSCs. Exo were isolated from the supernatants of BM-MSCs and MIF-BM-MSCs, respectively. The morphology of mitochondria in neonatal mice cardiomyocytes (NRCMs) was determined by MitoTracker staining. The apoptosis of NRCMs was examined by deoxynucleotidyl transferase-mediated dUTP nick end-labeling. BM-MSC-exo and MIF-BM-MSC-exo were intramuscularly injected into the peri-infarct region in a rat model of MI. The heart function of rats was assessed by echocardiography. The expression of MIF was greatly enhanced in MIF-BM-MSCs compared with BM-MSCs. Both BM-MSC-exo and MIF-BM-MSC-exo expressed CD63 and CD81. NRCMs treated with MIF-BM-MSC-exo exhibited less mitochondrial fragmentation and cell apoptosis under hypoxia/serum deprivation (H/SD) challenge than those treated with BM-MSC-exo via activating adenosine 5'-monophosphate-activated protein kinase signaling. Moreover, these effects were partially abrogated by Compound C. Injection of BM-MSC-exo or MIF-BM-MSC-exo greatly restored heart function in a rat model of MI. Compared with BM-MSC-exo, injection of MIF-BM-MSC-exo was associated with enhanced heart function, reduced heart remodeling, less cardiomyocyte mitochondrial fragmentation, reactive oxygen species generation, and apoptosis. Our study reveals a new mechanism of MIF-BM-MSC-exo-based therapy for MI and provides a novel strategy for cardiovascular disease treatment.
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Affiliation(s)
- Xiaolin Liu
- Section of Pacing and Electrophysiology, Division of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Xin Li
- Department of Emergency Medicine, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.,Department of Emergency and Critical Care Medicine, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Wenwu Zhu
- Section of Pacing and Electrophysiology, Division of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yuelin Zhang
- Department of Emergency Medicine, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.,Department of Emergency and Critical Care Medicine, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Yimei Hong
- Department of Emergency Medicine, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.,Department of Emergency and Critical Care Medicine, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Xiaoting Liang
- Clinical Translational Medical Research Center, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Baohan Fan
- Section of Pacing and Electrophysiology, Division of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Hongyan Zhao
- Section of Pacing and Electrophysiology, Division of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Haiwei He
- Department of Emergency Medicine, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.,Department of Emergency and Critical Care Medicine, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Fengxiang Zhang
- Section of Pacing and Electrophysiology, Division of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
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Zhang Y, Zhu W, He H, Fan B, Deng R, Hong Y, Liang X, Zhao H, Li X, Zhang F. Macrophage migration inhibitory factor rejuvenates aged human mesenchymal stem cells and improves myocardial repair. Aging (Albany NY) 2019; 11:12641-12660. [PMID: 31881006 PMCID: PMC6949107 DOI: 10.18632/aging.102592] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2019] [Accepted: 11/26/2019] [Indexed: 12/14/2022]
Abstract
The beneficial functions of mesenchymal stem cells (MSCs) decline with age, limiting their therapeutic efficacy for myocardial infarction (MI). Macrophage migration inhibitory factor (MIF) promotes cell proliferation and survival. We investigated whether MIF overexpression could rejuvenate aged MSCs and increase their therapeutic efficacy in MI. Young and aged MSCs were isolated from the bone marrow of young and aged donors. Young MSCs, aged MSCs, and MIF-overexpressing aged MSCs were transplanted into the peri-infarct region in a rat MI model. Aged MSCs exhibited a lower proliferative capacity, lower MIF level, greater cell size, greater senescence-associated-β-galactosidase activity, and weaker paracrine effects than young MSCs. Knocking down MIF in young MSCs induced cellular senescence, whereas overexpressing MIF in aged MSCs reduced cellular senescence. MIF rejuvenated aged MSCs by activating autophagy, an effect largely reversed by the autophagy inhibitor 3-methyladenine. MIF-overexpressing aged MSCs induced angiogenesis and prevented cardiomyocyte apoptosis to a greater extent than aged MSCs, and had improved heart function and cell survival more effectively than aged MSCs four weeks after MI. Thus, MIF rejuvenated aged MSCs by activating autophagy and enhanced their therapeutic efficacy in MI, suggesting a novel MSC-based therapeutic strategy for cardiovascular diseases in the aged population.
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Affiliation(s)
- Yuelin Zhang
- Department of Emergency Medicine, Department of Emergency and Critical Care Medicine, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Wenwu Zhu
- Section of Pacing and Electrophysiology, Division of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Haiwei He
- Department of Emergency Medicine, Department of Emergency and Critical Care Medicine, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Baohan Fan
- Section of Pacing and Electrophysiology, Division of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Rui Deng
- Department of General Surgery, The Second Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui, China
| | - Yimei Hong
- Department of Emergency Medicine, Department of Emergency and Critical Care Medicine, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Xiaoting Liang
- Clinical Translational Medical Research Center, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Hongyan Zhao
- Section of Pacing and Electrophysiology, Division of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Xin Li
- Department of Emergency Medicine, Department of Emergency and Critical Care Medicine, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Fengxiang Zhang
- Section of Pacing and Electrophysiology, Division of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
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Melgar-Sánchez LM, García-Ruiz I, Pardo-Marqués V, Agulló-Ortuño MT, Martínez-Galán I. Influence of mineral waters on in vitro proliferation, antioxidant response and cytokine production in a human lung fibroblasts cell line. INTERNATIONAL JOURNAL OF BIOMETEOROLOGY 2019; 63:1171-1180. [PMID: 31227887 DOI: 10.1007/s00484-019-01730-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/01/2019] [Revised: 05/05/2019] [Accepted: 05/06/2019] [Indexed: 06/09/2023]
Abstract
Spa mineral waters are used for the treatment of chronic diseases' symptoms. Anti-inflammatory, analgesic, anti-ageing and tissue repair effects have been attributed to them. This work seeks to improve knowledge about the effect of spa mineral waters on human cells. For this, human lung fibroblasts were treated with mineral waters from Ledesma, Paracuellos and Archena spas, three Spanish health resorts with different water chemical composition. A significant increase of cell proliferation together with an enhanced antioxidant capacity (reactive oxygen and nitrogen species, glutathione levels and superoxide dismutase activity) in mineral water-treated fibroblasts compared to control fibroblasts was observed. Moreover, cytokine profiling revealed an increase in the release of MIF, IL-6, CL-1, CCL-5 and ICAM-1, which are described as mediators in proliferation, wound healing and cell migration processes. In conclusion, our results could be in line with the effects attributed to spa mineral waters in wound healing strategies and oxidative damage protection.
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Affiliation(s)
- Laura María Melgar-Sánchez
- Department of Medical Sciences, Faculty of Medicine, Universidad de Castilla-La Mancha, Calle Almansa 14, 02006, Albacete, Spain
| | - Inmaculada García-Ruiz
- Laboratory of Clinical and Translational Oncology, Instituto de Investigación Sanitaria Hospital 12 de Octubre (i+12), Av. de Córdoba s/n, 28041, Madrid, Spain
| | - Virginia Pardo-Marqués
- Laboratory of Clinical and Translational Oncology, Instituto de Investigación Sanitaria Hospital 12 de Octubre (i+12), Av. de Córdoba s/n, 28041, Madrid, Spain
| | - María Teresa Agulló-Ortuño
- Laboratory of Clinical and Translational Oncology, Instituto de Investigación Sanitaria Hospital 12 de Octubre (i+12), Av. de Córdoba s/n, 28041, Madrid, Spain
- Department of Nursing, Physiotherapy and Occupational Therapy, School of Nursing and Physiotherapy, Universidad de Castilla-La Mancha, Av. Carlos III s/n,, 45071, Toledo, Spain
| | - Inés Martínez-Galán
- Department of Nursing, Physiotherapy and Occupational Therapy, School of Nursing and Physiotherapy, Universidad de Castilla-La Mancha, Av. Carlos III s/n,, 45071, Toledo, Spain.
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Abstract
Inflammatory processes underlie many diseases associated with injury of the heart muscle, including conditions without an obvious inflammatory pathogenic component such as hypertensive and diabetic cardiomyopathy. Persistence of cardiac inflammation can cause irreversible structural and functional deficits. Some are induced by direct damage of the heart muscle by cellular and soluble mediators but also by metabolic adaptations sustained by the inflammatory microenvironment. It is well established that both cardiomyocytes and immune cells undergo metabolic reprogramming in the site of inflammation, which allow them to deal with decreased availability of nutrients and oxygen. However, like in cancer, competition for nutrients and increased production of signalling metabolites such as lactate initiate a metabolic cross-talk between immune cells and cardiomyocytes which, we propose, might tip the balance between resolution of the inflammation versus adverse cardiac remodeling. Here we review our current understanding of the metabolic reprogramming of both heart tissue and immune cells during inflammation, and we discuss potential key mechanisms by which these metabolic responses intersect and influence each other and ultimately define the prognosis of the inflammatory process in the heart.
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Affiliation(s)
- Federica M Marelli-Berg
- William Harvey Research Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, United Kingdom.,Centre for Inflammation and Therapeutic Innovation, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, United Kingdom
| | - Dunja Aksentijevic
- School of Biological and Chemical Sciences, Queen Mary University of London, G.E. Fogg Building, Mile End Road, London E1 4NS, United Kingdom.,Centre for Inflammation and Therapeutic Innovation, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, United Kingdom
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36
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Meng X, Sun B, Xiao Z. Comparison in transcriptome and cytokine profiles of mesenchymal stem cells from human umbilical cord and cord blood. Gene 2019; 696:10-20. [PMID: 30769140 DOI: 10.1016/j.gene.2019.02.017] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2018] [Revised: 01/23/2019] [Accepted: 02/08/2019] [Indexed: 12/14/2022]
Abstract
Human umbilical cord (UC) and cord blood (CB) provide attractive sources of mesenchymal stem cells (MSCs) for cell therapy. Both UCMSCs and CBMSCs have been demonstrated to play prominent roles in clinical therapy. However, little is known about their functional differences in clinical application. Our transcriptome analysis uncovered high activity of insulin secretion related signaling pathways for CBMSCs and cell adhesion related signaling pathways for UCMSCs. Expression of a large number of immune related signaling pathways also showed the difference in both cells, implying their distinct immune modulatory functions. As the therapeutic effects of MSCs mainly dependent on the cytokines and growth factors produced by transplanted MSCs, we further compared the cytokine profiles of UCMSCs and CBMSCs using antibody array. By evaluating the expression of 106 cytokines, we found both MSCs abundantly secreted TSP-1, TSG-14, TIMP-1, IL-8, IL-6, CXCL1, GIF and IGFBP3. However, the expression of CCL2 in UCMSCs showed significantly higher than CBMSCs. IGFBP1 and IGFBP2 were secreted by CBMSCs with higher abundance than UCMSCs. Overall, these results suggest that UCMSCs and CBMSCs preserve different functional potentials, which have to be carefully considered before clinical treatment.
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Affiliation(s)
- Xianhui Meng
- State key laboratory of bioelectronics, School of biological science & medical engineering, Southeast University, Nanjing, 210096, China
| | - Bo Sun
- State key laboratory of bioelectronics, School of biological science & medical engineering, Southeast University, Nanjing, 210096, China.
| | - Zhongdang Xiao
- State key laboratory of bioelectronics, School of biological science & medical engineering, Southeast University, Nanjing, 210096, China.
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37
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Xia W, Hou M. Mesenchymal stem cells confer resistance to doxorubicin-induced cardiac senescence by inhibiting microRNA-34a. Oncol Lett 2018; 15:10037-10046. [PMID: 29928373 PMCID: PMC6004710 DOI: 10.3892/ol.2018.8438] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2017] [Accepted: 11/10/2017] [Indexed: 12/15/2022] Open
Abstract
Doxorubicin (DOXO) is a chemotherapeutic agent widely used in the treatment of various types of cancer. However, cardiotoxicity is a major side effect of DOXO therapy due to the ability of this compound to induce cardiac cellular senescence. It is well known that microRNA (miR)-34a serves a role in cardiac dysfunction and ageing, and that it is involved in several cellular processes associated with DOXO-induced cardiotoxicity. Furthermore, mesenchymal stem cell (MSC)-based therapies have been reported to modulate cellular senescence. In the present study, the Transwell system was used to co-culture H9c2 cells and MSCs, and cell proliferation and viability were assessed. The expression of senescence-related genes, p53 and p16, and telomere length were analyzed using reverse transcription-quantitative polymerase chain reaction (PCR), and the protein expression levels of situin 1 (SIRT1) were detected by western blotting. Additionally, telomerase activity of H9c2 was examined using the Telo TAGGG Telomerase PCR ELISA PLUS kit. The present study revealed that, in the presence of DOXO, H9c2 cells were in senescence, as characterized by a low proliferation rate, poor viability and a marked increase in the expression of p53 and p16. By contrast, when co-cultured with MSCs in the presence of DOXO, the proliferation and viability of H9c2 cells increased. Additionally, the expression of p53 and p16 decreased, and increased length of telomere and telomerase activity was also observed. Additionally, the mechanism underlying the anti-senescence function of MSCs was revealed to involve the miR-34a-SIRT1 axis, confirmed by overexpressing miR-34a using a miR-34a mimic or silencing SIRT1 using small interfering RNA, which abolished the anti-senescence effect of MSCs on DOXO-treated H9c2 cells. Taken together, the results of the present study suggest that MSCs may rejuvenate H9c2 cells from a state of DOXO-induced senescence by increasing SIRT1 expression, there by inhibiting miR-34a. Therefore, treatment with MSCs may have important therapeutic implications in the restoration of cardiotoxicity in patients with cancer undergoing treatment with DOXO.
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Affiliation(s)
- Wenzheng Xia
- Department of Neurosurgery, First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Meng Hou
- Department of Radiation Oncology, First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
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38
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Wei ZZ, Zhu YB, Zhang JY, McCrary MR, Wang S, Zhang YB, Yu SP, Wei L. Priming of the Cells: Hypoxic Preconditioning for Stem Cell Therapy. Chin Med J (Engl) 2018; 130:2361-2374. [PMID: 28937044 PMCID: PMC5634089 DOI: 10.4103/0366-6999.215324] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Objective: Stem cell-based therapies are promising in regenerative medicine for protecting and repairing damaged brain tissues after injury or in the context of chronic diseases. Hypoxia can induce physiological and pathological responses. A hypoxic insult might act as a double-edged sword, it induces cell death and brain damage, but on the other hand, sublethal hypoxia can trigger an adaptation response called hypoxic preconditioning or hypoxic tolerance that is of immense importance for the survival of cells and tissues. Data Sources: This review was based on articles published in PubMed databases up to August 16, 2017, with the following keywords: “stem cells,” “hypoxic preconditioning,” “ischemic preconditioning,” and “cell transplantation.” Study Selection: Original articles and critical reviews on the topics were selected. Results: Hypoxic preconditioning has been investigated as a primary endogenous protective mechanism and possible treatment against ischemic injuries. Many cellular and molecular mechanisms underlying the protective effects of hypoxic preconditioning have been identified. Conclusions: In cell transplantation therapy, hypoxic pretreatment of stem cells and neural progenitors markedly increases the survival and regenerative capabilities of these cells in the host environment, leading to enhanced therapeutic effects in various disease models. Regenerative treatments can mobilize endogenous stem cells for neurogenesis and angiogenesis in the adult brain. Furthermore, transplantation of stem cells/neural progenitors achieves therapeutic benefits via cell replacement and/or increased trophic support. Combinatorial approaches of cell-based therapy with additional strategies such as neuroprotective protocols, anti-inflammatory treatment, and rehabilitation therapy can significantly improve therapeutic benefits. In this review, we will discuss the recent progress regarding cell types and applications in regenerative medicine as well as future applications.
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Affiliation(s)
- Zheng Z Wei
- Department of Neurology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China; Department of Anesthesiology, Emory University School of Medicine, Atlanta, Georgia 30322, USA
| | - Yan-Bing Zhu
- Experimental and Translational Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
| | - James Y Zhang
- Department of Anesthesiology, Emory University School of Medicine, Atlanta, Georgia 30322, USA
| | - Myles R McCrary
- Department of Anesthesiology, Emory University School of Medicine, Atlanta, Georgia 30322, USA
| | - Song Wang
- Experimental and Translational Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China; Department of Anesthesiology, Emory University School of Medicine, Atlanta, Georgia 30322, USA
| | - Yong-Bo Zhang
- Department of Neurology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
| | - Shan-Ping Yu
- Department of Neurology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China; Department of Anesthesiology, Emory University School of Medicine, Atlanta, Georgia 30322, USA
| | - Ling Wei
- Department of Neurology, Beijing Friendship Hospital, Capital Medical University; Experimental and Translational Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China; Department of Anesthesiology, Emory University School of Medicine, Atlanta, Georgia 30322, USA
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Li Q, Zhu Z, Wang C, Cai L, Lu J, Wang Y, Xu J, Su Z, Zheng W, Chen X. CTRP9 ameliorates cellular senescence via PGC‑1α/AMPK signaling in mesenchymal stem cells. Int J Mol Med 2018; 42:1054-1063. [PMID: 29749459 DOI: 10.3892/ijmm.2018.3666] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2018] [Accepted: 05/03/2018] [Indexed: 11/06/2022] Open
Abstract
Stroke is the second most common cause of death worldwide, and thus, it imposes great financial burdens on both individuals and society. Mesenchymal stem cell (MSC) therapy is a promising approach for ischemic brain injury. However, MSC treatment potential is progressively reduced with age, limiting their therapeutic efficacy for brain repair post‑stroke. C1q and tumor necrosis factor‑related protein 9 (CTRP9) is a novel cytoprotective cytokine with antioxidant effects, which is highly expressed in brain tissue. The present study tested the hypothesis that CTRP9 might act as an antisenescence factor to promote the rejuvenation of aged MSCs. MSCs were isolated from the bone marrow of young (8‑weeks‑old) and aged (18‑months‑old) male C57BL/6 mice. Cell proliferation was measured by Cell Counting Kit‑8 assay and cell viability was determined by MTT assay. Gene expression levels of interleukin (IL)‑6 and IL‑10 were evaluated with reverse transcription‑quantitative polymerase chain reaction, and secretion of vascular endothelial growth factor, basic fibroblast growth factor, hepatocyte growth factor, and insulin‑like growth factor were measured by ELISA. The expression levels of proteins in the peroxisome proliferator‑activated receptor γcoactivator (PGC)‑1α/AMP‑activated protein kinase (AMPK) signaling pathway were investigated with western blotting. Oxidative stress was evaluated by detecting mitochondrial membrane potential, reactive oxygen species, superoxide dismutase activity and malondialdehyde. MSCs isolated from aged mice exhibited reduced proliferation and viability, and impaired immunoregulatory and paracrine abilities, compared with MSCs from younger mice. CTRP9 had a significant antisenescence effect in aged MSCs by activating PGC‑1α/AMPK signaling and decreasing the oxidative response. Silencing either PGC‑1α or AMPK abolished the above effects of CTRP9. These results suggest that CTRP9 may have a critical role in cellular senescence by facilitating stem cell rejuvenation, and may therefore have the potential to enhance the efficacy of stem cell therapy.
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Affiliation(s)
- Qun Li
- Department of Neurosurgery, First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Zhangzhang Zhu
- Department of Neurosurgery, First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Chengde Wang
- Department of Neurosurgery, First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Lin Cai
- Department of Neurosurgery, First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Jianglong Lu
- Department of Neurosurgery, First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Yongchun Wang
- Department of Neurosurgery, First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Jiadong Xu
- Department of Neurosurgery, First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Zhipeng Su
- Department of Neurosurgery, First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Weiming Zheng
- Department of Neurosurgery, First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Xianbin Chen
- Department of Neurosurgery, First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
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Chen L, Xia W, Hou M. Mesenchymal stem cells attenuate doxorubicin‑induced cellular senescence through the VEGF/Notch/TGF‑β signaling pathway in H9c2 cardiomyocytes. Int J Mol Med 2018; 42:674-684. [PMID: 29693137 DOI: 10.3892/ijmm.2018.3635] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2018] [Accepted: 04/05/2018] [Indexed: 11/06/2022] Open
Abstract
The clinical use of doxorubicin (Dox) is limited by its cardiotoxicity. The fundamental changes it induces include interstitial myocardial fibrosis and the appearance of senescent cardiomyocytes. Mesenchymal stem cell (MSC)‑based therapies have also been reported to modulate cellular senescence, and have been used effectively to treat age‑related cardiovascular diseases. In the present study, the Transwell system was used to coculture H9c2 cells with MSCs, and their proliferation and viability were assessed. The expression of senescence‑related genes p53 and p16, and telomere length were measured using reverse transcription‑quantitative polymerase chain reaction analysis, and the Jagged‑1/Notch‑1 signaling pathway was detected using western blot analysis. The results revealed that Dox induced the senescence of H9c2 cells, characterized by a low proliferation rate, poor viability, reduced telomere length and impaired telomerase activity, and by marked increases in the expression of p53 and p16. By contrast, when cocultured with MSCs in the presence of Dox, H9c2 cell proliferation and viability increased, whereas the expression levels of p53 and p16 decreased, and telomere length and telomerase activity increased. The mechanism underlying the antisenescence function of MSCs was clarified, which involved the vascular endothelial growth factor (VEGF)/Jagged‑1/Notch‑1/transforming growth factor‑β1 (TGF‑β1) signaling pathway. It was confirmed that inhibiting VEGF, or silencing Jagged‑1 or Notch‑1 with small interfering RNA, or using recombinant TGF‑β1 eliminated the antisenescence effects of MSCs on the Dox‑treated H9c2 cells. The results revealed that MSCs rescued H9c2 cells from Dox‑induced senescence through the release of VEGF, which activated the Jagged‑1/Notch‑1 signaling pathway, leading to the inhibition of TGF‑β1 release. Therefore, treatment with MSCs may have important therapeutic implications on the attenuation of cardiotoxicity in patients with cancer treated with Dox.
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Affiliation(s)
- Lingli Chen
- Department of Neurology, First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Wenzheng Xia
- Department of Neurosurgery, First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Meng Hou
- Department of Radiation Oncology, First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
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Nothnick WB, Falcone T, Olson MR, Fazleabas AT, Tawfik OW, Graham A. Macrophage Migration Inhibitory Factor Receptor, CD74, is Overexpressed in Human and Baboon ( Papio Anubis) Endometriotic Lesions and Modulates Endometriotic Epithelial Cell Survival and Interleukin 8 Expression. Reprod Sci 2018; 25:1557-1566. [PMID: 29592775 DOI: 10.1177/1933719118766262] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
CD74 is the primary receptor for macrophage migration inhibitory factor (MIF). Although expression of MIF has been described in endometriotic lesions, the cellular localization and function of the MIF receptor, CD74, are poorly understood. To further explore the role of CD74 in the pathophysiology of endometriosis, we utilized specimens from women with diagnostically confirmed endometriosis, women with no signs or symptoms of endometriosis (controls), and 8 baboons with experimentally induced endometriosis. Compared to eutopic endometrium from women with endometriosis, CD74 transcript expression was significantly increased in endometriotic lesion tissue. Similarly, cellular expression of CD74 was significantly greater in ectopic lesion tissue compared to paired eutopic endometrium, which both expressed greater CD74 expression compared to eutopic endometrium from control patients. Localization of CD74 was predominant to epithelial cells of ectopic and matched eutopic endometrium and was not influenced by the stage of the menstrual cycle. Eutopic endometrium from control patients did not express detectable levels of CD74 protein by immunohistochemistry. This pattern of expression and CD74 protein localization could be recapitulated in endometriotic lesion tissue from baboons with experimentally induced disease. Transfection of the endometriotic epithelial cell lines, 12Z with CD74 short hairpin RNA (shRNA), resulted in a significant decrease in CD74 protein expression, which was associated with a significant reduction in cellular proliferation as well as the expression of the prosurvival cytokine interleukin 8. Together, these data support the hypothesis that CD74 is elevated in endometriotic lesion tissue and may contribute to the pathogenesis of endometriosis by promoting cell survival.
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Affiliation(s)
- Warren B Nothnick
- 1 Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, KS, USA.,2 Center for Reproductive Sciences, University of Kansas Medical Center, Kansas City, KS, USA
| | - Tommaso Falcone
- 3 Department of Obstetrics, Gynecology and Women's Health Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Mark R Olson
- 4 Department of Obstetrics, Gynecology and Reproductive Biology, College of Human Medicine, Michigan State University, Grand Rapids, MI, USA
| | - Asgerally T Fazleabas
- 4 Department of Obstetrics, Gynecology and Reproductive Biology, College of Human Medicine, Michigan State University, Grand Rapids, MI, USA
| | - Ossama W Tawfik
- 5 Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, USA
| | - Amanda Graham
- 1 Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, KS, USA
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Current Progress in the Rejuvenation of Aging Stem/Progenitor Cells for Improving the Therapeutic Effectiveness of Myocardial Repair. Stem Cells Int 2018; 2018:9308301. [PMID: 29760740 PMCID: PMC5926481 DOI: 10.1155/2018/9308301] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2017] [Accepted: 03/13/2018] [Indexed: 12/31/2022] Open
Abstract
Ischemic heart disease affects a majority of people, especially elderly patients. Recent studies have utilized autologous adult stem/progenitor cells as a treatment option to heal cardiac tissue after myocardial infarction. However, donor cells from aging patients are more likely to be in a senescent stage. Rejuvenation is required to reverse the damage levied by aging and promote a youthful phenotype. This review aims to discuss current strategies that are effective in rejuvenating aging cardiac stem cells and represent novel therapeutic methods to treat the aging heart. Recent literature mainly focuses on three approaches that aim to reverse cardiac aging: genetic modification, pharmaceutical administration, and optimization of extracellular factors. In vitro genetic modification can be used to overexpress or knock down certain genes and allow for reversal of the aging phenotype. Pharmaceutical administration is another approach that allows for manipulation of signaling pathways related to cell proliferation and cell senescence. Since the stem cell niche can contribute to the age-related decline in stem cell function, rejuvenation strategies also include optimization of extracellular factors. Overall, improving the intrinsic properties of aging stem cells as well as the surrounding environment allows these cells to adopt a phenotype similar to their younger counterparts.
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Hu C, Li L. Preconditioning influences mesenchymal stem cell properties in vitro and in vivo. J Cell Mol Med 2018; 22:1428-1442. [PMID: 29392844 PMCID: PMC5824372 DOI: 10.1111/jcmm.13492] [Citation(s) in RCA: 291] [Impact Index Per Article: 41.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2017] [Accepted: 10/31/2017] [Indexed: 12/15/2022] Open
Abstract
Various diseases and toxic factors easily impair cellular and organic functions in mammals. Organ transplantation is used to rescue organ function, but is limited by scarce resources. Mesenchymal stem cell (MSC)-based therapy carries promising potential in regenerative medicine because of the self-renewal and multilineage potency of MSCs; however, MSCs may lose biological functions after isolation and cultivation for a long time in vitro. Moreover, after they are injected in vivo and migrate into the damaged tissues or organs, they encounter a harsh environment coupled with death signals due to the inadequate tensegrity structure between the cells and matrix. Preconditioning, genetic modification and optimization of MSC culture conditions are key strategies to improve MSC functions in vitro and in vivo, and all of these procedures will contribute to improving MSC transplantation efficacy in tissue engineering and regenerative medicine. Preconditioning with various physical, chemical and biological factors is possible to preserve the stemness of MSCs for further application in studies and clinical tests. In this review, we mainly focus on preconditioning and the corresponding mechanisms for improving MSC activities in vitro and in vivo; we provide a glimpse into the promotion of MSC-based cell therapy development for regenerative medicine. As a promising consequence, MSC transplantation can be applied for the treatment of some terminal diseases and can prolong the survival time of patients in the near future.
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Affiliation(s)
- Chenxia Hu
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesState Key Laboratory for Diagnosis and Treatment of Infectious DiseasesSchool of MedicineFirst Affiliated HospitalZhejiang UniversityHangzhouZhejiangChina
| | - Lanjuan Li
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesState Key Laboratory for Diagnosis and Treatment of Infectious DiseasesSchool of MedicineFirst Affiliated HospitalZhejiang UniversityHangzhouZhejiangChina
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Illescas O, Gomez-Verjan JC, García-Velázquez L, Govezensky T, Rodriguez-Sosa M. Macrophage Migration Inhibitory Factor -173 G/C Polymorphism: A Global Meta-Analysis across the Disease Spectrum. Front Genet 2018; 9:55. [PMID: 29545822 PMCID: PMC5839154 DOI: 10.3389/fgene.2018.00055] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2017] [Accepted: 02/06/2018] [Indexed: 12/13/2022] Open
Abstract
Human macrophage migration inhibitory factor (MIF) is a cytokine that plays a role in several metabolic and inflammatory processes. Single nucleotide polymorphism (SNP) -173 G/C (rs755622) on MIF gene has been associated with numerous diseases, such as arthritis and cancer. However, most of the reports concerning the association of MIF with these and other pathologies are inconsistent and remain quite controversial. Therefore, we performed a meta-analysis from 96 case-control studies on -173 G/C MIF SNP and stratified the data according to the subjects geographic localization or the disease pathophysiology, in order to determine a more meaningful significance to this SNP. The polymorphism was strongly associated with an increased risk in autoimmune-inflammatory, infectious and age-related diseases on the dominant (OR: 0.74 [0.58-0.93], P < 0.01; OR: 0.81 [0.74-0.89], P < 0.0001; and OR: 0.81 [0.76-0.87], P < 0.0001, respectively) and the recessive models (OR: 0.74 [0.57-0.095], P < 0.01; OR: 0.66 [0.48-0.92], P < 0.0154; and OR: 0.70 [0.60-0.82], P < 0.0001, respectively). Also, significant association was found in the geographic localization setting for Asia, Europe and Latin America subdivisions in the dominant (OR: 0.76 [0.69-0.84], P < 0.0001; OR: 0.77 [0.72-0.83], P < 0.0001; OR: 0.61 [0.44-0.83], P-value: 0.0017, respectively) and overdominant models (OR: 0.85 [0.77-0.94], P < 0.0001; OR: 0.80 [0.75-0.86], P < 0.0001; OR: 0.73 [0.63-0.85], P-value: 0.0017, respectively). Afterwards, we implemented a network meta-analysis to compare the association of the polymorphism for two different subdivisions. We found a stronger association for autoimmune than for age-related or autoimmune-inflammatory diseases, and stronger association for infectious than for autoimmune-inflammatory diseases. We report for the first time a meta-analysis of rs755622 polymorphism with a variety of stratified diseases and populations. The study reveals a strong association of the polymorphism with autoimmune and infectious diseases. These results may help direct future research on MIF-173 G/C in diseases in which the relation is clearer and thus assist the search for more plausible applications.
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Affiliation(s)
- Oscar Illescas
- Unidad de Biomedicina, Facultad de Estudios Superiores-Iztacala, Universidad Nacional Autónoma de México, Tlalnepantla de Baz, Mexico
| | - Juan C. Gomez-Verjan
- División de Investigación Básica, Instituto Nacional de Geriatría, Mexico City, Mexico
| | - Lizbeth García-Velázquez
- Departamento de Medicina Genómica y Toxicología Ambiental, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - Tzipe Govezensky
- Departamento de Biología Molecular, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - Miriam Rodriguez-Sosa
- Unidad de Biomedicina, Facultad de Estudios Superiores-Iztacala, Universidad Nacional Autónoma de México, Tlalnepantla de Baz, Mexico
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ZP2495 Protects against Myocardial Ischemia/Reperfusion Injury in Diabetic Mice through Improvement of Cardiac Metabolism and Mitochondrial Function: The Possible Involvement of AMPK-FoxO3a Signal Pathway. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2018; 2018:6451902. [PMID: 29576852 PMCID: PMC5822888 DOI: 10.1155/2018/6451902] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/23/2017] [Revised: 08/23/2017] [Accepted: 09/14/2017] [Indexed: 02/07/2023]
Abstract
Coronary heart disease patients with type 2 diabetes were subject to higher vulnerability for cardiac ischemia-reperfusion (I/R) injury. This study was designed to evaluate the impact of ZP2495 (a glucagon-GLP-1 dual-agonist) on cardiac function and energy metabolism after myocardial I/R injury in db/db mice with a focus on mitochondrial function. C57BLKS/J-lepr+/lepr+ (BKS) and db/db mice received 4-week treatment of glucagon, ZP131 (GLP-1 receptor agonist), or ZP2495, followed by cardiac I/R injury. The results showed that cardiac function, cardiac glucose metabolism, cardiomyocyte apoptosis, cardiac mitochondrial morphology, and energetic transition were improved or ameliorated by ZP2495 to a greater extent than that of glucagon and ZP131. In vitro study showed that ZP2495, rather than glucagon, alleviated mitochondrial depolarization, cytochrome C release, and mitochondria ROS generation in neonatal rat ventricular myocytes subjected to high-glucose and simulated I/R injury conditions, the effects of which were weaker in the ZP131 group. Furthermore, the expressions of Akt, FoxO3a, and AMPK phosphorylation were elevated by ZP2495 to a greater extent than that of ZP131. In conclusion, ZP2495 may contribute to the improvement of cardiac function and energy metabolism in db/db mice after myocardial I/R injury by improving mitochondrial function possibly through Akt/FoxO3a and AMPK/FoxO3a signal pathways.
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Xie Z, Xia W, Hou M. Long intergenic non‑coding RNA‑p21 mediates cardiac senescence via the Wnt/β‑catenin signaling pathway in doxorubicin-induced cardiotoxicity. Mol Med Rep 2017; 17:2695-2704. [PMID: 29207090 DOI: 10.3892/mmr.2017.8169] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2017] [Accepted: 11/06/2017] [Indexed: 11/06/2022] Open
Abstract
Doxorubicin (Dox)-induced cardiotoxicity has been a well‑known phenomenon to clinicians and scientists for decades. It has been confirmed that Dox‑dependent cardiotoxicity is accompanied by cardiac cellular senescence. However, the molecular mechanisms underlying Dox cardiotoxicity remains to be fully elucidated. Long non‑coding (lnc) RNAs regulate gene transcription and the fate of post‑transcriptional mRNA, which affects a broad range of age‑associated physiological and pathological conditions, including cardiovascular disease and cellular senescence. However, the functional role of lncRNAs in Dox‑induced cardiac cellular senescence remains largely unknown. Using the reverse transcription‑quantitative polymerase chain reaction method, the present study indicated that long intergenic non‑coding (linc) RNA‑p21 was highly expressed in Dox‑treated HL‑1 murine cardiomyocytes. Dox‑induced cardiac senescence was accompanied by decreased cellular proliferation and viability, increased expression of p53 and p16, and decreased telomere length and telomerase activity, while these effects were relieved by silencing endogenous lincRNA‑p21. We found that lincRNA‑p21 interacted with β‑catenin and that silencing β‑catenin abolished the anti‑senescent effect of lincRNA‑p21 silencing. It was observed that modulating lincRNA‑p21 to exert an anti‑senescent effect was dependent on decreasing oxidant stress. To conclude, the present findings suggest that lincRNA‑p21 may be involved in Dox‑associated cardiac cellular senescence and that silencing lincRNA‑p21 effectively protects against Dox cardiotoxicity by regulating the Wnt/β‑catenin signaling pathway and decreasing oxidant stress. Furthermore, modulating lincRNA‑p21 may have cardioprotective potential in patients with cancer receiving Dox treatment.
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Affiliation(s)
- Zhongdong Xie
- Department of General Surgery, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Wenzheng Xia
- Department of Neurosurgery, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Meng Hou
- Department of Radiation Oncology, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
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Xia W, Hou M. Macrophage migration inhibitory factor rescues mesenchymal stem cells from doxorubicin-induced senescence though the PI3K-Akt signaling pathway. Int J Mol Med 2017; 41:1127-1137. [PMID: 29207187 DOI: 10.3892/ijmm.2017.3282] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2017] [Accepted: 11/01/2017] [Indexed: 12/20/2022] Open
Abstract
Doxorubicin (DOXO), an anthracycline antibiotic, is a commonly used anticancer drug. Despite its widespread usage, the therapeutic effects of DOXO are limited by its cardiotoxicity. Mesenchymal stem cell (MSC)-based therapies have had positive outcomes in the treatment of DOXO-induced cardiac damage; however, DOXO exerts toxic effects on MSCs, decreasing the effectiveness of MSC therapy. Macrophage migration inhibitory factor (MIF) promotes MSC survival and rejuvenation, and thus is a promising candidate to protect MSCs against DOXO-induced injury. The present study revealed that DOXO induced the senescence of MSCs, resulting in decreased proliferation, viability and paracrine effects. However, pretreatment with MIF improved the proliferation rate, viability, paracrine function, telomere length and telomerase activity of MSCs. Furthermore, the results indicated that the molecular mechanism underlying the anti-senescent function of MIF involved the phosphatidylinositol 3-kinase (PI3K)-RAC-α serine/threonine-protein kinase (Akt) signaling pathway, which MIF activated. In agreement with this finding, silencing Akt was identified to abolish the anti-senescent effect of MIF. In addition, MIF decreased oxidative stress in MSCs, as revealed by the decreased production of reactive oxygen species and malondialdehyde, and the increased activity of superoxide dismutase. These results indicate that MIF can rescue MSCs from a state of DOXO-induced senescence by inhibiting oxidative stress and activating the PI3K-Akt signaling pathway. Thus, treatment with MIF may have an important therapeutic application for the rejuvenation of MSCs in patients with cancer being treated with DOXO.
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Affiliation(s)
- Wenzheng Xia
- Department of Neurosurgery, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Meng Hou
- Department of Radiation Oncology, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
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Wu J, Liu S, Meng H, Qu T, Fu S, Wang Z, Yang J, Jin D, Yu B. Neuropeptide Y enhances proliferation and prevents apoptosis in rat bone marrow stromal cells in association with activation of the Wnt/β-catenin pathway in vitro. Stem Cell Res 2017; 21:74-84. [PMID: 28411439 DOI: 10.1016/j.scr.2017.04.001] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2016] [Revised: 03/31/2017] [Accepted: 04/02/2017] [Indexed: 01/03/2023] Open
Abstract
Neuropeptide Y (NPY) exhibits a critical but poorly understood regulatory signaling function and has been shown to promote proliferation, vascularization and migration in several types of cells and tissues. However, little is known about the specific role of NPY in the proliferation and apoptosis of bone marrow stromal cells (also known as bone marrow-derived mesenchymal stem cells, BMSCs), which contain a subpopulation of multipotent skeletal stem cells. Based on BrdU incorporation tests, Cell Counting Kit-8, flow cytometry, quantitative polymerase chain reaction and western blotting, we showed that NPY significantly promoted the proliferation of BMSCs in a concentration-dependent manner, with a maximal effect observed at a concentration of 10-10M for pro-proliferative and 10-12M for anti-apoptotic activities. Furthermore, NPY significantly increased the percentage of cells in S and G2/M phases. In addition, NPY exhibited a protective effect after 24h of serum starvation as illustrated by a reduction in the apoptosis rate, degree of nuclear condensation, and expression of apoptosis markers, including caspase-3, caspase-9 and Bax mRNA expression. NPY also increased the mRNA and protein expression levels of canonical Wnt signaling pathway proteins, including β-catenin and c-myc, during the induced proliferative and anti-apoptotic processes. However, the proliferative and anti-apoptotic activities of NPY were partially blocked by both PD160170 (1μM) and DKK1 (0.2μg/mL). These compounds also blocked the mRNA and protein expression of β-catenin, p-GSK-3β and c-myc. Therefore, the results of the present study demonstrated that NPY exerts a proliferative and protective effect on BMSCs in a dose- and time-dependent manner in vitro, and importantly, these effects may be mediated via its Y1 receptor and involved in activation of the canonical Wnt signaling pathway.
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Affiliation(s)
- Jianqun Wu
- Department of Orthopedics and Traumatology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province 510515, China
| | - Song Liu
- Department of Orthopedics, The Third Hospital of Guangzhou Medical University, Guangzhou City, Guangdong Province 510515, China; Department of Orthopedics and Traumatology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province 510515, China
| | - Huan Meng
- Department of Orthopedics and Traumatology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province 510515, China
| | - Tianyu Qu
- Department of Orthopedics and Traumatology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province 510515, China
| | - Su Fu
- School of Engineering and Materials Science, Queen Mary University of London, Mile End Road, London E1 4NS, UK
| | - Zhao Wang
- Department of Orthopedics, The Third Hospital of Guangzhou Medical University, Guangzhou City, Guangdong Province 510515, China; Department of Orthopedics and Traumatology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province 510515, China
| | - Jianguo Yang
- Department of Orthopedics and Traumatology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province 510515, China; Department of Orthopaedics, The First Hospital Huhhot, Huhhot, Inner Mongolia 010020, China
| | - Dan Jin
- Department of Orthopedics and Traumatology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province 510515, China
| | - Bin Yu
- Department of Orthopedics and Traumatology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province 510515, China.
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Qian Z, Ren L, Wu D, Yang X, Zhou Z, Nie Q, Jiang G, Xue S, Weng W, Qiu Y, Lin Y. Overexpression of FoxO3a is associated with glioblastoma progression and predicts poor patient prognosis. Int J Cancer 2017; 140:2792-2804. [PMID: 28295288 DOI: 10.1002/ijc.30690] [Citation(s) in RCA: 65] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2016] [Revised: 02/09/2017] [Accepted: 03/01/2017] [Indexed: 12/28/2022]
Abstract
Forkhead transcription factor FoxO3a has been reported to have ambiguous functions and distinct mechanisms in various solid tumors, including glioblastoma (GBM). Although a preliminary analysis of a small sample of patients indicated that FoxO3a aberrations in glioma might be related to aggressive clinical behavior, the clinical significance of FoxO3a in glioblastoma remains unclear. We investigated the expression of FoxO3a in a cohort of 91 glioblastoma specimens and analyzed the correlations of protein expression with patient prognosis. Furthermore, the functional impact of FoxO3a on GBM progression and the underlying mechanisms of FoxO3a regulation were explored in a series of in vitro and in vivo assays. FoxO3a expression was elevated in glioblastoma tissues, and high nuclear FoxO3a expression in human GBM tissues was associated with poor prognosis. Moreover, knockdown of FoxO3a significantly reduced the colony formation and invasion ability of GBM cells, whereas overexpression of FoxO3a promoted the colony formation and invasion ability. The results of in vivo GBM models further confirmed that FoxO3a knockdown inhibited GBM progression. More, the pro-oncogenic effects of FoxO3a in GBM were mediated by the activation of c-Myc, microtubule-associated protein 1 light chain 3 beta (LC3B) and Beclin1 in a mixed-lineage leukemia 2 (MLL2)-dependent manner. These findings suggest that high FoxO3a expression is associated with glioblastoma progression and that FoxO3a independently indicates poor prognosis in patients. FoxO3a might be a novel prognostic biomarker or a potential therapeutic target in glioblastoma.
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Affiliation(s)
- Zhongrun Qian
- Department of Neurosurgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Li Ren
- Department of Neurosurgery, Shanghai Pudong Hospital, Fudan University, Shanghai, China
| | - Dingchang Wu
- Department of Clinical Laboratory, Longyan First Hospital, Fujian Medical University, Longyan, China
| | - Xi Yang
- Department of Neurosurgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Zhiyi Zhou
- Department of Neurosurgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Quanmin Nie
- Department of Neurosurgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Gan Jiang
- Department of Pharmacology, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Shuanglin Xue
- Department of Neurosurgery, Longyan First Hospital, Fujian Medical University, Longyan, China
| | - Weiji Weng
- Department of Neurosurgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yongming Qiu
- Department of Neurosurgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yingying Lin
- Department of Neurosurgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
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50
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Bozzi F, Mogavero A, Varinelli L, Belfiore A, Manenti G, Caccia C, Volpi CC, Beznoussenko GV, Milione M, Leoni V, Gloghini A, Mironov AA, Leo E, Pilotti S, Pierotti MA, Bongarzone I, Gariboldi M. MIF/CD74 axis is a target for novel therapies in colon carcinomatosis. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2017; 36:16. [PMID: 28114961 PMCID: PMC5260021 DOI: 10.1186/s13046-016-0475-z] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/17/2016] [Accepted: 12/13/2016] [Indexed: 12/16/2022]
Abstract
Background Strategies aimed at obtaining a complete cytoreduction are needed to improve long-term survival for patients with colorectal cancer peritoneal carcinomatosis (CRC-pc). Methods We established organoid models from peritoneal metastases of two naïve CRC patients. A standard paraffin inclusion was conducted to compare their 3D structure and immunohistochemical profile with that of the corresponding surgical samples. RNA expression levels of the CRC stem cell marker LGR5 was measured by in situ hybridization. The secretome of organoids was profiled by mass spectrometry. Energy homeostasis of organoids was interfered with 4-IPP and metformin. Biochemical and metabolic changes after drug treatments were investigated by western blot and mass spectrometry. Mitochondria impairment was evaluated by electron microscopy and mitotraker staining. Results The two organoids recapitulated their corresponding clinical samples in terms of 3D structure and immmunoistochemical profile and were positive for the cancer stem cells marker LGR5. Proteomic analyses of organoids highlighted their strong dependence on energy producing pathways, which suggest that their targeting could be an effective therapeutic approach. To test this hypothesis, we treated organoids with two drugs that target metabolism acting on AMP-activated protein kinase (AMPK), the main regulator of cellular energy homeostasis, which may act as metabolic tumour suppressor in CRC. Organoids were treated with 4-IPP, an inhibitor of MIF/CD74 signalling axis which activates AMPK function, or metformin that inhibits mitochondrial respiratory chain complex I. As a new finding we observed that treatment with 4-IPP downregulated AMPK signalling activity, reduced AKT phosphorylation and activated a JNK-mediated stress-signalling response, thus generating mitochondrial impairment and cell death. Metformin treatment enhanced AMPK activation, decreasing the activity of the anabolic factors ribosomal protein S6 and p4EBP-1 and inducing mitochondrial depolarization. Conclusion We provide evidence that the modulation of AMPK activity may be a strategy for targeting metabolism of CRC-pc organoids. Electronic supplementary material The online version of this article (doi:10.1186/s13046-016-0475-z) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Fabio Bozzi
- Department of Diagnostic Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, via G. Venezian 1, Milan, 20133, Italy
| | - Angela Mogavero
- Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, via G. Amadeo 42, Milan, 20133, Italy.,Molecular Genetics of Cancer, Fondazione Istituto FIRC di Oncologia Molecolare, via Adamello 16, Milan, 20139, Italy
| | - Luca Varinelli
- Proteomics Laboratory Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, via G. Amadeo 42, Milan, 20133, Italy
| | - Antonino Belfiore
- Department of Diagnostic Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, via G. Venezian 1, Milan, 20133, Italy
| | - Giacomo Manenti
- Department of Predictive and Preventive Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, via G. Amadeo 42, Milan, 20133, Italy
| | - Claudio Caccia
- Laboratory of Clinical Pathology and Medical Genetics, Fondazione IRCCS 'Carlo Besta' Istituto Neurologico, via G. Amadeo 42, Milan, 20133, Italy
| | - Chiara C Volpi
- Department of Diagnostic Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, via G. Venezian 1, Milan, 20133, Italy
| | - Galina V Beznoussenko
- Fondazione Istituto FIRC di Oncologia Molecolare, via Adamello 16, Milan, 20139, Italy
| | - Massimo Milione
- Department of Diagnostic Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, via G. Venezian 1, Milan, 20133, Italy
| | - Valerio Leoni
- Laboratory of Clinical Pathology and Medical Genetics, Fondazione IRCCS 'Carlo Besta' Istituto Neurologico, via G. Amadeo 42, Milan, 20133, Italy
| | - Annunziata Gloghini
- Department of Diagnostic Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, via G. Venezian 1, Milan, 20133, Italy
| | - Alexandre A Mironov
- Fondazione Istituto FIRC di Oncologia Molecolare, via Adamello 16, Milan, 20139, Italy
| | - Ermanno Leo
- Colorectal Cancer Unit-Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, via G. Venezian 1, Milan, 20133, Italy
| | - Silvana Pilotti
- Department of Diagnostic Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, via G. Venezian 1, Milan, 20133, Italy
| | - Marco A Pierotti
- Molecular Genetics of Cancer, Fondazione Istituto FIRC di Oncologia Molecolare, via Adamello 16, Milan, 20139, Italy
| | - Italia Bongarzone
- Proteomics Laboratory Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, via G. Amadeo 42, Milan, 20133, Italy.
| | - Manuela Gariboldi
- Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, via G. Amadeo 42, Milan, 20133, Italy.,Molecular Genetics of Cancer, Fondazione Istituto FIRC di Oncologia Molecolare, via Adamello 16, Milan, 20139, Italy
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