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Le HT, Venturini C, Lubian AF, Bowring B, Iredell J, George J, Ahlenstiel G, Read SA. Differences in Phage Recognition and Immunogenicity Contribute to Divergent Human Immune Responses to Escherichia coli and Klebsiella pneumoniae Phages. Eur J Immunol 2025; 55:e202451543. [PMID: 40071703 PMCID: PMC11898580 DOI: 10.1002/eji.202451543] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2024] [Revised: 02/18/2025] [Accepted: 02/19/2025] [Indexed: 03/15/2025]
Abstract
Bacteriophages (phages) are emerging as a viable adjunct to antibiotics for the treatment of multidrug-resistant (MDR) bacterial infections. While intravenous phage therapy has proven successful in many cases, clinical outcomes remain uncertain due to a limited understanding of host response to phages. In this study, we conducted a comprehensive examination of the interaction between clinical-grade phages used to treat MDR Escherichia coli and Klebsiella pneumoniae infections, and human peripheral blood immune cells. Using whole transcriptome as well as proteomic approaches, we identified a strong inflammatory response to E. coli phage vB_EcoM-JIPh_Ec70 (herein, JIPh_Ec70) that was absent upon exposure to K. pneumoniae phage JIPh_Kp127. We confirmed that JIPh_Ec70's DNA recognition by the STING pathway was principally responsible for the activation of NF-kB and the subsequent inflammatory response. We further show that monocytes and neutrophils play a dominant role in phage uptake, primarily through complement-mediated phagocytosis. Significant differences in complement-mediated phagocytosis of JIPh_Kp127 and JIPh_Ec70 were observed, suggesting that reduced recognition, phagocytosis, and immunogenicity all contribute to the significantly decreased response to JIPh_Kp127. Our findings contribute to the progress of our understanding of the innate immune response to therapeutic phages and offer potential insights into how to improve the safety and effectiveness of phage therapy.
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Affiliation(s)
- Huu Thanh Le
- Blacktown Clinical SchoolWestern Sydney UniversitySydneyNSWAustralia
- Storr Liver CentreWestmead Institute for Medical ResearchSydneyNSWAustralia
| | - Carola Venturini
- Centre for Infectious Diseases and Microbiology (CIDM)Westmead Institute for Medical ResearchSydneyNSWAustralia
- Sydney School of Veterinary Science, Faculty of ScienceUniversity of SydneySydneyNSWAustralia
| | - Alicia Fajardo Lubian
- Centre for Infectious Diseases and Microbiology (CIDM)Westmead Institute for Medical ResearchSydneyNSWAustralia
- Faculty of Medicine and HealthUniversity of SydneySydneyNSWAustralia
| | - Bethany Bowring
- Centre for Infectious Diseases and Microbiology (CIDM)Westmead Institute for Medical ResearchSydneyNSWAustralia
| | - Jonathan Iredell
- Centre for Infectious Diseases and Microbiology (CIDM)Westmead Institute for Medical ResearchSydneyNSWAustralia
- Faculty of Medicine and HealthUniversity of SydneySydneyNSWAustralia
| | - Jacob George
- Storr Liver CentreWestmead Institute for Medical ResearchSydneyNSWAustralia
- Faculty of Medicine and HealthUniversity of SydneySydneyNSWAustralia
- Department of Hepatology and GastroenterologyWestmead HospitalSydneyNSWAustralia
| | - Golo Ahlenstiel
- Blacktown Clinical SchoolWestern Sydney UniversitySydneyNSWAustralia
- Storr Liver CentreWestmead Institute for Medical ResearchSydneyNSWAustralia
- Blacktown Mt Druitt HospitalSydneyNSWAustralia
| | - Scott A. Read
- Blacktown Clinical SchoolWestern Sydney UniversitySydneyNSWAustralia
- Storr Liver CentreWestmead Institute for Medical ResearchSydneyNSWAustralia
- Blacktown Mt Druitt HospitalSydneyNSWAustralia
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Khaswaneh RR, Abu-El-Rub E, Alzu'bi A, Almahasneh FA, Almazari RA, Ai-Jariri HF, Al-Zoubi RM. Hypoxic Stress Induces Complement-Mediated Lysis of Mesenchymal Stem Cells by Downregulating Factor H and CD59. Tissue Eng Regen Med 2025; 22:105-112. [PMID: 39485618 PMCID: PMC11711716 DOI: 10.1007/s13770-024-00678-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2024] [Revised: 09/11/2024] [Accepted: 09/12/2024] [Indexed: 11/03/2024] Open
Abstract
BACKGROUND Factor H and membrane inhibitor of reactive lysis (CD59) are key regulators of complement activation. Mesenchymal stem cells (MSCs) secrete Factor H and express CD59 to protect themselves from complement-mediated damage. Severe hypoxia found to decrease the survival chances of MSCs after transplantation; however, little is known about the impact of severe hypoxia on modulating the complement system activity and its effect on MSCs survival. Our study seeks to explore the effect of severe hypoxia on modulating the complement cascade in MSCs. METHODS Human adipose tissue-derived MSCs (hAD-MSCs) were cultured under severe hypoxia using 400 μM Cobalt Chloride (CoCl2) for 48 h. The protein expressions of survival marker; Phosphoinositide 3-kinases (PI3K), and pro-apoptotic marker; Caspase-3 were assessed using western blotting. The level of complement system related factors; Factor H, CD59, C3b, iC3b, C5b, C9, and the complement membrane attack complex (MAC) were analyzed using Elisa assays, western blotting, and immunocytochemistry. RESULTS Our results showed for the first time that severe hypoxia can significantly impair Factor H secretion and CD59 expression in MSCs. This has been associated with upregulation of MAC complex and increased level of cell lysis and apoptosis marked by downregulation of PI3K and upregulation of Annexin v and Caspase-3. CONCLUSION The loss of Factor H and CD59 in hypoxic MSCs can initiate their lysis and apoptosis mediated by activating MAC complex. Preserving the level of Factor H and CD59 in MSCs has significant clinical implication to increase their retention rate in hypoxic conditions and prolong their survival.
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Affiliation(s)
- Ramada R Khaswaneh
- Department of Basic Medical Sciences, Faculty of Medicine, Yarmouk University, Irbid, 211-63, Jordan
| | - Ejlal Abu-El-Rub
- Department of Basic Medical Sciences, Faculty of Medicine, Yarmouk University, Irbid, 211-63, Jordan.
| | - Ayman Alzu'bi
- Department of Basic Medical Sciences, Faculty of Medicine, Yarmouk University, Irbid, 211-63, Jordan
| | - Fatimah A Almahasneh
- Department of Basic Medical Sciences, Faculty of Medicine, Yarmouk University, Irbid, 211-63, Jordan
| | - Rawan A Almazari
- Department of Basic Medical Sciences, Faculty of Medicine, Yarmouk University, Irbid, 211-63, Jordan
| | - Heba F Ai-Jariri
- Department of Basic Medical Sciences, Faculty of Medicine, Yarmouk University, Irbid, 211-63, Jordan
| | - Raed M Al-Zoubi
- Surgical Research Section, Department of Surgery, Hamad Medical Corporation, Doha, Qatar.
- Department of Biomedical Sciences, QU-Health, College of Health Sciences, Qatar University, 2713, Doha, Qatar.
- Department of Chemistry, Jordan University of Science and Technology, P.O.Box 3030, Irbid, 22110, Jordan.
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Kim YS, Lupatov AY, Burunova VV, Bagmet NN, Chardarov NK, Malov SL, Kholodenko RV, Shatverian GA, Manukyan GV, Yarygin KN, Kholodenko IV. Human Liver MSCs Retain Their Basic Cellular Properties in Chronically Inflamed Liver Tissue. Int J Mol Sci 2024; 25:13374. [PMID: 39769138 PMCID: PMC11676302 DOI: 10.3390/ijms252413374] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2024] [Revised: 12/04/2024] [Accepted: 12/09/2024] [Indexed: 01/11/2025] Open
Abstract
Every 25th death worldwide is associated with liver pathology. The development of novel approaches to liver diseases therapy and protocols for maintaining the vital functions of patients on the liver transplant waiting list are urgently needed. Resident mesenchymal stem cells (MSCs) play a significant role in supporting liver tissue integrity and improve the liver condition after infusion. However, it remains unclear whether MSCs isolated from chronically inflamed livers are similar in their basic cellular properties to MSCs obtained from healthy livers. We applied a large array of tests to compare resident MSCs isolated from apparently normal liver tissue and from chronically inflamed livers of patients with fibrosis, cirrhosis, and viral hepatitis. Chronic inflammatory environment did not alter the major cellular characteristics of MSCs, including the expression of MSC markers, stem cell markers, adhesion molecules, and the hallmarks of senescence, as well as cell proliferation, migration, and secretome. Only the expression of some immune checkpoints and toll-like receptors was different. Evidently, MSCs with unchanged cellular properties are present in human liver even at late stages of inflammatory diseases. These cells can be isolated and used as starting material in the development of cell therapies of liver diseases.
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Affiliation(s)
- Yan S. Kim
- Laboratory of Cell Biology, V.N. Orekhovich Institute of Biomedical Chemistry, 119121 Moscow, Russia (K.N.Y.)
| | - Alexey Yu. Lupatov
- Laboratory of Cell Biology, V.N. Orekhovich Institute of Biomedical Chemistry, 119121 Moscow, Russia (K.N.Y.)
| | - Veronika V. Burunova
- Laboratory of Cell Biology, V.N. Orekhovich Institute of Biomedical Chemistry, 119121 Moscow, Russia (K.N.Y.)
| | - Nikolay N. Bagmet
- Department of Abdominal Surgery and Oncology, Laboratory of Emergency Surgery and Portal Hypertension, Petrovsky National Research Centre of Surgery, 119435 Moscow, Russia
| | - Nikita K. Chardarov
- Department of Abdominal Surgery and Oncology, Laboratory of Emergency Surgery and Portal Hypertension, Petrovsky National Research Centre of Surgery, 119435 Moscow, Russia
| | - Svyatoslav L. Malov
- Department of Abdominal Surgery and Oncology, Laboratory of Emergency Surgery and Portal Hypertension, Petrovsky National Research Centre of Surgery, 119435 Moscow, Russia
| | - Roman V. Kholodenko
- Laboratory of Molecular Immunology, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia
| | - Garnik A. Shatverian
- Department of Abdominal Surgery and Oncology, Laboratory of Emergency Surgery and Portal Hypertension, Petrovsky National Research Centre of Surgery, 119435 Moscow, Russia
| | - Garik V. Manukyan
- Department of Abdominal Surgery and Oncology, Laboratory of Emergency Surgery and Portal Hypertension, Petrovsky National Research Centre of Surgery, 119435 Moscow, Russia
| | - Konstantin N. Yarygin
- Laboratory of Cell Biology, V.N. Orekhovich Institute of Biomedical Chemistry, 119121 Moscow, Russia (K.N.Y.)
- Department of General Pathology and Pathophysiology, Russian Medical Academy of Continuous Professional Education, 125284 Moscow, Russia
| | - Irina V. Kholodenko
- Laboratory of Cell Biology, V.N. Orekhovich Institute of Biomedical Chemistry, 119121 Moscow, Russia (K.N.Y.)
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Wang J, Zhou Y, Donohoe E, Canning A, Moosavizadeh S, Ryan AE, Ritter T. Immunomodulatory potential of cytokine-licensed human bone marrow-derived mesenchymal stromal cells correlates with potency marker expression profile. Stem Cells 2024; 42:1040-1054. [PMID: 39208292 PMCID: PMC11630899 DOI: 10.1093/stmcls/sxae053] [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: 03/12/2024] [Accepted: 08/09/2024] [Indexed: 09/04/2024]
Abstract
Cytokine(s) pre-activation/licensing is an effective way to enhance the immunomodulatory potency of mesenchymal stromal cells (MSCs). Currently, IFN-γ licensing received the most attention in comparison with other cytokines. After licensing human bone marrow-derived MSCs with pro-/anti-inflammatory cytokines IFN-γ, IL-1β, TNF-α, TGF-β1 alone or in combination, the in vitro immunomodulatory potency of these MSCs was studied by incubating with allogeneic T cells and macrophage-like THP-1 cells. In addition, immunomodulation-related molecules filtered by bioinformatics, complement 1 subcomponent (C1s), and interferon-induced GTP-binding protein Mx2 (MX2), were studied to verify whether to reflect the immunomodulatory potency. Herein, we reported that different cytokines cause different effects on the function of MSC. While TGF-β1 licensing enhances the capacity of MSCs to induce T cells with an immunosuppressive phenotype, IFN-γ-licensing strengthens the inhibitory effect of MSC on T cell proliferation. Both TGF-β1 and IFN-γ licensing can enhance the effect of MSC on reducing the expression of pro-inflammatory cytokines by M1 macrophage-like THP-1 cells. Interestingly, IFN-γ upregulates potential potency markers extracellular C1s and kynurenine (KYN) and intracellular MX2. These 3 molecules have the potential to reflect mesenchymal stromal cell immunomodulatory potency. In addition, we reported that there is a synergistic effect of TGF-β1 and IFN-γ in immunomodulation.
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Affiliation(s)
- Jiemin Wang
- Regenerative Medicine Institute, School of Medicine, University of Galway, Galway H91FD82, Ireland
| | - Yingying Zhou
- Changsha Centre for Disease Control and Prevention, Changsha, Hunan Province 410011, People’s Republic of China
| | - Ellen Donohoe
- Regenerative Medicine Institute, School of Medicine, University of Galway, Galway H91FD82, Ireland
| | - Aoife Canning
- Regenerative Medicine Institute, School of Medicine, University of Galway, Galway H91FD82, Ireland
| | - Seyedmohammad Moosavizadeh
- Regenerative Medicine Institute, School of Medicine, University of Galway, Galway H91FD82, Ireland
- CURAM Centre for Research in Medical Devices, University of Galway, Galway H91FD82, Ireland
| | - Aideen E Ryan
- Regenerative Medicine Institute, School of Medicine, University of Galway, Galway H91FD82, Ireland
- CURAM Centre for Research in Medical Devices, University of Galway, Galway H91FD82, Ireland
- Discipline of Pharmacology and Therapeutics, School of Medicine, University of Galway, Galway H91TK33, Ireland
| | - Thomas Ritter
- Regenerative Medicine Institute, School of Medicine, University of Galway, Galway H91FD82, Ireland
- CURAM Centre for Research in Medical Devices, University of Galway, Galway H91FD82, Ireland
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Francisco da Silva T, Akemi Amamura T, Cordeiro Valadão I, Carvalho Carneiro M, Morais Freitas V, Paula Lepique A, Isaac L. Complement system component 3 deficiency modulates the phenotypic profile of murine macrophages. Cell Immunol 2024; 405-406:104886. [PMID: 39503081 DOI: 10.1016/j.cellimm.2024.104886] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2024] [Revised: 09/13/2024] [Accepted: 10/16/2024] [Indexed: 12/02/2024]
Abstract
The Complement System is composed of more than 40 proteins that act in innate and adaptive immunity. C3 is the most abundant one and C3-deficient patients are more susceptible to recurrent and severe infections. Several studies have demonstrated the importance of C3 in controlling infections. However, its role in leukocyte biology is still poorly understood. This study aimed to evaluate several cellular parameters in macrophages from C3-deficient mice and compare them to similar cells from wild-type counterparts. We observed that in the absence of C3, the population of F4/80low macrophages in the peritoneal cavity of thioglycolate-treated mice is diminished, probably due to the lack of chemotactic factors like C3a and low levels of C5a. Using fluorescence microscopy analysis, we observed that macrophages from C3-deficient mice exhibited morphological alterations when compared to similar cells from wild-type mice. We observed a significant increase in the expression of CD11c, which is part of CR4 (CD11c/CD18), in macrophages from C3-deficient compared to cells from wild-type mice. Treatment with 12-o-tetradecanoylphorbol-13-acetate, stimulated ROS production and MAPK activation by macrophages. However, these parameters were lower in macrophages from C3-deficient mice when compared to wild-type counterparts. In addition, the phagocytosis of iC3b-opsonized Zymosan particles was diminished in macrophages from C3-deficient mice. Our results suggest that C3 deficiency in C57Black/6 mice may influence specific morphological and functional parameters of macrophages, cells of fundamental importance for both the innate and acquired immune responses.
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Affiliation(s)
- Tiago Francisco da Silva
- Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP, Brazil
| | - Thaís Akemi Amamura
- Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP, Brazil
| | - Iuri Cordeiro Valadão
- Tumor Microenvironment Laboratory, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP, Brazil
| | - Milena Carvalho Carneiro
- Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP, Brazil
| | - Vanessa Morais Freitas
- Tumor Microenvironment Laboratory, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP, Brazil
| | - Ana Paula Lepique
- Laboratory of Immunomodulation, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP, Brazil
| | - Lourdes Isaac
- Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP, Brazil.
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Shan Y, Zhang M, Tao E, Wang J, Wei N, Lu Y, Liu Q, Hao K, Zhou F, Wang G. Pharmacokinetic characteristics of mesenchymal stem cells in translational challenges. Signal Transduct Target Ther 2024; 9:242. [PMID: 39271680 PMCID: PMC11399464 DOI: 10.1038/s41392-024-01936-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2024] [Revised: 07/04/2024] [Accepted: 07/23/2024] [Indexed: 09/15/2024] Open
Abstract
Over the past two decades, mesenchymal stem/stromal cell (MSC) therapy has made substantial strides, transitioning from experimental clinical applications to commercial products. MSC therapies hold considerable promise for treating refractory and critical conditions such as acute graft-versus-host disease, amyotrophic lateral sclerosis, and acute respiratory distress syndrome. Despite recent successes in clinical and commercial applications, MSC therapy still faces challenges when used as a commercial product. Current detection methods have limitations, leaving the dynamic biodistribution, persistence in injured tissues, and ultimate fate of MSCs in patients unclear. Clarifying the relationship between the pharmacokinetic characteristics of MSCs and their therapeutic effects is crucial for patient stratification and the formulation of precise therapeutic regimens. Moreover, the development of advanced imaging and tracking technologies is essential to address these clinical challenges. This review provides a comprehensive analysis of the kinetic properties, key regulatory molecules, different fates, and detection methods relevant to MSCs and discusses concerns in evaluating MSC druggability from the perspective of integrating pharmacokinetics and efficacy. A better understanding of these challenges could improve MSC clinical efficacy and speed up the introduction of MSC therapy products to the market.
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Affiliation(s)
- Yunlong Shan
- Key Laboratory of Drug Metabolism and Pharmacokinetics, Haihe Laboratory of Cell Ecosystem, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China.
| | - Mengying Zhang
- Key Laboratory of Drug Metabolism and Pharmacokinetics, Haihe Laboratory of Cell Ecosystem, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China
| | - Enxiang Tao
- Key Laboratory of Drug Metabolism and Pharmacokinetics, Haihe Laboratory of Cell Ecosystem, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China
| | - Jing Wang
- Jiangsu Renocell Biotech Co. Ltd., Nanjing, China
| | - Ning Wei
- Key Laboratory of Drug Metabolism and Pharmacokinetics, Haihe Laboratory of Cell Ecosystem, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China
- Jiangsu Renocell Biotech Co. Ltd., Nanjing, China
| | - Yi Lu
- Key Laboratory of Drug Metabolism and Pharmacokinetics, Haihe Laboratory of Cell Ecosystem, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China
| | - Qing Liu
- Jiangsu Renocell Biotech Co. Ltd., Nanjing, China
| | - Kun Hao
- Key Laboratory of Drug Metabolism and Pharmacokinetics, Haihe Laboratory of Cell Ecosystem, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China.
| | - Fang Zhou
- Key Laboratory of Drug Metabolism and Pharmacokinetics, Haihe Laboratory of Cell Ecosystem, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China.
| | - Guangji Wang
- Key Laboratory of Drug Metabolism and Pharmacokinetics, Haihe Laboratory of Cell Ecosystem, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China.
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7
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Brouwer H, Porbahaie M, Boeren S, Busch M, Bouwmeester H. The in vitro gastrointestinal digestion-associated protein corona of polystyrene nano- and microplastics increases their uptake by human THP-1-derived macrophages. Part Fibre Toxicol 2024; 21:4. [PMID: 38311718 PMCID: PMC10838446 DOI: 10.1186/s12989-024-00563-z] [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: 10/16/2023] [Accepted: 01/16/2024] [Indexed: 02/06/2024] Open
Abstract
BACKGROUND Micro- and nanoplastics (MNPs) represent one of the most widespread environmental pollutants of the twenty-first century to which all humans are orally exposed. Upon ingestion, MNPs pass harsh biochemical conditions within the gastrointestinal tract, causing a unique protein corona on the MNP surface. Little is known about the digestion-associated protein corona and its impact on the cellular uptake of MNPs. Here, we systematically studied the influence of gastrointestinal digestion on the cellular uptake of neutral and charged polystyrene MNPs using THP-1-derived macrophages. RESULTS The protein corona composition was quantified using LC‒MS-MS-based proteomics, and the cellular uptake of MNPs was determined using flow cytometry and confocal microscopy. Gastrointestinal digestion resulted in a distinct protein corona on MNPs that was retained in serum-containing cell culture medium. Digestion increased the uptake of uncharged MNPs below 500 nm by 4.0-6.1-fold but did not affect the uptake of larger sized or charged MNPs. Forty proteins showed a good correlation between protein abundance and MNP uptake, including coagulation factors, apolipoproteins and vitronectin. CONCLUSION This study provides quantitative data on the presence of gastrointestinal proteins on MNPs and relates this to cellular uptake, underpinning the need to include the protein corona in hazard assessment of MNPs.
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Affiliation(s)
- Hugo Brouwer
- Division of Toxicology, Wageningen University, Stippeneng 4, 6708 WE, Wageningen, The Netherlands.
| | - Mojtaba Porbahaie
- Laboratory of Cell Biology and Immunology, Wageningen University, Wageningen, The Netherlands
| | - Sjef Boeren
- Laboratory of Biochemistry, Wageningen University, Wageningen, The Netherlands
| | - Mathias Busch
- Division of Toxicology, Wageningen University, Stippeneng 4, 6708 WE, Wageningen, The Netherlands
| | - Hans Bouwmeester
- Division of Toxicology, Wageningen University, Stippeneng 4, 6708 WE, Wageningen, The Netherlands
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Brown LN, Barth JL, Jafri S, Rumschlag JA, Jenkins TR, Atkinson C, Lang H. Complement factor B is essential for the proper function of the peripheral auditory system. Front Neurol 2023; 14:1214408. [PMID: 37560455 PMCID: PMC10408708 DOI: 10.3389/fneur.2023.1214408] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2023] [Accepted: 07/05/2023] [Indexed: 08/11/2023] Open
Abstract
Sensorineural hearing loss is associated with dysfunction of cochlear cells. Although immune cells play a critical role in maintaining the inner ear microenvironment, the precise immune-related molecular mechanisms underlying the pathophysiology of hearing loss remain unclear. The complement cascade contributes to the regulation of immune cell activity. Additionally, activation of the complement cascade can lead to the cellular opsonization of cells and pathogens, resulting in their engulfment and elimination by phagocytes. Complement factor B (fB) is an essential activator protein in the alternative complement pathway, and variations in the fB gene are associated with age-related macular degeneration. Here we show that mice of both sexes deficient in fB functional alleles (fB-/-) demonstrate progressive hearing impairment. Transcriptomic analysis of auditory nerves from adult mice detected 706 genes that were significantly differentially expressed between fB-/- and wild-type control animals, including genes related to the extracellular matrix and neural development processes. Additionally, a subset of differentially expressed genes was related to myelin function and neural crest development. Histological and immunohistochemical investigations revealed pathological alterations in auditory nerve myelin sheathes of fB-/- mice. Pathological alterations were also seen in the stria vascularis of the cochlear lateral wall in these mice. Our results implicate fB as an integral regulator of myelin maintenance and stria vascularis integrity, underscoring the importance of understanding the involvement of immune signaling pathways in sensorineural hearing loss.
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Affiliation(s)
- LaShardai N. Brown
- Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC, United States
| | - Jeremy L. Barth
- Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC, United States
| | - Shabih Jafri
- Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC, United States
| | - Jeffrey A. Rumschlag
- Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC, United States
| | - Tyreek R. Jenkins
- Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC, United States
| | - Carl Atkinson
- Division of Pulmonary Medicine, University of Florida, Gainesville, FL, United States
| | - Hainan Lang
- Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC, United States
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Krawetz RJ, Larijani L, Corpuz JM, Ninkovic N, Das N, Olsen A, Mohtadi N, Rezansoff A, Dufour A. Mesenchymal progenitor cells from non-inflamed versus inflamed synovium post-ACL injury present with distinct phenotypes and cartilage regeneration capacity. Stem Cell Res Ther 2023; 14:168. [PMID: 37357305 DOI: 10.1186/s13287-023-03396-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2022] [Accepted: 06/05/2023] [Indexed: 06/27/2023] Open
Abstract
BACKGROUND Osteoarthritis (OA) is a chronic debilitating disease impacting a significant percentage of the global population. While there are numerous surgical and non-invasive interventions that can postpone joint replacement, there are no current treatments which can reverse the joint damage occurring during the pathogenesis of the disease. While many groups are investigating the use of stem cell therapies in the treatment of OA, we still don't have a clear understanding of the role of these cells in the body, including heterogeneity of tissue resident adult mesenchymal progenitor cells (MPCs). METHODS In the current study, we examined MPCs from the synovium and individuals with or without a traumatic knee joint injury and explored the chondrogenic differentiation capacity of these MPCs in vitro and in vivo. RESULTS We found that there is heterogeneity of MPCs with the adult synovium and distinct sub-populations of MPCs and the abundancy of these sub-populations change with joint injury. Furthermore, only some of these sub-populations have the ability to effect cartilage repair in vivo. Using an unbiased proteomics approach, we were able to identify cell surface markers that identify this pro-chondrogenic MPC population in normal and injured joints, specifically CD82LowCD59+ synovial MPCs have robust cartilage regenerative properties in vivo. CONCLUSIONS The results of this study clearly show that cells within the adult human joint can impact cartilage repair and that these sub-populations exist within joints that have undergone a traumatic joint injury. Therefore, these populations can be exploited for the treatment of cartilage injuries and OA in future clinical trials.
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Affiliation(s)
- Roman J Krawetz
- McCaig Institute for Bone and Joint Health, Faculty of Medicine, University of Calgary, 3330 Hospital Drive NW, Calgary, AB, T2N 4N1, Canada.
- Department Cell Biology and Anatomy, University of Calgary, Calgary, AB, Canada.
- Department of Surgery, University of Calgary, Calgary, AB, Canada.
- Department of Biomedical Engineering, University of Calgary, Calgary, AB, Canada.
| | - Leila Larijani
- McCaig Institute for Bone and Joint Health, Faculty of Medicine, University of Calgary, 3330 Hospital Drive NW, Calgary, AB, T2N 4N1, Canada
| | - Jessica May Corpuz
- McCaig Institute for Bone and Joint Health, Faculty of Medicine, University of Calgary, 3330 Hospital Drive NW, Calgary, AB, T2N 4N1, Canada
- Department of Biomedical Engineering, University of Calgary, Calgary, AB, Canada
| | - Nicoletta Ninkovic
- McCaig Institute for Bone and Joint Health, Faculty of Medicine, University of Calgary, 3330 Hospital Drive NW, Calgary, AB, T2N 4N1, Canada
| | - Nabangshu Das
- McCaig Institute for Bone and Joint Health, Faculty of Medicine, University of Calgary, 3330 Hospital Drive NW, Calgary, AB, T2N 4N1, Canada
| | - Alexandra Olsen
- McCaig Institute for Bone and Joint Health, Faculty of Medicine, University of Calgary, 3330 Hospital Drive NW, Calgary, AB, T2N 4N1, Canada
- Department of Biomedical Engineering, University of Calgary, Calgary, AB, Canada
| | - Nicholas Mohtadi
- McCaig Institute for Bone and Joint Health, Faculty of Medicine, University of Calgary, 3330 Hospital Drive NW, Calgary, AB, T2N 4N1, Canada
- Department of Surgery, University of Calgary, Calgary, AB, Canada
- Sport Medicine Centre, Faculty of Kinesiology, University of Calgary, Calgary, AB, Canada
| | - Alexander Rezansoff
- McCaig Institute for Bone and Joint Health, Faculty of Medicine, University of Calgary, 3330 Hospital Drive NW, Calgary, AB, T2N 4N1, Canada
- Department of Surgery, University of Calgary, Calgary, AB, Canada
- Sport Medicine Centre, Faculty of Kinesiology, University of Calgary, Calgary, AB, Canada
| | - Antoine Dufour
- McCaig Institute for Bone and Joint Health, Faculty of Medicine, University of Calgary, 3330 Hospital Drive NW, Calgary, AB, T2N 4N1, Canada
- Department of Physiology and Pharmacology, University of Calgary, Calgary, AB, Canada
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10
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Kadri N, Amu S, Iacobaeus E, Boberg E, Le Blanc K. Current perspectives on mesenchymal stromal cell therapy for graft versus host disease. Cell Mol Immunol 2023; 20:613-625. [PMID: 37165014 DOI: 10.1038/s41423-023-01022-z] [Citation(s) in RCA: 38] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Accepted: 04/07/2023] [Indexed: 05/12/2023] Open
Abstract
Graft versus host disease (GvHD) is the clinical condition in which bone marrow-derived mesenchymal stromal cells (MSCs) have been most frequently studied. In this review, we summarize the experience from clinical trials that have paved the way to translation. While MSC-based therapy has shown an exceptional safety profile, identifying potency assays and disease biomarkers that reliably predict the capacity of a specific MSC batch to alleviate GvHD has been difficult. As GvHD diagnosis and staging are based solely on clinical criteria, individual patients recruited in the same clinical trial may have vastly different underlying biology, obscuring trial outcomes and making it difficult to determine the benefit of MSCs in subgroups of patients. An accumulating body of evidence indicates the importance of considering not only the cell product but also patient-specific biomarkers and/or immune characteristics in determining MSC responsiveness. A mode of action where intravascular MSC destruction is followed by monocyte-efferocytosis-mediated skewing of the immune repertoire in a permissive inflammatory environment would both explain why cell engraftment is irrelevant for MSC efficacy and stress the importance of biologic differences between responding and nonresponding patients. We recommend a combined analysis of clinical outcomes and both biomarkers of disease activity and MSC potency assays to identify patients with GvHD who are likely to benefit from MSC therapy.
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Affiliation(s)
- Nadir Kadri
- Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Sylvie Amu
- Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Ellen Iacobaeus
- Department of Clinical Neuroscience, Division of Neurology, Karolinska Institute and Karolinska University Hospital, Stockholm, Sweden
| | - Erik Boberg
- Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
- Department of Haematology, Karolinska University Hospital, Stockholm, Sweden
| | - Katarina Le Blanc
- Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
- Department of Cell Therapies and Allogeneic Stem Cell Transplantation Karolinska University Hospital, Stockholm, Sweden.
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11
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Lin X, Tian T, Wei Z, Hakonarson H. Clustering of single-cell multi-omics data with a multimodal deep learning method. Nat Commun 2022; 13:7705. [PMID: 36513636 PMCID: PMC9748135 DOI: 10.1038/s41467-022-35031-9] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Accepted: 11/16/2022] [Indexed: 12/15/2022] Open
Abstract
Single-cell multimodal sequencing technologies are developed to simultaneously profile different modalities of data in the same cell. It provides a unique opportunity to jointly analyze multimodal data at the single-cell level for the identification of distinct cell types. A correct clustering result is essential for the downstream complex biological functional studies. However, combining different data sources for clustering analysis of single-cell multimodal data remains a statistical and computational challenge. Here, we develop a novel multimodal deep learning method, scMDC, for single-cell multi-omics data clustering analysis. scMDC is an end-to-end deep model that explicitly characterizes different data sources and jointly learns latent features of deep embedding for clustering analysis. Extensive simulation and real-data experiments reveal that scMDC outperforms existing single-cell single-modal and multimodal clustering methods on different single-cell multimodal datasets. The linear scalability of running time makes scMDC a promising method for analyzing large multimodal datasets.
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Affiliation(s)
- Xiang Lin
- Department of Computer Science, New Jersey Institute of Technology, Newark, NJ, USA
| | - Tian Tian
- Center of Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | - Zhi Wei
- Department of Computer Science, New Jersey Institute of Technology, Newark, NJ, USA.
| | - Hakon Hakonarson
- Center of Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA, USA
- Division of Human Genetics, Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
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12
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Ting AE, Baker EK, Champagne J, Desai TJ, Dos Santos CC, Heijink IH, Itescu S, Le Blanc K, Matthay MA, McAuley DF, McIntyre L, Mei SHJ, Parekkadan B, Rocco PRM, Sheridan J, Thébaud B, Weiss DJ. Proceedings of the ISCT scientific signature series symposium, "Advances in cell and gene therapies for lung diseases and critical illnesses": International Society for Cell & Gene Therapy, Burlington VT, US, July 16, 2021. Cytotherapy 2022; 24:774-788. [PMID: 35613962 DOI: 10.1016/j.jcyt.2021.11.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Accepted: 11/05/2021] [Indexed: 11/20/2022]
Abstract
The ISCT Scientific Signature Series Symposium "Advances in Cell and Gene Therapies for Lung Diseases and Critical Illnesses" was held as an independent symposium in conjunction with the biennial meeting, "Stem Cells, Cell Therapies, and Bioengineering in Lung Biology and Diseases," which took place July 12-15, 2021, at the University of Vermont. This is the third Respiratory System-based Signature Series event; the first 2, "Tracheal Bioengineering, the Next Steps" and "Cellular Therapies for Pulmonary Diseases and Critical Illnesses: State of the Art of European Science," took place in 2014 and 2015, respectively. Cell- and gene-based therapies for respiratory diseases and critical illnesses continue to be a source of great promise and opportunity. This reflects ongoing advancements in understanding of the mechanisms by which cell-based therapies, particularly those using mesenchymal stromal cells (MSCs), can mitigate different lung injuries and the increasing sophistication with which preclinical data is translated into clinical investigations. This also reflects continuing evolution in gene transfer vectors, including those designed for in situ gene editing in parallel with those targeting gene or cell replacement. Therefore, this symposium convened global thought leaders in a forum designed to catalyze communication and collaboration to bring the greatest possible innovation and value of cell- and gene-based therapies for patients with respiratory diseases and critical illnesses.
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Affiliation(s)
| | - Elizabeth K Baker
- Newborn Research Centre, Royal Women's Hospital, Melbourne, Victoria, Australia
| | | | - Tushar J Desai
- Stanford University School of Medicine, Stanford, California, USA
| | - Claudia C Dos Santos
- Interdepartmental Division of Critical Care, Department of Medicine and the Keenan Center for Biomedical Research, St. Michael's Hospital, University of Toronto, Toronto, Canada
| | - Irene H Heijink
- Medical Center Groningen, Department of Pathology and Medical Biology, University of Groningen, Groningen, the Netherlands
| | | | - Katarina Le Blanc
- Department of Laboratory Medicine, Karolinska Institutet, Sweden; Department of Cellular Therapy and Allogeneic Stem Cell Transplantation, Karolinska University Hospital, Stockholm, Sweden
| | - Michael A Matthay
- University of San Francisco, San Francisco, California, United States
| | - Daniel F McAuley
- Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, NI, UK
| | | | - Shirley H J Mei
- Sinclair Centre for Regenerative Medicine, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
| | - Biju Parekkadan
- Sentien Biotechnologies, Lexington, Massachusetts, USA; Rutgers University, Piscataway, New Jersey, USA
| | - Patricia R M Rocco
- Laboratory of Pulmonary Investigation, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | | | | | - Daniel J Weiss
- University of Vermont College of Medicine, Burlington, Vermont, USA.
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13
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Cross Talk between Mesenchymal Stem/Stromal Cells and Innate Immunocytes Concerning Lupus Disease. Stem Cell Rev Rep 2022; 18:2781-2796. [DOI: 10.1007/s12015-022-10397-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/15/2022] [Indexed: 10/16/2022]
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14
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Biomimetic approaches for targeting tumor inflammation. Semin Cancer Biol 2022; 86:555-567. [DOI: 10.1016/j.semcancer.2022.04.007] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 03/31/2022] [Accepted: 04/20/2022] [Indexed: 02/08/2023]
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15
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Muthu S, Mir AA, Kumar R, Yadav V, Jeyaraman M, Khanna M. What is the clinically significant ideal mesenchymal stromal cell count in the management of osteoarthritis of the knee? - Meta-analysis of randomized controlled trials. J Clin Orthop Trauma 2022; 25:101744. [PMID: 35004170 PMCID: PMC8719017 DOI: 10.1016/j.jcot.2021.101744] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Accepted: 12/17/2021] [Indexed: 02/08/2023] Open
Abstract
STUDY DESIGN Meta-analysis. OBJECTIVES We aim to identify the clinically significant ideal Mesenchymal Stem Cell (MSC) count in the management of osteoarthritis of knee from Randomized Controlled Trials (RCTs) available in the literature. MATERIALS AND METHODS We conducted independent and duplicate electronic database searches including PubMed, Embase, Web of Science, and Cochrane Library till August 2021 for RCTs conducted in the management of knee osteoarthritis using MSC therapy specifying the quantity of MSCs delivered. We categorized the studies based on the MSC count utilized in them into four groups namely <1 × 107 MSCs (Group I), 1-5x107 MSCs (Group II), 5-10 × 107 MSCs (Group III), and >10 × 107 MSCs (Group IV). Visual Analog Score (VAS) for Pain, Western Ontario McMaster Universities Osteoarthritis Index (WOMAC), Lysholm score, Knee Osteoarthritis Outcome Score (KOOS), and adverse events were the outcomes analyzed. Analysis was performed in R-platform using OpenMeta [Analyst] software. RESULTS 14 studies involving 564 patients were included for analysis. We noted incremental decrease in the VAS with increasing dosage of MSCs at 12 months [Group I,WMD = 2.641(p = 0.854); Group II, WMD = -4.853(p = 0.379); Group III, WMD = -12.154 (p = 0.316); Group IV, WMD = -15.935(p = 0.116)], and 24 months [Group I,WMD = -6(p = 0.001); Group II, WMD = -15(p = 0.001); Group IV, WMD = -20(p = 0.001)]. We also noted incremental improvement in the WOMAC, KOOS with increasing dosage of MSCs at 12 months [Group I, WMD = 7(p = 0.001); Group II, WMD = 28(p = 0.001); Group IV, WMD = 30(p = 0.001)] and [Group II, WMD = -2.562(p = 0.676); Group III, WMD = 7.670(p = 0.099); Group IV, WMD = 13.475(p = 0.261)] respectively. However, we noted significant reduction in the Lysholm score in Group IV, compared to the others at 12 months (WMD = -12.5, 95%CI[-25.883,0.883]) and 24 months (WMD = -6.6, 95%CI[-23.596,10.396]). We did not find any significant increase in the adverse events with incremental dosage of MSCs in any of the groups compared. CONCLUSION Compared to the four dosage groups of MSCs analyzed, Group III showed consistent significant improvement in pain and functional outcomes analyzed compared to the other groups. Hence, we recommend a cell volume of 5-10 × 107 cells to be delivered to the target site to obtain superior benefits out of the procedure. However, we urge future trials of sufficient quality to validate our findings to arrive at a consensus on the ideal count of MSCs to be delivered in the cellular therapy for knee osteoarthritis.
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Affiliation(s)
- Sathish Muthu
- Department of Orthopaedics, Government Medical College and Hospital, Dindigul, Tamil Nadu, India
- Department of Biotechnology, School of Engineering and Technology, Sharda University, Greater Noida, Uttar Pradesh, India
- Indian Stem Cell Study Group (ISCSG) Association, Lucknow, Uttar Pradesh, India
| | - Ayaz Ali Mir
- Indian Stem Cell Study Group (ISCSG) Association, Lucknow, Uttar Pradesh, India
- Fellow in Orthopaedic Rheumatology, Dr. RML National Law University, Lucknow, Uttar Pradesh, India
| | - Rakesh Kumar
- Department of Orthopaedics, School of Medical Sciences and Research, Sharda University, Greater Noida, Uttar Pradesh, India
| | - Vijendra Yadav
- Department of Orthopaedics, Sanjay Gandhi Institute of Trauma & Orthopaedics, Bengaluru, Karnataka, India
| | - Madhan Jeyaraman
- Department of Biotechnology, School of Engineering and Technology, Sharda University, Greater Noida, Uttar Pradesh, India
- Indian Stem Cell Study Group (ISCSG) Association, Lucknow, Uttar Pradesh, India
- Department of Orthopaedics, School of Medical Sciences and Research, Sharda University, Greater Noida, Uttar Pradesh, India
- Corresponding author. Department of Orthopaedics, School of Medical Sciences and Research, Sharda University, Greater Noida, Uttar Pradesh, India.
| | - Manish Khanna
- Indian Stem Cell Study Group (ISCSG) Association, Lucknow, Uttar Pradesh, India
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16
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Najar M, Melki R, Khalife F, Lagneaux L, Bouhtit F, Moussa Agha D, Fahmi H, Lewalle P, Fayyad-Kazan M, Merimi M. Therapeutic Mesenchymal Stem/Stromal Cells: Value, Challenges and Optimization. Front Cell Dev Biol 2022; 9:716853. [PMID: 35096805 PMCID: PMC8795900 DOI: 10.3389/fcell.2021.716853] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2021] [Accepted: 11/02/2021] [Indexed: 12/13/2022] Open
Abstract
Cellular therapy aims to replace damaged resident cells by restoring cellular and molecular environments suitable for tissue repair and regeneration. Among several candidates, mesenchymal stem/stromal cells (MSCs) represent a critical component of stromal niches known to be involved in tissue homeostasis. In vitro, MSCs appear as fibroblast-like plastic adherent cells regardless of the tissue source. The therapeutic value of MSCs is being explored in several conditions, including immunological, inflammatory and degenerative diseases, as well as cancer. An improved understanding of their origin and function would facilitate their clinical use. The stemness of MSCs is still debated and requires further study. Several terms have been used to designate MSCs, although consensual nomenclature has yet to be determined. The presence of distinct markers may facilitate the identification and isolation of specific subpopulations of MSCs. Regarding their therapeutic properties, the mechanisms underlying their immune and trophic effects imply the secretion of various mediators rather than direct cellular contact. These mediators can be packaged in extracellular vesicles, thus paving the way to exploit therapeutic cell-free products derived from MSCs. Of importance, the function of MSCs and their secretome are significantly sensitive to their environment. Several features, such as culture conditions, delivery method, therapeutic dose and the immunobiology of MSCs, may influence their clinical outcomes. In this review, we will summarize recent findings related to MSC properties. We will also discuss the main preclinical and clinical challenges that may influence the therapeutic value of MSCs and discuss some optimization strategies.
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Affiliation(s)
- Mehdi Najar
- Laboratory of Clinical Cell Therapy, Institut Jules Bordet, Université Libre de Bruxelles (ULB), Brussels, Belgium
- Osteoarthritis Research Unit, University of Montreal Hospital Research Center (CRCHUM), Montreal, QC, Canada
| | - Rahma Melki
- Genetics and Immune-Cell Therapy Unit, LBBES Laboratory, Faculty of Sciences, University Mohammed Premier, Oujda, Morocco
| | - Ferial Khalife
- Laboratory of Cancer Biology and Molecular Immunology, Faculty of Sciences I, Hadath, Lebanon
| | - Laurence Lagneaux
- Laboratory of Clinical Cell Therapy, Institut Jules Bordet, Université Libre de Bruxelles (ULB), Brussels, Belgium
| | - Fatima Bouhtit
- Genetics and Immune-Cell Therapy Unit, LBBES Laboratory, Faculty of Sciences, University Mohammed Premier, Oujda, Morocco
- Laboratory of Experimental Hematology, Institut Jules Bordet, Université Libre de Bruxelles (ULB), Bruxelles, Belgium
| | - Douaa Moussa Agha
- Genetics and Immune-Cell Therapy Unit, LBBES Laboratory, Faculty of Sciences, University Mohammed Premier, Oujda, Morocco
- Laboratory of Experimental Hematology, Institut Jules Bordet, Université Libre de Bruxelles (ULB), Bruxelles, Belgium
| | - Hassan Fahmi
- Osteoarthritis Research Unit, University of Montreal Hospital Research Center (CRCHUM), Montreal, QC, Canada
| | - Philippe Lewalle
- Laboratory of Experimental Hematology, Institut Jules Bordet, Université Libre de Bruxelles (ULB), Bruxelles, Belgium
| | - Mohammad Fayyad-Kazan
- Department of Natural Sciences, School of Arts and Sciences, Lebanese American University, Hadath, Lebanon
- Laboratory of Cancer Biology and Molecular Immunology, Faculty of Sciences-I, Lebanese University, Hadath, Lebanon
| | - Makram Merimi
- Genetics and Immune-Cell Therapy Unit, LBBES Laboratory, Faculty of Sciences, University Mohammed Premier, Oujda, Morocco
- Laboratory of Experimental Hematology, Institut Jules Bordet, Université Libre de Bruxelles (ULB), Bruxelles, Belgium
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17
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Fu G, Chen T, Wu J, Jiang T, Tang D, Bonaroti J, Conroy J, Scott MJ, Deng M, Billiar TR. Single-Cell Transcriptomics Reveals Compartment-Specific Differences in Immune Responses and Contributions for Complement Factor 3 in Hemorrhagic Shock Plus Tissue Trauma. Shock 2021; 56:994-1008. [PMID: 33710107 PMCID: PMC8429528 DOI: 10.1097/shk.0000000000001765] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
ABSTRACT Hemorrhagic shock with tissue trauma (HS/T) leads to the activation of a system-wide immune-inflammatory response that involves all organs and body compartments. Recent advances in single-cell analysis permit the simultaneous assessment of transcriptomic patterns in a large number of cells making it feasible to survey the landscape of immune cell responses across numerous anatomic sites. Here, we used single-cell RNA sequencing of leukocytes from the blood, liver, and spleen to identify the major shifts in gene expression by cell type and compartment in a mouse HS/T model. At 6 h, dramatic changes in gene expression were observed across multiple-cell types and in all compartments in wild-type mice. Monocytes from circulation and liver exhibited a significant upregulation of genes associated with chemotaxis and migration and a simultaneous suppression of genes associated with interferon signaling and antigen presentation. In contrast, liver conventional DC exhibited a unique pattern compared with other myeloid cells that included a pronounced increase in major histocompatibility complex class II (MHCII) gene expression. The dominant pattern across all compartments for B and T cells was a suppression of genes associated with cell activation and signaling after HS/T. Using complement factor 3 (C3) knockout mice we unveiled a role for C3 in the suppression of monocyte Major Histocompatibility Complex class II expression and activation of gene expression associated with migration, phagocytosis and cytokine upregulation, and an unexpected role in promoting interferon-signaling in a subset of B and T cells across all three compartments after HS/T. This transcriptomic landscape study of immune cells provides new insights into the host immune response to trauma, as well as a rich resource for further investigation of trauma-induced immune responses and complement in driving interferon signaling.
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Affiliation(s)
- Guang Fu
- Department of General Surgery, the Third Xiangya Hospital, Central South University, Changsha, Hunan, China
- Department of Surgery, University of Pittsburgh, PA, USA
| | - Tianmeng Chen
- Department of Surgery, University of Pittsburgh, PA, USA
- Cellular and Molecular Pathology Program, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA
| | - Junru Wu
- Department of General Surgery, the Third Xiangya Hospital, Central South University, Changsha, Hunan, China
- Department of Surgery, University of Pittsburgh, PA, USA
| | - Ting Jiang
- Department of Surgery, University of Pittsburgh, PA, USA
- School of Medicine, Tsinghua University, Beijing, China
| | - Da Tang
- Department of General Surgery, the Third Xiangya Hospital, Central South University, Changsha, Hunan, China
- Department of Surgery, University of Pittsburgh, PA, USA
| | | | - Julia Conroy
- Department of Surgery, University of Pittsburgh, PA, USA
| | - Melanie J Scott
- Department of Surgery, University of Pittsburgh, PA, USA
- Trauma Research Center, University of Pittsburgh, PA, USA
| | - Meihong Deng
- Department of Surgery, University of Pittsburgh, PA, USA
- Department of Surgery, Ohio State University, Ohio, USA
| | - Timothy R Billiar
- Department of Surgery, University of Pittsburgh, PA, USA
- Trauma Research Center, University of Pittsburgh, PA, USA
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18
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Ehnert S, Relja B, Schmidt-Bleek K, Fischer V, Ignatius A, Linnemann C, Rinderknecht H, Huber-Lang M, Kalbitz M, Histing T, Nussler AK. Effects of immune cells on mesenchymal stem cells during fracture healing. World J Stem Cells 2021; 13:1667-1695. [PMID: 34909117 PMCID: PMC8641016 DOI: 10.4252/wjsc.v13.i11.1667] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Revised: 03/31/2021] [Accepted: 09/03/2021] [Indexed: 02/06/2023] Open
Abstract
In vertebrates, bone is considered an osteoimmune system which encompasses functions of a locomotive organ, a mineral reservoir, a hormonal organ, a stem cell pool and a cradle for immune cells. This osteoimmune system is based on cooperatively acting bone and immune cells, cohabitating within the bone marrow. They are highly interdependent, a fact that is confounded by shared progenitors, mediators, and signaling pathways. Successful fracture healing requires the participation of all the precursors, immune and bone cells found in the osteoimmune system. Recent evidence demonstrated that changes of the immune cell composition and function may negatively influence bone healing. In this review, first the interplay between different immune cell types and osteoprogenitor cells will be elaborated more closely. The separate paragraphs focus on the specific cell types, starting with the cells of the innate immune response followed by cells of the adaptive immune response, and the complement system as mediator between them. Finally, a brief overview on the challenges of preclinical testing of immune-based therapeutic strategies to support fracture healing will be given.
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Affiliation(s)
- Sabrina Ehnert
- Siegfried Weller Research Institute at the BG Trauma Center Tübingen, Department of Trauma and Reconstructive Surgery, University of Tübingen, Tübingen 72076, Germany
| | - Borna Relja
- Experimental Radiology, Department of Radiology and Nuclear Medicine, Otto-von-Guericke University, Magdeburg 39120, Germany
| | - Katharina Schmidt-Bleek
- Julius Wolff Institute and Berlin Institute of Health Center of Regenerative Therapies, Charité - University Medicine Berlin, Berlin 13353, Germany
| | - Verena Fischer
- Institute of Orthopedic Research and Biomechanics, Ulm University Medical Center, Ulm 89091, Germany
| | - Anita Ignatius
- Institute of Orthopedic Research and Biomechanics, Ulm University Medical Center, Ulm 89091, Germany
| | - Caren Linnemann
- Siegfried Weller Research Institute at the BG Trauma Center Tübingen, Department of Trauma and Reconstructive Surgery, University of Tübingen, Tübingen 72076, Germany
| | - Helen Rinderknecht
- Siegfried Weller Research Institute at the BG Trauma Center Tübingen, Department of Trauma and Reconstructive Surgery, University of Tübingen, Tübingen 72076, Germany
| | - Markus Huber-Lang
- Institute for Clinical and Experimental Trauma-Immunology (ITI), University Hospital Ulm, Ulm 89091, Germany
| | - Miriam Kalbitz
- Department of Trauma and Orthopedic Surgery, University Hospital Erlangen Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen 91054, Germany
| | - Tina Histing
- Siegfried Weller Research Institute at the BG Trauma Center Tübingen, Department of Trauma and Reconstructive Surgery, University of Tübingen, Tübingen 72076, Germany
| | - Andreas K Nussler
- Siegfried Weller Research Institute at the BG Trauma Center Tübingen, Department of Trauma and Reconstructive Surgery, University of Tübingen, Tübingen 72076, Germany
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19
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Immunomodulatory Actions of Mesenchymal Stromal Cells (MSCs) in Osteoarthritis of the Knee. OSTEOLOGY 2021. [DOI: 10.3390/osteology1040020] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Cellular therapy offers regeneration which curbs osteoarthritis of the knee. Among cellular therapies, mesenchymal stromal cells (MSCs) are readily isolated from various sources as culture expanded and unexpanded cellular population which are used as therapeutic products. Though MSCs possess a unique immunological and regulatory profile through cross-talk between MSCs and immunoregulatory cells (T cells, NK cells, dendritic cells, B cells, neutrophils, monocytes, and macrophages), they provide an immunotolerant environment when transplanted to the site of action. Immunophenotypic profile allows MSCs to escape immune surveillance and promotes their hypoimmunogenic or immune-privileged status. MSCs do not elicit a proliferative response when co-cultured with allogeneic T cells in vitro. MSCs secrete a wide range of anti-inflammatory mediators such as PGE-2, IDO, IL-1Ra, and IL-10. They also stimulate the resilient chondrogenic progenitors and enhance the chondrocyte differentiation by secretion of BMPs and TGFβ1. We highlight the various mechanisms of MSCs during tissue healing signals, their interaction with the immune system, and the impact of their lifespan in the management of osteoarthritis of the knee. A better understanding of the immunobiology of MSC renders them as an efficient therapeutic product for the management of osteoarthritis of the knee.
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20
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Amadeo F, Trivino Cepeda K, Littlewood J, Wilm B, Taylor A, Murray P. Mesenchymal stromal cells: what have we learned so far about their therapeutic potential and mechanisms of action? Emerg Top Life Sci 2021; 5:549-562. [PMID: 34495324 PMCID: PMC8589440 DOI: 10.1042/etls20210013] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Revised: 08/11/2021] [Accepted: 08/27/2021] [Indexed: 01/10/2023]
Abstract
Mesenchymal stromal cells (MSCs) have been found to be safe and effective in a wide range of animal models of human disease. MSCs have been tested in thousands of clinical trials, but results show that while these cells appear to be safe, they tend to lack efficacy. This has raised questions about whether animal models are useful for predicting efficacy in patients. However, a problem with animal studies is that there is a lack of standardisation in the models and MSC therapy regimes used; there appears to be publication bias towards studies reporting positive outcomes; and the reproducibility of results from animal experiments tends not to be confirmed prior to clinical translation. A further problem is that while some progress has been made towards investigating the mechanisms of action (MoA) of MSCs, we still fail to understand how they work. To make progress, it is important to ensure that prior to clinical translation, the beneficial effects of MSCs in animal studies are real and can be repeated by independent research groups. We also need to understand the MoA of MSCs to assess whether their effects are likely to be beneficial across different species. In this review, we give an overview of the current clinical picture of MSC therapies and discuss what we have learned from animal studies. We also give a comprehensive update of what we know about the MoA of MSCs, particularly in relation to their role in immunomodulation.
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Affiliation(s)
- Francesco Amadeo
- Department of Molecular Physiology and Cell Signalling, Integrative Biology, University of Liverpool, Crown Street, L69 3GE Liverpool, U.K
- Centre for Pre-clinical Imaging, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Crown Street, L69 3GE Liverpool, U.K
| | - Katherine Trivino Cepeda
- Department of Molecular Physiology and Cell Signalling, Integrative Biology, University of Liverpool, Crown Street, L69 3GE Liverpool, U.K
- Centre for Pre-clinical Imaging, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Crown Street, L69 3GE Liverpool, U.K
| | - James Littlewood
- Department of Molecular Physiology and Cell Signalling, Integrative Biology, University of Liverpool, Crown Street, L69 3GE Liverpool, U.K
- Centre for Pre-clinical Imaging, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Crown Street, L69 3GE Liverpool, U.K
| | - Bettina Wilm
- Department of Molecular Physiology and Cell Signalling, Integrative Biology, University of Liverpool, Crown Street, L69 3GE Liverpool, U.K
- Centre for Pre-clinical Imaging, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Crown Street, L69 3GE Liverpool, U.K
| | - Arthur Taylor
- Department of Molecular Physiology and Cell Signalling, Integrative Biology, University of Liverpool, Crown Street, L69 3GE Liverpool, U.K
- Centre for Pre-clinical Imaging, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Crown Street, L69 3GE Liverpool, U.K
| | - Patricia Murray
- Department of Molecular Physiology and Cell Signalling, Integrative Biology, University of Liverpool, Crown Street, L69 3GE Liverpool, U.K
- Centre for Pre-clinical Imaging, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Crown Street, L69 3GE Liverpool, U.K
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21
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Krampera M, Le Blanc K. Mesenchymal stromal cells: Putative microenvironmental modulators become cell therapy. Cell Stem Cell 2021; 28:1708-1725. [PMID: 34624232 DOI: 10.1016/j.stem.2021.09.006] [Citation(s) in RCA: 145] [Impact Index Per Article: 36.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
An exceptional safety profile has been shown in a large number of cell therapy clinical trials that use mesenchymal stromal cells (MSCs). However, reliable potency assays are still lacking to predict MSC immunosuppressive efficacy in the clinical setting. Nevertheless, MSCs are approved in Japan and Europe for the treatment of graft-versus-host and Crohn's fistular diseases, but not in the United States for any clinical indication. We discuss potential mechanisms of action for the therapeutic effects of MSC transplantation, experimental models that dissect tissue modulating function of MSCs, and approaches for identifying MSC effects in vivo by integrating biomarkers of disease and MSC activity.
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Affiliation(s)
- Mauro Krampera
- Section of Hematology and Bone Marrow Transplant Unit, Department of Medicine, University of Verona, Verona, Italy.
| | - Katarina Le Blanc
- Division of Clinical Immunology and Transfusion Medicine, Karolinska Institutet, Stockholm, Sweden; Center of Allogeneic Stem Cell Transplantation and Cellular Therapy (CAST), Karolinska University Hospital, Huddinge, Stockholm, Sweden.
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22
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Merimi M, El-Majzoub R, Lagneaux L, Moussa Agha D, Bouhtit F, Meuleman N, Fahmi H, Lewalle P, Fayyad-Kazan M, Najar M. The Therapeutic Potential of Mesenchymal Stromal Cells for Regenerative Medicine: Current Knowledge and Future Understandings. Front Cell Dev Biol 2021; 9:661532. [PMID: 34490235 PMCID: PMC8416483 DOI: 10.3389/fcell.2021.661532] [Citation(s) in RCA: 95] [Impact Index Per Article: 23.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Accepted: 05/28/2021] [Indexed: 12/11/2022] Open
Abstract
In recent decades, research on the therapeutic potential of progenitor cells has advanced considerably. Among progenitor cells, mesenchymal stromal cells (MSCs) have attracted significant interest and have proven to be a promising tool for regenerative medicine. MSCs are isolated from various anatomical sites, including bone marrow, adipose tissue, and umbilical cord. Advances in separation, culture, and expansion techniques for MSCs have enabled their large-scale therapeutic application. This progress accompanied by the rapid improvement of transplantation practices has enhanced the utilization of MSCs in regenerative medicine. During tissue healing, MSCs may exhibit several therapeutic functions to support the repair and regeneration of injured tissue. The process underlying these effects likely involves the migration and homing of MSCs, as well as their immunotropic functions. The direct differentiation of MSCs as a cell replacement therapeutic mechanism is discussed. The fate and behavior of MSCs are further regulated by their microenvironment, which may consequently influence their repair potential. A paracrine pathway based on the release of different messengers, including regulatory factors, chemokines, cytokines, growth factors, and nucleic acids that can be secreted or packaged into extracellular vesicles, is also implicated in the therapeutic properties of MSCs. In this review, we will discuss relevant outcomes regarding the properties and roles of MSCs during tissue repair and regeneration. We will critically examine the influence of the local microenvironment, especially immunological and inflammatory signals, as well as the mechanisms underlying these therapeutic effects. Importantly, we will describe the interactions of local progenitor and immune cells with MSCs and their modulation during tissue injury. We will also highlight the crucial role of paracrine pathways, including the role of extracellular vesicles, in this healing process. Moreover, we will discuss the therapeutic potential of MSCs and MSC-derived extracellular vesicles in the treatment of COVID-19 (coronavirus disease 2019) patients. Overall, this review will provide a better understanding of MSC-based therapies as a novel immunoregenerative strategy.
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Affiliation(s)
- Makram Merimi
- Laboratory of Experimental Hematology, Institut Jules Bordet, Université Libre de Bruxelles (ULB), Bruxelles, Belgium
- LBBES Laboratory, Genetics and Immune-Cell Therapy Unit, Faculty of Sciences, University Mohammed Premier, Oujda, Morocco
| | - Rania El-Majzoub
- Department of Biomedical Sciences, School of Pharmacy, Lebanese International University, Beirut, Lebanon
- Laboratory of Cancer Biology and Molecular Immunology, Faculty of Sciences-I, Lebanese University, Beirut, Lebanon
| | - Laurence Lagneaux
- Laboratory of Clinical Cell Therapy, Institut Jules Bordet, Université Libre de Bruxelles (ULB), Brussels, Belgium
| | - Douâa Moussa Agha
- Laboratory of Experimental Hematology, Institut Jules Bordet, Université Libre de Bruxelles (ULB), Bruxelles, Belgium
| | - Fatima Bouhtit
- Laboratory of Experimental Hematology, Institut Jules Bordet, Université Libre de Bruxelles (ULB), Bruxelles, Belgium
- LBBES Laboratory, Genetics and Immune-Cell Therapy Unit, Faculty of Sciences, University Mohammed Premier, Oujda, Morocco
| | - Nathalie Meuleman
- Laboratory of Experimental Hematology, Institut Jules Bordet, Université Libre de Bruxelles (ULB), Bruxelles, Belgium
| | - Hassan Fahmi
- Osteoarthritis Research Unit, University of Montreal Hospital Research Center (CRCHUM), Montreal, QC, Canada
| | - Philippe Lewalle
- Laboratory of Experimental Hematology, Institut Jules Bordet, Université Libre de Bruxelles (ULB), Bruxelles, Belgium
| | - Mohammad Fayyad-Kazan
- Laboratory of Cancer Biology and Molecular Immunology, Faculty of Sciences-I, Lebanese University, Beirut, Lebanon
- Department of Natural Sciences, School of Arts and Sciences, Lebanese American University, Beirut, Lebanon
| | - Mehdi Najar
- Laboratory of Clinical Cell Therapy, Institut Jules Bordet, Université Libre de Bruxelles (ULB), Brussels, Belgium
- Osteoarthritis Research Unit, University of Montreal Hospital Research Center (CRCHUM), Montreal, QC, Canada
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23
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Varma S, Dey S, S P D. Cellular Uptake Pathways of Nanoparticles: Process of Endocytosis and Factors Affecting Their Fate. Curr Pharm Biotechnol 2021; 23:679-706. [PMID: 34264182 DOI: 10.2174/1389201022666210714145356] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Revised: 05/06/2021] [Accepted: 05/07/2021] [Indexed: 11/22/2022]
Abstract
BACKGROUND Efficient and controlled internalization of NPs into the cells depends on their physicochemical properties and dynamics of the plasma membrane. NPs-cell interaction is a complex process that decides the fate of NPs internalization through different endocytosis pathways. OBJECTIVE The aim of this review is to highlight the physicochemical properties of synthesized nanoparticles (NPs) and their interaction with the cellular-dynamics and pathways like phagocytosis, pinocytosis, macropinocytosis, clathrin, and caveolae-mediated endocytosis and the involvement of effector proteins domain such as clathrin, AP2, caveolin, Arf6, Cdc42, dynamin and cell surface receptors during the endocytosis process of NPs. METHOD An electronic search was performed to explore the focused reviews and research articles on types of endocytosis and physicochemical properties of nanoparticles and their impact on cellular internalizations. The search was limited to peer-reviewed journals in the PubMed database. RESULTS This article discusses in detail how different types of NPs and their physicochemical properties such as size, shape, aspect ratio, surface charge, hydrophobicity, elasticity, stiffness, corona formation, surface functionalization changes the pattern of endocytosis in the presence of different pharmacological blockers. Some external forces like a magnetic field, electric field, and ultrasound exploit the cell membrane dynamics to permeabilize them for efficient internalization with respect to fundamental principles of membrane bending and pore formation. CONCLUSION This review will be useful to attract and guide the audience to understand the endocytosis mechanism and their pattern with respect to physicochemical properties of NPs to improve their efficacy and targeting to achieve the impactful outcome in drug-delivery and theranostics applications.
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Affiliation(s)
- Sameer Varma
- Department of Pharmaceutical Biotechnology, JSS Academy of Higher Education & Research- JSS College of Pharmacy, Ooty-643001, Tamil Nadu, India
| | - Smita Dey
- Department of Pharmaceutical Biotechnology, JSS Academy of Higher Education & Research- JSS College of Pharmacy, Ooty-643001, Tamil Nadu, India
| | - Dhanabal S P
- Department of Pharmacognosy & Phytopharmacy, JSS Academy of Higher Education & Research- JSS College of Pharmacy, Ooty-643001, Tamil Nadu, India
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24
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Rajasekaran S, Chitraa T, Dilip Chand Raja S, Raveendran M, Sharon Miracle N, Sri Vijayanand KS, Ajoy Prasad S, Rishi Mugesh K. Subclinical infection can be an initiator of inflammaging leading to degenerative disk disease: evidence from host-defense response mechanisms. EUROPEAN SPINE JOURNAL : OFFICIAL PUBLICATION OF THE EUROPEAN SPINE SOCIETY, THE EUROPEAN SPINAL DEFORMITY SOCIETY, AND THE EUROPEAN SECTION OF THE CERVICAL SPINE RESEARCH SOCIETY 2021; 30:2586-2604. [PMID: 33835272 DOI: 10.1007/s00586-021-06826-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/19/2020] [Revised: 02/06/2021] [Accepted: 03/20/2021] [Indexed: 12/19/2022]
Abstract
PURPOSE There is considerable controversy on the role of genetics, mechanical and environmental factors, and, recently, on subclinical infection in triggering inflammaging leading to disk degeneration. The present study investigated sequential molecular events in the host, analyzing proteome level changes that will reveal triggering factors of inflammaging and degeneration. METHODS Ten MRI normal disks (ND) from braindead organ donors and 17 degenerated disks (DD) from surgery were subjected to in-gel-based label-free ESI-LC-MS/MS analysis. Bacterial-responsive host-defense response proteins/pathways leading to Inflammaging were identified and compared between ND and DD. RESULTS Out of the 263 well-established host-defense response proteins (HDRPs), 243 proteins were identified, and 64 abundantly expressed HDRPs were analyzed further. Among the 21 HDRPs common to both ND and DD, complement factor 3 (C3) and heparan sulfate proteoglycan 2 (HSPG2) were significantly upregulated, and lysozyme (LYZ), superoxide dismutase 3 (SOD3), phospholipase-A2 (PLA2G2A), and tissue inhibitor of metalloproteinases 3 (TIMP-3) were downregulated in DD. Forty-two specific HDRPs mainly, complement proteins, apolipoproteins, and antimicrobial proteins involved in the complement cascade, neutrophil degranulation, and oxidative-stress regulation pathways representing an ongoing host response to subclinical infection and uncontrolled inflammation were identified in DD. Protein-Protein interaction analysis revealed cross talk between most of the expressed HDRPs, adding evidence to bacterial presence and stimulation of these defense pathways. CONCLUSIONS The predominance of HDRPs involved in complement cascades, neutrophil degranulation, and oxidative-stress regulation indicated an ongoing infection mediated inflammatory process in DD. Our study has documented increasing evidence for bacteria's role in triggering the innate immune system leading to chronic inflammation and degenerative disk disease.
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Affiliation(s)
- S Rajasekaran
- Department of Orthopaedics and Spine Surgery, Ganga Hospital, 313, Mettupalayam road, Coimbatore, India.
| | - Tangavel Chitraa
- Ganga Research Centre, No 91, Mettupalayam road, Coimbatore, 641030, India
| | - S Dilip Chand Raja
- Department of Orthopaedics and Spine Surgery, Ganga Hospital, 313, Mettupalayam road, Coimbatore, India
| | - M Raveendran
- Department of Plant Biotechnology, Tamil Nadu Agricultural University, Coimbatore, 641003, India
| | | | - K S Sri Vijayanand
- Department of Orthopaedics and Spine Surgery, Ganga Hospital, 313, Mettupalayam road, Coimbatore, India
| | - Shetty Ajoy Prasad
- Department of Orthopaedics and Spine Surgery, Ganga Hospital, 313, Mettupalayam road, Coimbatore, India
| | - Kanna Rishi Mugesh
- Department of Orthopaedics and Spine Surgery, Ganga Hospital, 313, Mettupalayam road, Coimbatore, India
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25
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Hasgur S, Desbourdes L, Relation T, Overholt KM, Stanek JR, Guess AJ, Yu M, Patel P, Roback L, Dominici M, Otsuru S, Horwitz EM. Splenic macrophage phagocytosis of intravenously infused mesenchymal stromal cells attenuates tumor localization. Cytotherapy 2021; 23:411-422. [PMID: 33781710 DOI: 10.1016/j.jcyt.2020.04.102] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2019] [Revised: 04/17/2020] [Accepted: 04/28/2020] [Indexed: 12/13/2022]
Abstract
Mesenchymal stromal cells (MSCs) possess remarkable tumor tropism, making them ideal vehicles to deliver tumor-targeted therapeutic agents; however, their value in clinical medicine has yet to be realized. A barrier to clinical utilization is that only a small fraction of infused MSCs ultimately localize to the tumor. In an effort to overcome this obstacle, we sought to enhance MSC trafficking by focusing on the factors that govern MSC arrival within the tumor microenvironment. Our findings show that MSC chemoattraction is only present in select tumors, including osteosarcoma, and that the chemotactic potency among similar tumors varies substantially. Using an osteosarcoma xenograft model, we show that human MSCs traffic to the tumor within several hours of infusion. After arrival, MSCs are observed to localize in clusters near blood vessels and MSC-associated bioluminescence signal intensity is increased, suggesting that the seeded cells expand after engraftment. However, our studies reveal that a significant portion of MSCs are eliminated en route by splenic macrophage phagocytosis, effectively limiting the number of cells available for tumor engraftment. To increase MSC survival, we transiently depleted macrophages with liposomal clodronate, which resulted in increased tumor localization without substantial reduction in tumor-associated macrophages. Our data suggest that transient macrophage depletion will significantly increase the number of MSCs in the spleen and thus improve MSC localization within a tumor, theoretically increasing the effective dose of an anti-cancer agent. This strategy may subsequently improve the clinical efficacy of MSCs as vehicles for the tumor-directed delivery of therapeutic agents.
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Affiliation(s)
- Suheyla Hasgur
- Center for Childhood Cancer and Blood Diseases, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA
| | - Laura Desbourdes
- Center for Childhood Cancer and Blood Diseases, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA
| | - Theresa Relation
- Center for Childhood Cancer and Blood Diseases, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA
| | - Kathleen M Overholt
- Center for Childhood Cancer and Blood Diseases, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA
| | - Joseph R Stanek
- Center for Childhood Cancer and Blood Diseases, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA
| | - Adam J Guess
- Center for Childhood Cancer and Blood Diseases, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA
| | - Minjun Yu
- Center for Childhood Cancer and Blood Diseases, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA
| | - Pratik Patel
- Aflac Cancer & Blood Disorders Center, Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Linda Roback
- Aflac Cancer & Blood Disorders Center, Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Massimo Dominici
- Department of Medical and Surgical Sciences of Children and Adults, University of Modena and Reggio Emilia, Modena, Italy
| | - Satoru Otsuru
- Center for Childhood Cancer and Blood Diseases, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA
| | - Edwin M Horwitz
- Center for Childhood Cancer and Blood Diseases, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA; Aflac Cancer & Blood Disorders Center, Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, Georgia, USA.
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26
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Wauters E, Van Mol P, Garg AD, Jansen S, Van Herck Y, Vanderbeke L, Bassez A, Boeckx B, Malengier-Devlies B, Timmerman A, Van Brussel T, Van Buyten T, Schepers R, Heylen E, Dauwe D, Dooms C, Gunst J, Hermans G, Meersseman P, Testelmans D, Yserbyt J, Tejpar S, De Wever W, Matthys P, Neyts J, Wauters J, Qian J, Lambrechts D. Discriminating mild from critical COVID-19 by innate and adaptive immune single-cell profiling of bronchoalveolar lavages. Cell Res 2021; 31:272-290. [PMID: 33473155 PMCID: PMC8027624 DOI: 10.1038/s41422-020-00455-9] [Citation(s) in RCA: 218] [Impact Index Per Article: 54.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Accepted: 11/20/2020] [Indexed: 02/08/2023] Open
Abstract
How the innate and adaptive host immune system miscommunicate to worsen COVID-19 immunopathology has not been fully elucidated. Here, we perform single-cell deep-immune profiling of bronchoalveolar lavage (BAL) samples from 5 patients with mild and 26 with critical COVID-19 in comparison to BALs from non-COVID-19 pneumonia and normal lung. We use pseudotime inference to build T-cell and monocyte-to-macrophage trajectories and model gene expression changes along them. In mild COVID-19, CD8+ resident-memory (TRM) and CD4+ T-helper-17 (TH17) cells undergo active (presumably antigen-driven) expansion towards the end of the trajectory, and are characterized by good effector functions, while in critical COVID-19 they remain more naïve. Vice versa, CD4+ T-cells with T-helper-1 characteristics (TH1-like) and CD8+ T-cells expressing exhaustion markers (TEX-like) are enriched halfway their trajectories in mild COVID-19, where they also exhibit good effector functions, while in critical COVID-19 they show evidence of inflammation-associated stress at the end of their trajectories. Monocyte-to-macrophage trajectories show that chronic hyperinflammatory monocytes are enriched in critical COVID-19, while alveolar macrophages, otherwise characterized by anti-inflammatory and antigen-presenting characteristics, are depleted. In critical COVID-19, monocytes contribute to an ATP-purinergic signaling-inflammasome footprint that could enable COVID-19 associated fibrosis and worsen disease-severity. Finally, viral RNA-tracking reveals infected lung epithelial cells, and a significant proportion of neutrophils and macrophages that are involved in viral clearance.
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Affiliation(s)
- Els Wauters
- grid.5596.f0000 0001 0668 7884Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium ,grid.410569.f0000 0004 0626 3338Department of Pneumology, University Hospitals Leuven, Leuven, Belgium
| | - Pierre Van Mol
- grid.410569.f0000 0004 0626 3338Department of Pneumology, University Hospitals Leuven, Leuven, Belgium ,grid.5596.f0000 0001 0668 7884Laboratory of Translational Genetics, Department of Human Genetics, KU Leuven, Leuven, Belgium ,grid.511459.dVIB Center for Cancer Biology, VIB, Leuven, Belgium
| | - Abhishek Dinkarnath Garg
- grid.5596.f0000 0001 0668 7884Laboratory for Cell Stress & Immunity (CSI), Department of Cellular and Molecular Medicine (CMM), KU Leuven, Leuven, Belgium
| | - Sander Jansen
- grid.5596.f0000 0001 0668 7884Laboratory of Virology and Chemotherapy, Department of Microbiology, Immunology and Transplantation, Rega Institute, KU Leuven, Leuven, Belgium
| | - Yannick Van Herck
- grid.5596.f0000 0001 0668 7884Laboratory of Experimental Oncology, Department of Oncology, KU Leuven, Leuven, Belgium
| | - Lore Vanderbeke
- grid.5596.f0000 0001 0668 7884Laboratory of Clinical Bacteriology and Mycology, Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium
| | - Ayse Bassez
- grid.5596.f0000 0001 0668 7884Laboratory of Translational Genetics, Department of Human Genetics, KU Leuven, Leuven, Belgium ,grid.511459.dVIB Center for Cancer Biology, VIB, Leuven, Belgium
| | - Bram Boeckx
- grid.5596.f0000 0001 0668 7884Laboratory of Translational Genetics, Department of Human Genetics, KU Leuven, Leuven, Belgium ,grid.511459.dVIB Center for Cancer Biology, VIB, Leuven, Belgium
| | - Bert Malengier-Devlies
- grid.5596.f0000 0001 0668 7884Laboratory of Immunobiology, Department of Microbiology, Immunology and Transplantation, Rega Institute, KU Leuven, Leuven, Belgium
| | - Anna Timmerman
- grid.5596.f0000 0001 0668 7884Laboratory of Translational Genetics, Department of Human Genetics, KU Leuven, Leuven, Belgium ,grid.511459.dVIB Center for Cancer Biology, VIB, Leuven, Belgium
| | - Thomas Van Brussel
- grid.5596.f0000 0001 0668 7884Laboratory of Translational Genetics, Department of Human Genetics, KU Leuven, Leuven, Belgium ,grid.511459.dVIB Center for Cancer Biology, VIB, Leuven, Belgium
| | - Tina Van Buyten
- grid.5596.f0000 0001 0668 7884Laboratory of Virology and Chemotherapy, Department of Microbiology, Immunology and Transplantation, Rega Institute, KU Leuven, Leuven, Belgium
| | - Rogier Schepers
- grid.5596.f0000 0001 0668 7884Laboratory of Translational Genetics, Department of Human Genetics, KU Leuven, Leuven, Belgium ,grid.511459.dVIB Center for Cancer Biology, VIB, Leuven, Belgium
| | - Elisabeth Heylen
- grid.5596.f0000 0001 0668 7884Laboratory of Virology and Chemotherapy, Department of Microbiology, Immunology and Transplantation, Rega Institute, KU Leuven, Leuven, Belgium
| | - Dieter Dauwe
- grid.5596.f0000 0001 0668 7884Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium
| | - Christophe Dooms
- grid.5596.f0000 0001 0668 7884Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium ,grid.410569.f0000 0004 0626 3338Department of Pneumology, University Hospitals Leuven, Leuven, Belgium
| | - Jan Gunst
- grid.5596.f0000 0001 0668 7884Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium
| | - Greet Hermans
- grid.5596.f0000 0001 0668 7884Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium
| | - Philippe Meersseman
- grid.5596.f0000 0001 0668 7884Laboratory for Clinical Infectious and Inflammatory Disorders, Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium
| | - Dries Testelmans
- grid.5596.f0000 0001 0668 7884Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium ,grid.410569.f0000 0004 0626 3338Department of Pneumology, University Hospitals Leuven, Leuven, Belgium
| | - Jonas Yserbyt
- grid.5596.f0000 0001 0668 7884Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium ,grid.410569.f0000 0004 0626 3338Department of Pneumology, University Hospitals Leuven, Leuven, Belgium
| | - Sabine Tejpar
- grid.5596.f0000 0001 0668 7884Molecular Digestive Oncology, Department of Oncology, KU Leuven, Leuven, Belgium
| | - Walter De Wever
- grid.5596.f0000 0001 0668 7884Department of Imaging & Pathology, KU Leuven, Leuven, Belgium
| | - Patrick Matthys
- grid.5596.f0000 0001 0668 7884Laboratory of Immunobiology, Department of Microbiology, Immunology and Transplantation, Rega Institute, KU Leuven, Leuven, Belgium
| | | | - Johan Neyts
- grid.5596.f0000 0001 0668 7884Laboratory of Virology and Chemotherapy, Department of Microbiology, Immunology and Transplantation, Rega Institute, KU Leuven, Leuven, Belgium
| | - Joost Wauters
- grid.5596.f0000 0001 0668 7884Laboratory for Clinical Infectious and Inflammatory Disorders, Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium
| | - Junbin Qian
- grid.13402.340000 0004 1759 700XDepartment of Gynecologic Oncology, Women’s Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310006 China
| | - Diether Lambrechts
- grid.5596.f0000 0001 0668 7884Laboratory of Translational Genetics, Department of Human Genetics, KU Leuven, Leuven, Belgium ,grid.511459.dVIB Center for Cancer Biology, VIB, Leuven, Belgium
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27
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Kamm JL, Riley CB, Parlane N, Gee EK, McIlwraith CW. Interactions Between Allogeneic Mesenchymal Stromal Cells and the Recipient Immune System: A Comparative Review With Relevance to Equine Outcomes. Front Vet Sci 2021; 7:617647. [PMID: 33521090 PMCID: PMC7838369 DOI: 10.3389/fvets.2020.617647] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Accepted: 12/02/2020] [Indexed: 12/27/2022] Open
Abstract
Despite significant immunosuppressive activity, allogeneic mesenchymal stromal cells (MSCs) carry an inherent risk of immune rejection when transferred into a recipient. In naïve recipients, this immune response is initially driven by the innate immune system, an immediate reaction to the foreign cells, and later, the adaptive immune system, a delayed response that causes cell death due to recognition of specific alloantigens by host cells and antibodies. This review describes the actions of MSCs to both suppress and activate the different arms of the immune system. We then review the survival and effectiveness of the currently used allogeneic MSC treatments.
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Affiliation(s)
- J Lacy Kamm
- School of Veterinary Science, Massey University, Palmerston North, New Zealand
| | - Christopher B Riley
- School of Veterinary Science, Massey University, Palmerston North, New Zealand
| | - Natalie Parlane
- Hopkirk Laboratory, AgResearch, Palmerston North, New Zealand
| | - Erica K Gee
- School of Veterinary Science, Massey University, Palmerston North, New Zealand
| | - C Wayne McIlwraith
- Orthopaedic Research Center, C. Wayne McIlwraith Translational Medical Institute, Colorado State University, Fort Collins, CO, United States
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28
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Najar M, Martel-Pelletier J, Pelletier JP, Fahmi H. Novel insights for improving the therapeutic safety and efficiency of mesenchymal stromal cells. World J Stem Cells 2020; 12:1474-1491. [PMID: 33505596 PMCID: PMC7789128 DOI: 10.4252/wjsc.v12.i12.1474] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Revised: 08/13/2020] [Accepted: 09/25/2020] [Indexed: 02/06/2023] Open
Abstract
Mesenchymal stromal cells (MSCs) have attracted great interest in the field of regenerative medicine. They can home to damaged tissue, where they can exert pro-regenerative and anti-inflammatory properties. These therapeutic effects involve the secretion of growth factors, cytokines, and chemokines. Moreover, the functions of MSCs could be mediated by extracellular vesicles (EVs) that shuttle various signaling messengers. Although preclinical studies and clinical trials have demonstrated promising therapeutic results, the efficiency and the safety of MSCs need to be improved. After transplantation, MSCs face harsh environmental conditions, which likely dampen their therapeutic efficacy. A possible strategy aiming to improve the survival and therapeutic functions of MSCs needs to be developed. The preconditioning of MSCs ex vivo would strength their capacities by preparing them to survive and to better function in this hostile environment. In this review, we will discuss several preconditioning approaches that may improve the therapeutic capacity of MSCs. As stated above, EVs can recapitulate the beneficial effects of MSCs and may help avoid many risks associated with cell transplantation. As a result, this novel type of cell-free therapy may be safer and more efficient than the whole cell product. We will, therefore, also discuss current knowledge regarding the therapeutic properties of MSC-derived EVs.
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Affiliation(s)
- Mehdi Najar
- Department of Medicine, University of Montreal, Osteoarthritis Research Unit, University of Montreal Hospital Research Center (CRCHUM), Montreal, QC H2X 0A9, Canada.
| | - Johanne Martel-Pelletier
- Department of Medicine, University of Montreal, Osteoarthritis Research Unit, University of Montreal Hospital Research Center (CRCHUM), Montreal, QC H2X 0A9, Canada
| | - Jean Pierre Pelletier
- Department of Medicine, University of Montreal, Osteoarthritis Research Unit, University of Montreal Hospital Research Center (CRCHUM), Montreal, QC H2X 0A9, Canada
| | - Hassan Fahmi
- Department of Medicine, University of Montreal, Osteoarthritis Research Unit, University of Montreal Hospital Research Center (CRCHUM), Montreal, QC H2X 0A9, Canada
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Najar M, Martel-Pelletier J, Pelletier JP, Fahmi H. Mesenchymal Stromal Cell Immunology for Efficient and Safe Treatment of Osteoarthritis. Front Cell Dev Biol 2020; 8:567813. [PMID: 33072752 PMCID: PMC7536322 DOI: 10.3389/fcell.2020.567813] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2020] [Accepted: 08/24/2020] [Indexed: 12/11/2022] Open
Abstract
Mesenchymal stem cell (MSC) therapy represents a promising approach for the treatment of osteoarthritis (OA). MSCs can be readily isolated from multiple sources and expanded ex vivo for possible clinical application. They possess a unique immunological profile and regulatory machinery that underline their therapeutic effects. They also have the capacity to sense the changes within the tissue environment to display the adequate response. Indeed, there is a close interaction between MSCs and the host cells. Accordingly, MSCs demonstrate encouraging results for a variety of diseases including OA. However, their effectiveness needs to be improved. In this review, we selected to discuss the importance of the immunological features of MSCs, including the type of transplantation and the immune and blood compatibility. It is important to consider MSC immune evasive rather than immune privileged. We also highlighted some of the actions/mechanisms that are displayed during tissue healing including the response of MSCs to injury signals, their interaction with the immune system, and the impact of their lifespan. Finally, we briefly summarized the results of clinical studies reporting on the application of MSCs for the treatment of OA. The research field of MSCs is inspiring and innovative but requires more knowledge about the immunobiological properties of these cells. A better understanding of these features will be key for developing a safe and efficient medicinal product for clinical use in OA.
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Affiliation(s)
- Mehdi Najar
- Osteoarthritis Research Unit, University of Montreal Hospital Research Center, Department of Medicine, University of Montreal, Montreal, QC, Canada
| | - Johanne Martel-Pelletier
- Osteoarthritis Research Unit, University of Montreal Hospital Research Center, Department of Medicine, University of Montreal, Montreal, QC, Canada
| | - Jean-Pierre Pelletier
- Osteoarthritis Research Unit, University of Montreal Hospital Research Center, Department of Medicine, University of Montreal, Montreal, QC, Canada
| | - Hassan Fahmi
- Osteoarthritis Research Unit, University of Montreal Hospital Research Center, Department of Medicine, University of Montreal, Montreal, QC, Canada
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Bhaskar S, Rastogi A, Chattu VK, Adisesh A, Thomas P, Alvarado N, Riahi AD, Varun CN, Pai AR, Barsam S, Walker AH. Key Strategies for Clinical Management and Improvement of Healthcare Services for Cardiovascular Disease and Diabetes Patients in the Coronavirus (COVID-19) Settings: Recommendations From the REPROGRAM Consortium. Front Cardiovasc Med 2020; 7:112. [PMID: 32613010 PMCID: PMC7308556 DOI: 10.3389/fcvm.2020.00112] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Accepted: 06/01/2020] [Indexed: 01/08/2023] Open
Abstract
Patients with cardiovascular disease and diabetes are at potentially higher risk of infection and fatality due to COVID-19. Given the social and economic costs associated with disability due to these conditions, it is imperative that specific considerations for clinical management of these patients be observed. Moreover, the reorganization of health services around the pandemic response further exacerbates the growing crisis around limited access, treatment compliance, acute medical needs, and mental health of patients in this specific subgroup. Existing recommendations and guidelines emanating from respective bodies have addressed some of the pressure points; however, there are variations and limitations vis a vis patient with multiple comorbidities such as obesity. This article will pull together a comprehensive assessment of the association of cardiovascular disease, diabetes, obesity and COVID-19, its impact on the health systems and how best health systems can respond to mitigate current challenges and future needs. We anticipate that in the context of this pandemic, the cardiovascular disease and diabetes patients need a targeted strategy to ensure the harm to this group does not translate to huge costs to society and to the economy. Finally, we propose a triage and management protocol for patients with cardiovascular disease and diabetes in the COVID-19 settings to minimize harm to patients, health systems and healthcare workers alike.
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Affiliation(s)
- Sonu Bhaskar
- Pandemic Health System REsilience PROGRAM (REPROGRAM) Consortium, CVD and Metabolic REPROGRAM Sub-committee, Sydney, NSW, Australia
- Liverpool Hospital & South West Sydney Local Health District (SWSLHD), Department of Neurology & Neurophysiology, Sydney, NSW, Australia
- Neurovascular Imaging Laboratory, Ingham Institute for Applied Medical Research, Clinical Sciences Stream, Sydney, NSW, Australia
- NSW Brain Clot Bank, NSW Health Statewide Biobank, Sydney, NSW, Australia
- South Western Sydney Clinical School, University of New South Wales (UNSW), Sydney, NSW, Australia
| | - Aarushi Rastogi
- Pandemic Health System REsilience PROGRAM (REPROGRAM) Consortium, CVD and Metabolic REPROGRAM Sub-committee, Sydney, NSW, Australia
- Neurovascular Imaging Laboratory, Ingham Institute for Applied Medical Research, Clinical Sciences Stream, Sydney, NSW, Australia
- South Western Sydney Clinical School, University of New South Wales (UNSW), Sydney, NSW, Australia
| | - Vijay Kumar Chattu
- Pandemic Health System REsilience PROGRAM (REPROGRAM) Consortium, CVD and Metabolic REPROGRAM Sub-committee, Sydney, NSW, Australia
- Department of Medicine, St. Michael's Hospital, University of Toronto, Toronto, ON, Canada
| | - Anil Adisesh
- Pandemic Health System REsilience PROGRAM (REPROGRAM) Consortium, CVD and Metabolic REPROGRAM Sub-committee, Sydney, NSW, Australia
- Department of Medicine, St. Michael's Hospital, University of Toronto, Toronto, ON, Canada
| | - Pravin Thomas
- Pandemic Health System REsilience PROGRAM (REPROGRAM) Consortium, CVD and Metabolic REPROGRAM Sub-committee, Sydney, NSW, Australia
- University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom
| | - Negman Alvarado
- Pandemic Health System REsilience PROGRAM (REPROGRAM) Consortium, CVD and Metabolic REPROGRAM Sub-committee, Sydney, NSW, Australia
- Department of Neurophysiology, Instituto Médico Dr. Rodriguez Alfici, Godoy Cruz, Argentina
| | - Anis D. Riahi
- Pandemic Health System REsilience PROGRAM (REPROGRAM) Consortium, CVD and Metabolic REPROGRAM Sub-committee, Sydney, NSW, Australia
- Department of Neurology, Faculty of Medicine, Military Hospital of Tunis, University of Tunis El Manar, Tunis, Tunisia
| | - Chakrakodi N. Varun
- Pandemic Health System REsilience PROGRAM (REPROGRAM) Consortium, CVD and Metabolic REPROGRAM Sub-committee, Sydney, NSW, Australia
- State Level Virus Research and Diagnostics Laboratory, Bangalore Medical College and Research Institute, Bengaluru, India
| | - Anupama R. Pai
- Pandemic Health System REsilience PROGRAM (REPROGRAM) Consortium, CVD and Metabolic REPROGRAM Sub-committee, Sydney, NSW, Australia
- Department of Neuromicrobiology, National Institute of Mental Health and Neurosciences (NIMHANS), Bengaluru, India
| | - Sarah Barsam
- Pandemic Health System REsilience PROGRAM (REPROGRAM) Consortium, CVD and Metabolic REPROGRAM Sub-committee, Sydney, NSW, Australia
- Department of Hematology, North Middlesex Hospital, King's Thrombosis Center & King's College Hospital NHS Foundation Trust, King's College London, London, United Kingdom
| | - Antony H. Walker
- Pandemic Health System REsilience PROGRAM (REPROGRAM) Consortium, CVD and Metabolic REPROGRAM Sub-committee, Sydney, NSW, Australia
- Department of Cardiothoracic Surgery, Lancashire Cardiac Centre, Blackpool Victoria Hospital, NHS, Blackpool, United Kingdom
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Identifying the Therapeutic Significance of Mesenchymal Stem Cells. Cells 2020; 9:cells9051145. [PMID: 32384763 PMCID: PMC7291143 DOI: 10.3390/cells9051145] [Citation(s) in RCA: 95] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2020] [Revised: 05/04/2020] [Accepted: 05/05/2020] [Indexed: 12/12/2022] Open
Abstract
The pleiotropic behavior of mesenchymal stem cells (MSCs) has gained global attention due to their immense potential for immunosuppression and their therapeutic role in immune disorders. MSCs migrate towards inflamed microenvironments, produce anti-inflammatory cytokines and conceal themselves from the innate immune system. These signatures are the reason for the uprising in the sciences of cellular therapy in the last decades. Irrespective of their therapeutic role in immune disorders, some factors limit beneficial effects such as inconsistency of cell characteristics, erratic protocols, deviating dosages, and diverse transfusion patterns. Conclusive protocols for cell culture, differentiation, expansion, and cryopreservation of MSCs are of the utmost importance for a better understanding of MSCs in therapeutic applications. In this review, we address the immunomodulatory properties and immunosuppressive actions of MSCs. Also, we sum up the results of the enhancement, utilization, and therapeutic responses of MSCs in treating inflammatory diseases, metabolic disorders and diabetes.
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Phagocytosis assays with different pH-sensitive fluorescent particles and various readouts. Biotechniques 2020; 68:245-250. [PMID: 32079414 DOI: 10.2144/btn-2020-0003] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
Phagocytosis is a fundamental mechanism of innate immunity and its impairment is associated with severe chronic diseases, for example, chronic obstructive pulmonary disease. Investigating phagocytosis requires flexible tools and assay conditions, such as different fluorescent particle types, detection colors and readouts. We comprehensively evaluated and optimized phagocytosis assays using particles labeled with fluorescent pH-sensitive pHrodo® dyes, facilitating the specific detection of phagocytosed particles. Beads, bacterial and yeast particles labeled with pHrodo red and green were tested for their uptake by THP-1 cells and primary human macrophages by flow cytometry and high-content imaging. Whereas the latter allowed kinetic phagocytosis measurement, the former demonstrated the feasibility of using cell sorting for periods of up to 6 h, enabling downstream applications such as pooled genetic screens.
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Short and Long Term Clinical and Immunologic Follow up after Bone Marrow Mesenchymal Stromal Cell Therapy in Progressive Multiple Sclerosis-A Phase I Study. J Clin Med 2019; 8:jcm8122102. [PMID: 31810187 PMCID: PMC6947442 DOI: 10.3390/jcm8122102] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2019] [Revised: 11/20/2019] [Accepted: 11/21/2019] [Indexed: 12/20/2022] Open
Abstract
Bone marrow derived mesenchymal stromal cells (BM-MSCs) have emerged as a possible new therapy for Multiple Sclerosis (MS), however studies regarding efficacy and in vivo immune response have been limited and inconclusive. We conducted a phase I clinical study assessing safety and clinical and peripheral immune responses after MSC therapy in MS. Seven patients with progressive MS were intravenously infused with a single dose of autologous MSC (1–2 × 106 MSCs/kg body weight). The infusions were safe and well tolerated when given during clinical remission. Five out of seven patients completed the follow up of 48 weeks post-infusion. Brain magnetic resonance imaging (MRI) showed the absence of new T2 lesions at 12 weeks in 5/6 patients, while 3/5 had accumulated new T2 lesions at 48 weeks. Patient expanded disability status scales (EDSS) were stable in 6/6 at 12 weeks but declined in 3/5 patients at 48 weeks. Early changes of circulating microRNA levels (2 h) and increased proportion of FOXP3+ Tregs were detected at 7 days post-infusion compared to baseline levels. In conclusion, MSC therapy was safe and well tolerated and is associated with possible transient beneficial clinical and peripheral immunotolerogenic effects.
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