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2.
Cell Mol Immunol ; 19(2): 210-221, 2022 02.
Article in English | MEDLINE | ID: covidwho-1608557

ABSTRACT

Exploring the cross-talk between the immune system and advanced biomaterials to treat SARS-CoV-2 infection is a promising strategy. Here, we show that ACE2-overexpressing A549 cell-derived microparticles (AO-MPs) are a potential therapeutic agent against SARS-CoV-2 infection. Intranasally administered AO-MPs dexterously navigate the anatomical and biological features of the lungs to enter the alveoli and are taken up by alveolar macrophages (AMs). Then, AO-MPs increase the endosomal pH but decrease the lysosomal pH in AMs, thus escorting bound SARS-CoV-2 from phago-endosomes to lysosomes for degradation. This pH regulation is attributable to oxidized cholesterol, which is enriched in AO-MPs and translocated to endosomal membranes, thus interfering with proton pumps and impairing endosomal acidification. In addition to promoting viral degradation, AO-MPs also inhibit the proinflammatory phenotype of AMs, leading to increased treatment efficacy in a SARS-CoV-2-infected mouse model without side effects. These findings highlight the potential use of AO-MPs to treat SARS-CoV-2-infected patients and showcase the feasibility of MP therapies for combatting emerging respiratory viruses in the future.


Subject(s)
Angiotensin-Converting Enzyme 2/administration & dosage , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/metabolism , COVID-19/therapy , Cell- and Tissue-Based Therapy/methods , Cell-Derived Microparticles/metabolism , Cholesterol/metabolism , Endosomes/chemistry , Macrophages, Alveolar/metabolism , SARS-CoV-2/metabolism , A549 Cells , Angiotensin-Converting Enzyme 2/genetics , Animals , COVID-19/virology , Chlorocebus aethiops , Disease Models, Animal , Female , Humans , Hydrogen-Ion Concentration , Lysosomes/chemistry , Mice , Mice, Inbred ICR , Mice, Transgenic , Oxidation-Reduction , RAW 264.7 Cells , Treatment Outcome , Vero Cells
3.
Adv Sci (Weinh) ; 8(24): e2102330, 2021 12.
Article in English | MEDLINE | ID: covidwho-1599388

ABSTRACT

Immune modulation is one of the most effective approaches in the therapy of complex diseases, including public health emergency. However, most immune therapeutics such as drugs, vaccines, and cellular therapy suffer from the limitations of poor efficacy and adverse side effects. Fortunately, cell membrane-derived nanoparticles (CMDNs) have superior compatibility with other therapeutics and offer new opportunities to push the limits of current treatments in immune modulation. As the interface between cells and outer surroundings, cell membrane contains components which instruct intercellular communication and the plasticity of cytomembrane has significantly potentiated CMDNs to leverage our immune system. Therefore, cell membranes employed in immunomodulatory CMDNs have gradually shifted from natural to engineered. In this review, unique properties of immunomodulatory CMDNs and engineering strategies of emerging CMDNs for immune modulation, with an emphasis on the design logic are summarized. Further, this review points out some pressing problems to be solved during clinical translation and put forward some suggestions on the prospect of immunoregulatory CMDNs. It is anticipated that this review can provide new insights on the design of immunoregulatory CMDNs and expand their potentiation in the precise control of the dysregulated immune system.


Subject(s)
Cell Membrane/immunology , Cell- and Tissue-Based Therapy/methods , Immunotherapy/methods , Nanoparticles/therapeutic use , Animals , Disease Models, Animal , Humans , Immunomodulation , Mice
4.
Scand J Immunol ; 95(2): e13131, 2022 Feb.
Article in English | MEDLINE | ID: covidwho-1583260

ABSTRACT

The role of the immune system against coronavirus disease 2019 (COVID-19) is unknown in many aspects, and the protective or pathologic mechanisms of the immune response are poorly understood. Pro-inflammatory cytokine release and a consequent cytokine storm can lead to acute respiratory distress syndrome (ARDS) and result in multi-organ failure. There are many T cell subsets during anti-viral immunity. The Th17-associated response, as a pro-inflammatory pathway, and its consequent outcomes in many autoimmune disorders play a fundamental role in progression of systemic hyper-inflammation during COVID-19. Therapeutic strategies based on immunomodulation therapy could be helpful for targeting hyper-inflammatory immune responses in COVID-19, especially Th17-related inflammation and hyper-cytokinemia. Cell-based immunotherapeutic approaches including mesenchymal stem cells (MSCs), tolerogenic dendritic cells (tolDCs) and regulatory T cells (Tregs) seem to be promising strategies as orchestrators of the immune response against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In this review, we highlight Th17-related immunopathology of SARS-CoV-2 infection and discuss cell-based immunomodulatory strategies and their mechanisms for regulation of the hyper-inflammation during COVID-19.


Subject(s)
COVID-19/pathology , COVID-19/therapy , Cytokine Release Syndrome/pathology , Immunomodulation/immunology , Th17 Cells/immunology , Adoptive Transfer/methods , COVID-19/immunology , Cell- and Tissue-Based Therapy/methods , Cytokines/blood , Dendritic Cells/transplantation , Humans , Mesenchymal Stem Cell Transplantation , SARS-CoV-2/immunology , T-Lymphocytes, Regulatory/transplantation
5.
Int Immunol ; 33(10): 515-519, 2021 09 25.
Article in English | MEDLINE | ID: covidwho-1574756

ABSTRACT

Blockade of IL-6 function by an anti-IL-6 receptor (IL-6R) antibody (tocilizumab, trade name Actemra) has been shown to be effective for the treatment of chronic autoimmune inflammatory diseases including rheumatoid arthritis. Interestingly, treatment with tocilizumab has also been found to alleviate the cytokine storm induced by chimeric antigen receptor (CAR)-T-cell therapy. Patients with serious cases of coronavirus disease 2019 (COVID-19) exhibit cytokine release syndrome (CRS), which suggested that tocilizumab might be an effective therapeutic for serious cases of COVID-19. In the first part of this short review, the therapeutic effect of tocilizumab for the disease induced by IL-6 overproduction is described. CRS induced by CAR-T-cell therapy and COVID-19 is then discussed.


Subject(s)
Arthritis/immunology , COVID-19/immunology , Interleukin-6/immunology , Receptors, Chimeric Antigen/immunology , SARS-CoV-2/immunology , Cell- and Tissue-Based Therapy/methods , Cytokine Release Syndrome/immunology , Humans
6.
J Cell Mol Med ; 26(1): 228-234, 2022 01.
Article in English | MEDLINE | ID: covidwho-1532813

ABSTRACT

The outbreak of COVID-19 has become a serious public health emergency. The virus targets cells by binding the ACE2 receptor. After infection, the virus triggers in some humans an immune storm containing the release of proinflammatory cytokines and chemokines followed by multiple organ failure. Several vaccines are enrolled, but an effective treatment is still missing. Mesenchymal stem cells (MSCs) have shown to secrete immunomodulatory factors that suppress this cytokine storm. Therefore, MSCs have been suggested as a potential treatment option for COVID-19. We report here that the ACE2 expression is minimal or nonexistent in MSC derived from three different human tissue sources (adipose tissue, umbilical cord Wharton`s jelly and bone marrow). In contrast, TMPRSS2 that is implicated in SARS-CoV-2 entry has been detected in all MSC samples. These results are of particular importance for future MSC-based cell therapies to treat severe cases after COVID-19 infection.


Subject(s)
Angiotensin-Converting Enzyme 2/genetics , COVID-19/therapy , Cell- and Tissue-Based Therapy/methods , Cytokine Release Syndrome/therapy , Mesenchymal Stem Cell Transplantation/methods , SARS-CoV-2/pathogenicity , Spike Glycoprotein, Coronavirus/genetics , Adipose Tissue/cytology , Adipose Tissue/metabolism , Angiotensin-Converting Enzyme 2/metabolism , Bone Marrow Cells/cytology , Bone Marrow Cells/metabolism , COVID-19/genetics , COVID-19/pathology , COVID-19/virology , Cytokine Release Syndrome/genetics , Cytokine Release Syndrome/pathology , Cytokine Release Syndrome/virology , Gene Expression Profiling , Gene Expression Regulation , Humans , Mesenchymal Stem Cells/cytology , Mesenchymal Stem Cells/metabolism , Primary Cell Culture , Protein Binding , SARS-CoV-2/genetics , Serine Endopeptidases/genetics , Serine Endopeptidases/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Umbilical Cord/cytology , Umbilical Cord/metabolism
7.
Int J Mol Sci ; 22(21)2021 Nov 07.
Article in English | MEDLINE | ID: covidwho-1512380

ABSTRACT

Heparin and its derivatives are saving thousands of human lives annually, by successfully preventing and treating thromboembolic events. Although the mode of action during anticoagulation is well studied, their influence on cell behavior is not fully understood as is the risk of bleeding and other side effects. New applications in regenerative medicine have evolved supporting production of cell-based therapeutics or as a substrate for creating functionalized matrices in biotechnology. The currently resurgent interest in heparins is related to the expected combined anti-inflammatory, anti-thrombotic and anti-viral action against COVID-19. Based on a concise summary of key biochemical and clinical data, this review summarizes the impact for manufacturing and application of cell therapeutics and highlights the need for discriminating the different heparins.


Subject(s)
Anticoagulants/chemistry , Cell- and Tissue-Based Therapy/methods , Heparin/analogs & derivatives , Anticoagulants/adverse effects , Anticoagulants/therapeutic use , Biocompatible Materials/chemistry , Biocompatible Materials/therapeutic use , Cell Adhesion , Hemorrhage/etiology , Heparin/adverse effects , Heparin/therapeutic use , Humans , Mesenchymal Stem Cells/cytology , Mesenchymal Stem Cells/metabolism , Regenerative Medicine , Thromboembolism/drug therapy
8.
J Immunother Cancer ; 9(10)2021 10.
Article in English | MEDLINE | ID: covidwho-1495513

ABSTRACT

Recipients of chimeric antigen receptor-modified T (CAR-T) cell therapies for B cell malignancies have profound and prolonged immunodeficiencies and are at risk for serious infections, including respiratory virus infections. Vaccination may be important for infection prevention, but there are limited data on vaccine immunogenicity in this population. We conducted a prospective observational study of the humoral immunogenicity of commercially available 2019-2020 inactivated influenza vaccines in adults immediately prior to or while in durable remission after CD19-, CD20-, or B cell maturation antigen-targeted CAR-T-cell therapy, as well as controls. We tested for antibodies to all four vaccine strains using neutralization and hemagglutination inhibition (HAI) assays. Antibody responses were defined as at least fourfold titer increases from baseline. Seroprotection was defined as a HAI titer ≥40. Enrolled CAR-T-cell recipients were vaccinated 14-29 days prior to (n=5) or 13-57 months following therapy (n=13), and the majority had hypogammaglobulinemia and cellular immunodeficiencies prevaccination. Eight non-immunocompromised adults served as controls. Antibody responses to ≥1 vaccine strain occurred in 2 (40%) individuals before CAR-T-cell therapy and in 4 (31%) individuals vaccinated after CAR-T-cell therapy. An additional 1 (20%) and 6 (46%) individuals had at least twofold increases, respectively. One individual vaccinated prior to CAR-T-cell therapy maintained a response for >3 months following therapy. Across all tested vaccine strains, seroprotection was less frequent in CAR-T-cell recipients than in controls. There was evidence of immunogenicity even among individuals with low immunoglobulin, CD19+ B cell, and CD4+ T-cell counts. These data support consideration for vaccination before and after CAR-T-cell therapy for influenza and other relevant pathogens such as SARS-CoV-2, irrespective of hypogammaglobulinemia or B cell aplasia. However, relatively impaired humoral vaccine immunogenicity indicates the need for additional infection-prevention strategies. Larger studies are needed to refine our understanding of potential correlates of vaccine immunogenicity, and durability of immune responses, in CAR-T-cell therapy recipients.


Subject(s)
Cell- and Tissue-Based Therapy/methods , Hemagglutination Inhibition Tests/methods , Immunogenicity, Vaccine/immunology , Influenza, Human/drug therapy , Influenza, Human/immunology , Adolescent , Adult , Aged , Humans , Middle Aged , Prospective Studies , Young Adult
9.
Front Immunol ; 12: 738697, 2021.
Article in English | MEDLINE | ID: covidwho-1477824

ABSTRACT

The severe respiratory consequences of the coronavirus disease 2019 (COVID-19) pandemic have prompted the urgent need for novel therapies. Cell-based therapies, primarily using mesenchymal stromal cells (MSCs), have demonstrated safety and potential efficacy in the treatment of critical illness, particularly sepsis and acute respiratory distress syndrome (ARDS). However, there are limited preclinical data for MSCs in COVID-19. Recent studies have shown that MSCs could decrease inflammation, improve lung permeability, enhance microbe and alveolar fluid clearance, and promote lung epithelial and endothelial repair. In addition, MSC-based therapy has shown promising effects in preclinical studies and phase 1 clinical trials in sepsis and ARDS. Here, we review recent advances related to MSC-based therapy in the context of sepsis and ARDS and evaluate the potential value of MSCs as a therapeutic strategy for COVID-19.


Subject(s)
COVID-19/therapy , Cell- and Tissue-Based Therapy/methods , Cytokine Release Syndrome/therapy , Mesenchymal Stem Cell Transplantation/methods , Cytokine Release Syndrome/pathology , Humans , Inflammation/therapy , Mesenchymal Stem Cells/immunology , SARS-CoV-2 , Sepsis/therapy
10.
Adv Drug Deliv Rev ; 179: 114002, 2021 12.
Article in English | MEDLINE | ID: covidwho-1465981

ABSTRACT

After thirty years of intensive research shaping and optimizing the technology, the approval of the first mRNA-based formulation by the EMA and FDA in order to stop the COVID-19 pandemic was a breakthrough in mRNA research. The astonishing success of these vaccines have brought the mRNA platform into the spotlight of the scientific community. The remarkable persistence of the groundwork is mainly attributed to the exceptional benefits of mRNA application, including the biological origin, immediate but transitory mechanism of action, non-integrative properties, safe and relatively simple manufacturing as well as the flexibility to produce any desired protein. Based on these advantages, a practical implementation of in vitro transcribed mRNA has been considered in most areas of medicine. In this review, we discuss the key preconditions for the rise of the mRNA in the medical field, including the unique structural and functional features of the mRNA molecule and its vehicles, which are crucial aspects for a production of potent mRNA-based therapeutics. Further, we focus on the utility of mRNA tools particularly in the scope of regenerative medicine, i.e. cell reprogramming approaches or manipulation strategies for targeted tissue restoration. Finally, we highlight the strong clinical potential but also the remaining hurdles to overcome for the mRNA-based regenerative therapy, which is only a few steps away from becoming a reality.


Subject(s)
Cell- and Tissue-Based Therapy/methods , RNA, Messenger/therapeutic use , Regenerative Medicine/trends , Tissue Engineering/methods , Animals , COVID-19 , Humans
11.
BMJ ; 374: n2231, 2021 09 23.
Article in English | MEDLINE | ID: covidwho-1438073

ABSTRACT

OBJECTIVE: To evaluate the efficacy and safety of antiviral antibody therapies and blood products for the treatment of novel coronavirus disease 2019 (covid-19). DESIGN: Living systematic review and network meta-analysis, with pairwise meta-analysis for outcomes with insufficient data. DATA SOURCES: WHO covid-19 database, a comprehensive multilingual source of global covid-19 literature, and six Chinese databases (up to 21 July 2021). STUDY SELECTION: Trials randomising people with suspected, probable, or confirmed covid-19 to antiviral antibody therapies, blood products, or standard care or placebo. Paired reviewers determined eligibility of trials independently and in duplicate. METHODS: After duplicate data abstraction, we performed random effects bayesian meta-analysis, including network meta-analysis for outcomes with sufficient data. We assessed risk of bias using a modification of the Cochrane risk of bias 2.0 tool. The certainty of the evidence was assessed using the grading of recommendations assessment, development, and evaluation (GRADE) approach. We meta-analysed interventions with ≥100 patients randomised or ≥20 events per treatment arm. RESULTS: As of 21 July 2021, we identified 47 trials evaluating convalescent plasma (21 trials), intravenous immunoglobulin (IVIg) (5 trials), umbilical cord mesenchymal stem cells (5 trials), bamlanivimab (4 trials), casirivimab-imdevimab (4 trials), bamlanivimab-etesevimab (2 trials), control plasma (2 trials), peripheral blood non-haematopoietic enriched stem cells (2 trials), sotrovimab (1 trial), anti-SARS-CoV-2 IVIg (1 trial), therapeutic plasma exchange (1 trial), XAV-19 polyclonal antibody (1 trial), CT-P59 monoclonal antibody (1 trial) and INM005 polyclonal antibody (1 trial) for the treatment of covid-19. Patients with non-severe disease randomised to antiviral monoclonal antibodies had lower risk of hospitalisation than those who received placebo: casirivimab-imdevimab (odds ratio (OR) 0.29 (95% CI 0.17 to 0.47); risk difference (RD) -4.2%; moderate certainty), bamlanivimab (OR 0.24 (0.06 to 0.86); RD -4.1%; low certainty), bamlanivimab-etesevimab (OR 0.31 (0.11 to 0.81); RD -3.8%; low certainty), and sotrovimab (OR 0.17 (0.04 to 0.57); RD -4.8%; low certainty). They did not have an important impact on any other outcome. There was no notable difference between monoclonal antibodies. No other intervention had any meaningful effect on any outcome in patients with non-severe covid-19. No intervention, including antiviral antibodies, had an important impact on any outcome in patients with severe or critical covid-19, except casirivimab-imdevimab, which may reduce mortality in patients who are seronegative. CONCLUSION: In patients with non-severe covid-19, casirivimab-imdevimab probably reduces hospitalisation; bamlanivimab-etesevimab, bamlanivimab, and sotrovimab may reduce hospitalisation. Convalescent plasma, IVIg, and other antibody and cellular interventions may not confer any meaningful benefit. SYSTEMATIC REVIEW REGISTRATION: This review was not registered. The protocol established a priori is included as a data supplement. FUNDING: This study was supported by the Canadian Institutes of Health Research (grant CIHR- IRSC:0579001321). READERS' NOTE: This article is a living systematic review that will be updated to reflect emerging evidence. Interim updates and additional study data will be posted on our website (www.covid19lnma.com).


Subject(s)
Antibodies, Viral/therapeutic use , COVID-19/therapy , Cell- and Tissue-Based Therapy/methods , SARS-CoV-2/immunology , Antibodies, Monoclonal/therapeutic use , Antiviral Agents/therapeutic use , Bayes Theorem , COVID-19/immunology , Clinical Trials as Topic , Humans , Immunization, Passive , Network Meta-Analysis , Treatment Outcome
12.
Curr Stem Cell Res Ther ; 16(4): 406-413, 2021.
Article in English | MEDLINE | ID: covidwho-1435705

ABSTRACT

COVID-19 pandemic is a global health crisis of the 21st Century. There are currently no approved vaccines and no particular anti-viral treatment for coronavirus disease. As COVID-19 has a broad range of illnesses, it is necessary to find a safe and effective therapeutic method for COVID-19. An attractive approach for treating COVID-19 is cell therapy. Cell therapy aims to inject new and healthy stem cells into a patient's body, to repair the damaged cells and tissues. Stem cell therapy is one of the most studied and important approaches in the treatment of COVID-19 these days. The significant clinical outcome was observed by the adoptive transfer of stem cells, specifically mesenchymal stem cells. This study reviews the characteristics of stem cells and clinical trials that have used stem cells in treating COVID-19.


Subject(s)
COVID-19/drug therapy , COVID-19/therapy , Cell- and Tissue-Based Therapy , Mesenchymal Stem Cells/immunology , SARS-CoV-2/pathogenicity , COVID-19/virology , Cell- and Tissue-Based Therapy/methods , Humans , Mesenchymal Stem Cell Transplantation/methods
15.
Front Immunol ; 12: 726909, 2021.
Article in English | MEDLINE | ID: covidwho-1359195

ABSTRACT

Mesenchymal stem cells (MSCs) have been widely used in preclinical and clinical trials for various diseases and have shown great potential in the treatment of sepsis and coronavirus disease (COVID-19). Inflammatory factors play vital roles in the pathogenesis of diseases. The interaction between inflammatory factors is extremely complex. Once the dynamics of inflammatory factors are unbalanced, inflammatory responses and cytokine storm syndrome develop, leading to disease exacerbation and even death. Stem cells have become ideal candidates for the treatment of such diseases due to their immunosuppressive and anti-inflammatory properties. However, the mechanisms by which stem cells affect inflammation and immune regulation are still unclear. This article discusses the therapeutic mechanism and potential value of MSCs in the treatment of sepsis and the novel COVID-19, outlines how MSCs mediate innate and acquired immunity at both the cellular and molecular levels, and described the anti-inflammatory mechanisms and related molecular pathways. Finally, we review the safety and efficacy of stem cell therapy in these two diseases at the preclinical and clinical levels.


Subject(s)
COVID-19/therapy , Cytokine Release Syndrome/therapy , Mesenchymal Stem Cell Transplantation , Mesenchymal Stem Cells/immunology , SARS-CoV-2/immunology , COVID-19/immunology , COVID-19/pathology , Cell- and Tissue-Based Therapy/methods , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/pathology , Humans , Respiratory Distress Syndrome/immunology , Respiratory Distress Syndrome/pathology , Respiratory Distress Syndrome/prevention & control
16.
Hum Cell ; 34(6): 1585-1600, 2021 Nov.
Article in English | MEDLINE | ID: covidwho-1316345

ABSTRACT

Mesenchymal stem cells (MSCs), a kind of multipotent stem cells with self-renewal ability and multi-differentiation ability, have become the "practical stem cells" for the treatment of diseases. MSCs have immunomodulatory properties and can be used to treat autoimmune diseases, such as systemic lupus erythematosus (SLE) and Crohn's disease. MSCs also can be used in cancer and aging. At present, many clinical experiments are using MSCs. MSCs can reduce the occurrence of inflammation and apoptosis of tissue cells, and promote the proliferation of endogenous tissue and organ cells, so as to achieve the effect of repairing tissue and organs. MSCs presumably also play an important role in Corona Virus Disease 2019 (COVID-19) infection.


Subject(s)
COVID-19/therapy , Cell- and Tissue-Based Therapy/methods , Mesenchymal Stem Cells , Animals , Apoptosis , Autoimmune Diseases/therapy , Cell Proliferation , Cell- and Tissue-Based Therapy/trends , Crohn Disease/therapy , Humans , Immunomodulation , Inflammation , Lupus Erythematosus, Systemic/therapy , Mesenchymal Stem Cell Transplantation , Mesenchymal Stem Cells/immunology , Mice , Neoplasms/therapy
17.
Regen Med ; 16(5): 477-494, 2021 05.
Article in English | MEDLINE | ID: covidwho-1229139

ABSTRACT

In many countries, COVID-19 now accounts for more deaths per year than car accidents and even the deadliest wars. Combating the viral pandemics requires a coordinated effort to develop therapeutic protocols adaptable to the disease severity. In this review article, we summarize a graded approach aiming to shield cells from SARS-CoV-2 entry and infection, inhibit excess inflammation and evasion of the immune response, and ultimately prevent systemic organ failure. Moreover, we focus on mesenchymal stem cell therapy, which has shown safety and efficacy as a treatment of inflammatory and immune diseases. The cell therapy approach is now repurposed in patients with severe COVID-19. Numerous trials of mesenchymal stem cell therapy are ongoing, especially in China and the USA. Leader companies in cell therapy have also started controlled trials utilizing their quality assessed cell products. Results are too premature to reach definitive conclusions.


Subject(s)
COVID-19/therapy , Cell- and Tissue-Based Therapy/methods , Mesenchymal Stem Cell Transplantation/methods , Mesenchymal Stem Cells/cytology , SARS-CoV-2/isolation & purification , COVID-19/virology , Clinical Trials as Topic , Humans
18.
J Cell Physiol ; 236(10): 7266-7289, 2021 10.
Article in English | MEDLINE | ID: covidwho-1168883

ABSTRACT

Mesenchymal stem cells (MSCs) are located in various tissues where these cells show niche-dependent multilineage differentiation and secrete immunomodulatory molecules to support numerous physiological processes. Due to their regenerative and reparative properties, MSCs are extremely valuable for cell-based therapy in tackling several pathological conditions including COVID-19. Iron is essential for MSC processes but iron-loading, which is common in several chronic conditions, hinders normal MSC functionality. This not only aggravates disease pathology but can also affect allogeneic and autologous MSC therapy. Thus, understanding MSCs from an iron perspective is of clinical significance. Accordingly, this review highlights the roles of iron and iron-related proteins in MSC physiology. It describes the contribution of iron and endogenous iron-related effectors like hepcidin, ferroportin, transferrin receptor, lactoferrin, lipocalin-2, bone morphogenetic proteins and hypoxia inducible factors in MSC biology. It summarises the excess-iron-induced alterations in MSC components, processes and discusses signalling pathways involving ROS, PI3K/AKT, MAPK, p53, AMPK/MFF/DRP1 and Wnt. Additionally, it evaluates the endogenous and exogenous saviours of MSCs against iron-toxicity. Lastly, it elaborates on the involvement of MSCs in the pathology of clinical conditions of iron-excess, namely, hereditary hemochromatosis, diabetes, ß-thalassaemia and myelodysplastic syndromes. This unique review integrates the distinct fields of iron regulation and MSC physiology. Through an iron-perspective, it describes both mechanistic and clinical aspects of MSCs and proposes an iron-linked MSC-contribution to physiology, pathology and therapeutics. It advances the understanding of MSC biology and may aid in identifying signalling pathways, molecular targets and compounds for formulating adjunctive iron-based therapies for excess-iron conditions, and thereby inform regenerative medicine.


Subject(s)
Iron/metabolism , Mesenchymal Stem Cells/metabolism , Animals , Cell Differentiation/physiology , Cell- and Tissue-Based Therapy/methods , Humans , Immunomodulation/physiology , Mesenchymal Stem Cell Transplantation/methods , Regenerative Medicine/methods , Signal Transduction/physiology
19.
Front Immunol ; 11: 591065, 2020.
Article in English | MEDLINE | ID: covidwho-1146667

ABSTRACT

Mesenchymal stem cells (MSCs) are non-hematopoietic, multipotent stem cells derived from mesoderm, which can be easily isolated from many sources such as bone marrow, umbilical cord or adipose tissue. MSCs provide support for hematopoietic stem cells and have an ability to differentiate into multiple cell lines. Moreover, they have proangiogenic, protective and immunomodulatory properties. MSCs have the capacity to modulate both innate and adaptive immune responses, which accompany many diseases, by inhibiting pro-inflammatory reactions and stimulating anti-inflammatory activity. Recent findings revealed that the positive effect of MSCs is at least partly associated with the production of extracellular vesicles (EVs). EVs are small membrane structures, containing proteins, lipids and nuclei acids, which take part in intra-cellular communication. Many studies indicate that EVs contain protective and pro-regenerative properties and can modulate an immune response that is activated in various diseases such as CNS diseases, myocardial infarction, liver injury, lung diseases, ulcerative colitis or kidney injury. Thus, EVs have similar functions as their cells of origin and since they do not carry the risk of cell transplantation, such as tumor formation or small vessel blockage, they can be considered a potential therapeutic tool for cell-free therapy.


Subject(s)
Extracellular Vesicles/metabolism , Immunomodulation , Mesenchymal Stem Cells/metabolism , Animals , Biomarkers , Cell Communication/immunology , Cell- and Tissue-Based Therapy/methods , Clinical Trials as Topic , Disease Management , Humans , Immunity, Innate , Mesenchymal Stem Cell Transplantation/methods , Mesenchymal Stem Cells/cytology
20.
Int Immunol ; 33(10): 515-519, 2021 09 25.
Article in English | MEDLINE | ID: covidwho-1132523

ABSTRACT

Blockade of IL-6 function by an anti-IL-6 receptor (IL-6R) antibody (tocilizumab, trade name Actemra) has been shown to be effective for the treatment of chronic autoimmune inflammatory diseases including rheumatoid arthritis. Interestingly, treatment with tocilizumab has also been found to alleviate the cytokine storm induced by chimeric antigen receptor (CAR)-T-cell therapy. Patients with serious cases of coronavirus disease 2019 (COVID-19) exhibit cytokine release syndrome (CRS), which suggested that tocilizumab might be an effective therapeutic for serious cases of COVID-19. In the first part of this short review, the therapeutic effect of tocilizumab for the disease induced by IL-6 overproduction is described. CRS induced by CAR-T-cell therapy and COVID-19 is then discussed.


Subject(s)
Arthritis/immunology , COVID-19/immunology , Interleukin-6/immunology , Receptors, Chimeric Antigen/immunology , SARS-CoV-2/immunology , Cell- and Tissue-Based Therapy/methods , Cytokine Release Syndrome/immunology , Humans
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