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1.
Cells ; 11(21)2022 Oct 25.
Article in English | MEDLINE | ID: covidwho-2199804

ABSTRACT

Extracellular vesicles (EVs) are small lipid bilayer-delimited particles that are naturally released from cells into body fluids, and therefore can travel and convey regulatory functions in the distal parts of the body. EVs can transmit paracrine signaling by carrying over cytokines, chemokines, growth factors, interleukins (ILs), transcription factors, and nucleic acids such as DNA, mRNAs, microRNAs, piRNAs, lncRNAs, sn/snoRNAs, mtRNAs and circRNAs; these EVs travel to predecided destinations to perform their functions. While mesenchymal stem cells (MSCs) have been shown to improve healing and facilitate treatments of various diseases, the allogenic use of these cells is often accompanied by serious adverse effects after transplantation. MSC-produced EVs are less immunogenic and can serve as an alternative to cellular therapies by transmitting signaling or delivering biomaterials to diseased areas of the body. This review article is focused on understanding the properties of EVs derived from different types of MSCs and MSC-EV-based therapeutic options. The potential of modern technologies such as 3D bioprinting to advance EV-based therapies is also discussed.


Subject(s)
Extracellular Vesicles , Mesenchymal Stem Cells , MicroRNAs , Extracellular Vesicles/metabolism , Mesenchymal Stem Cells/metabolism , Cell- and Tissue-Based Therapy , MicroRNAs/genetics , MicroRNAs/metabolism , Bioengineering
2.
Int J Mol Sci ; 23(19)2022 Sep 23.
Article in English | MEDLINE | ID: covidwho-2066119

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial fibrotic disease that leads to disability and death within 5 years of diagnosis. Pulmonary fibrosis is a disease with a multifactorial etiology. The concept of aberrant regeneration of the pulmonary epithelium reveals the pathogenesis of IPF, according to which repeated damage and death of alveolar epithelial cells is the main mechanism leading to the development of progressive IPF. Cell death provokes the migration, proliferation and activation of fibroblasts, which overproduce extracellular matrix, resulting in fibrotic deformity of the lung tissue. Mesenchymal stem cells (MSCs) and extracellular vesicles (EVs) are promising therapies for pulmonary fibrosis. MSCs, and EVs derived from MSCs, modulate the activity of immune cells, inhibit the expression of profibrotic genes, reduce collagen deposition and promote the repair of damaged lung tissue. This review considers the molecular mechanisms of the development of IPF and the multifaceted role of MSCs in the therapy of IPF. Currently, EVs-MSCs are regarded as a promising cell-free therapy tool, so in this review we discuss the results available to date of the use of EVs-MSCs for lung tissue repair.


Subject(s)
Extracellular Vesicles , Idiopathic Pulmonary Fibrosis , Mesenchymal Stem Cells , Extracellular Vesicles/metabolism , Fibroblasts/metabolism , Humans , Idiopathic Pulmonary Fibrosis/genetics , Idiopathic Pulmonary Fibrosis/therapy , Lung/pathology , Mesenchymal Stem Cells/metabolism
3.
Front Immunol ; 13: 943333, 2022.
Article in English | MEDLINE | ID: covidwho-2022722

ABSTRACT

Mesenchymal stromal cell (MSC) therapy has seen increased attention as a possible option to treat a number of inflammatory conditions including COVID-19 acute respiratory distress syndrome (ARDS). As rates of obesity and metabolic disease continue to rise worldwide, increasing proportions of patients treated with MSC therapy will be living with obesity. The obese environment poses critical challenges for immunomodulatory therapies that should be accounted for during development and testing of MSCs. In this review, we look to cancer immunotherapy as a model for the challenges MSCs may face in obese environments. We then outline current evidence that obesity alters MSC immunomodulatory function, drastically modifies the host immune system, and therefore reshapes interactions between MSCs and immune cells. Finally, we argue that obese environments may alter essential features of allogeneic MSCs and offer potential strategies for licensing of MSCs to enhance their efficacy in the obese microenvironment. Our aim is to combine insights from basic research in MSC biology and clinical trials to inform new strategies to ensure MSC therapy is effective for a broad range of patients.


Subject(s)
COVID-19 , Mesenchymal Stem Cells , COVID-19/therapy , Cells, Cultured , Humans , Immunomodulation , Mesenchymal Stem Cells/metabolism , Obesity/metabolism , Obesity/therapy
4.
Int J Mol Sci ; 23(17)2022 Sep 02.
Article in English | MEDLINE | ID: covidwho-2010107

ABSTRACT

Mesenchymal stem cells (MSCs) are multipotent stem cells with the capacity of self-renewal, homing, and low immunogenicity. These distinct biological characteristics have already shown immense potential in regenerative medicine. MSCs also possess immunomodulatory properties that can maintain immune homeostasis when the immune response is over-activated or under-activated. The secretome of MSCs consists of cytokines, chemokines, signaling molecules, and growth factors, which effectively contribute to the regulation of immune and inflammatory responses. The immunomodulatory effects of MSCs can also be achieved through direct cell contact with microenvironmental factors and immune cells. Furthermore, preconditioned and engineered MSCs can specifically improve the immunomodulation effects in diverse clinical applications. These multifunctional properties of MSCs enable them to be used as a prospective therapeutic strategy to treat immune disorders, including autoimmune diseases and incurable inflammatory diseases. Here we review the recent exploration of immunomodulatory mechanisms of MSCs and briefly discuss the promotion of the genetically engineered MSCs. Additionally, we review the potential clinical applications of MSC-mediated immunomodulation in four types of immune diseases, including systemic lupus erythematosus, Crohn's disease, graft-versus-host disease, and COVID-19.


Subject(s)
COVID-19 , Immune System Diseases , Mesenchymal Stem Cell Transplantation , Mesenchymal Stem Cells , COVID-19/therapy , Cytokines/metabolism , Humans , Immune System Diseases/metabolism , Immunity , Immunomodulation , Mesenchymal Stem Cells/metabolism
5.
Cells ; 11(17)2022 08 29.
Article in English | MEDLINE | ID: covidwho-2005945

ABSTRACT

Medical health systems continue to be challenged due to newly emerging COVID-19, and there is an urgent need for alternative approaches for treatment. An increasing number of clinical observations indicate cytokine storms to be associated with COVID-19 severity and also to be a significant cause of death among COVID-19 patients. Cytokine storm involves the extensive proliferative and hyperactive activity of T and macrophage cells and the overproduction of pro-inflammatory cytokines. Stem cells are the type of cell having self-renewal properties and giving rise to differentiated cells. Currently, stem cell therapy is an exciting and promising therapeutic approach that can treat several diseases that were considered incurable in the past. It may be possible to develop novel methods to treat various diseases by identifying stem cells' growth and differentiation factors. Treatment with mesenchymal stem cells (MSCs) in medicine is anticipated to be highly effective. The present review article is organized to put forward the positive arguments and implications in support of mesenchymal stem cell therapy as an alternative therapy to cytokine storms, to combat COVID-19. Using the immunomodulatory potential of the MSCs, it is possible to fight against COVID-19 and counterbalance the cytokine storm.


Subject(s)
COVID-19 , Cytokine Release Syndrome , Mesenchymal Stem Cell Transplantation , Mesenchymal Stem Cells , COVID-19/therapy , Cytokine Release Syndrome/therapy , Cytokines/metabolism , Humans , Mesenchymal Stem Cells/metabolism
6.
Int J Mol Sci ; 23(14)2022 Jul 21.
Article in English | MEDLINE | ID: covidwho-1958594

ABSTRACT

Mesenchymal stem cells (MSCs) play a critical role in response to stress such as infection. They initiate the removal of cell debris, exert major immunoregulatory activities, control pathogens, and lead to a remodeling/scarring phase. Thus, host-derived 'danger' factors released from damaged/infected cells (called alarmins, e.g., HMGB1, ATP, DNA) as well as pathogen-associated molecular patterns (LPS, single strand RNA) can activate MSCs located in the parenchyma and around vessels to upregulate the expression of growth factors and chemoattractant molecules that influence immune cell recruitment and stem cell mobilization. MSC, in an ultimate contribution to tissue repair, may also directly trans- or de-differentiate into specific cellular phenotypes such as osteoblasts, chondrocytes, lipofibroblasts, myofibroblasts, Schwann cells, and they may somehow recapitulate their neural crest embryonic origin. Failure to terminate such repair processes induces pathological scarring, termed fibrosis, or vascular calcification. Interestingly, many viruses and particularly those associated to chronic infection and inflammation may hijack and polarize MSC's immune regulatory activities. Several reports argue that MSC may constitute immune privileged sanctuaries for viruses and contributing to long-lasting effects posing infectious challenges, such as viruses rebounding in immunocompromised patients or following regenerative medicine therapies using MSC. We will herein review the capacity of several viruses not only to infect but also to polarize directly or indirectly the functions of MSC (immunoregulation, differentiation potential, and tissue repair) in clinical settings.


Subject(s)
Mesenchymal Stem Cells , Viruses , Cell Differentiation , Chondrocytes/metabolism , Cicatrix/metabolism , Humans , Mesenchymal Stem Cells/metabolism
7.
Front Cell Infect Microbiol ; 12: 850744, 2022.
Article in English | MEDLINE | ID: covidwho-1952256

ABSTRACT

The endemic and pandemic caused by respiratory virus infection are a major cause of mortality and morbidity globally. Thus, broadly effective antiviral drugs are needed to treat respiratory viral diseases. Small extracellular vesicles derived from human umbilical cord mesenchymal stem cells (U-exo) have recently gained attention as a cell-free therapeutic strategy due to their potential for safety and efficacy. Anti-viral activities of U-exo to countermeasure respiratory virus-associated diseases are currently unknown. Here, we tested the antiviral activities of U-exo following influenza A/B virus (IFV) and human seasonal coronavirus (HCoV) infections in vitro. Cells were subject to IFV or HCoV infection followed by U-exo treatment. U-exo treatment significantly reduced IFV or HCoV replication and combined treatment with recombinant human interferon-alpha protein (IFN-α) exerted synergistically enhanced antiviral effects against IFV or HCoV. Interestingly, microRNA (miR)-125b, which is one of the most abundantly expressed small RNAs in U-exo, was found to suppress IFV replication possibly via the induction of IFN-stimulated genes (ISGs). Furthermore, U-exo markedly enhanced RNA virus-triggered IFN signaling and ISGs production. Similarly, human nasal epithelial cells cultured at the air-liquid interface (ALI) studies broadly effective anti-viral and anti-inflammatory activities of U-exo against IFV and HCoV, suggesting the potential role of U-exo as a promising intervention for respiratory virus-associated diseases.


Subject(s)
Coronavirus , Exosomes , Extracellular Vesicles , Mesenchymal Stem Cells , Antiviral Agents/metabolism , Antiviral Agents/pharmacology , Humans , Mesenchymal Stem Cells/metabolism , Umbilical Cord
8.
Cells ; 11(14)2022 07 12.
Article in English | MEDLINE | ID: covidwho-1938702

ABSTRACT

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is an enveloped, positive sense, single stranded RNA (+ssRNA) virus, belonging to the genus Betacoronavirus and family Coronaviridae. It is primarily transmitted from infected persons to healthy ones through inhalation of virus-laden respiratory droplets. After an average incubation period of 2-14 days, the majority of infected individuals remain asymptomatic and/or mildly symptomatic, whereas the remaining individuals manifest a myriad of clinical symptoms, including fever, sore throat, dry cough, fatigue, chest pain, and breathlessness. SARS-CoV-2 exploits the angiotensin converting enzyme 2 (ACE-2) receptor for cellular invasion, and lungs are amongst the most adversely affected organs in the body. Thereupon, immune responses are elicited, which may devolve into a cytokine storm characterized by enhanced secretion of multitude of inflammatory cytokines/chemokines and growth factors, such as interleukin (IL)-2, IL-6, IL-7, IL-8, IL-9, tumor necrosis factor alpha (TNF-α), granulocyte colony-stimulating factor (GCSF), basic fibroblast growth factor 2 (bFGF2), monocyte chemotactic protein-1 (MCP1), interferon-inducible protein 10 (IP10), macrophage inflammatory protein 1A (MIP1A), platelet-derived growth factor subunit B (PDGFB), and vascular endothelial factor (VEGF)-A. The systemic persistence of inflammatory molecules causes widespread histological injury, leading to functional deterioration of the infected organ(s). Although multiple treatment modalities with varying effectiveness are being employed, nevertheless, there is no curative COVID-19 therapy available to date. In this regard, one plausible supportive therapeutic modality may involve administration of mesenchymal stem cells (MSCs) and/or MSC-derived bioactive factors-based secretome to critically ill COVID-19 patients with the intention of accomplishing better clinical outcome owing to their empirically established beneficial effects. MSCs are well established adult stem cells (ASCs) with respect to their immunomodulatory, anti-inflammatory, anti-oxidative, anti-apoptotic, pro-angiogenic, and pro-regenerative properties. The immunomodulatory capabilities of MSCs are not constitutive but rather are highly dependent on a holistic niche. Following intravenous infusion, MSCs are known to undergo considerable histological trapping in the lungs and, therefore, become well positioned to directly engage with lung infiltrating immune cells, and thereby mitigate excessive inflammation and reverse/regenerate damaged alveolar epithelial cells and associated tissue post SARS-CoV-2 infection. Considering the myriad of abovementioned biologically beneficial properties and emerging translational insights, MSCs may be used as potential supportive therapy to counteract cytokine storms and reduce disease severity, thereby facilitating speedy recovery and health restoration.


Subject(s)
COVID-19 , Mesenchymal Stem Cells , Adult , COVID-19/therapy , Cytokine Release Syndrome , Humans , Immunity , Immunomodulation , Mesenchymal Stem Cells/metabolism , SARS-CoV-2
9.
Sci Adv ; 8(25): eabm6504, 2022 06 24.
Article in English | MEDLINE | ID: covidwho-1909560

ABSTRACT

Aging has been reported to deteriorate the quantity and quality of mesenchymal stem cells (MSCs), which affect their therapeutic use in regenerative medicine. A dearth of age-related stem cell research further restricts their clinical applications. The present study explores the possibility of using MSCs derived from human gingival tissues (GMSCs) for studying their ex vivo growth characteristics and differentiation potential with respect to donor age. GMSCs displayed decreased in vitro adipogenesis and in vitro and in vivo osteogenesis with age, but in vitro neurogenesis remained unaffected. An increased expression of p53 and SIRT1 with donor age was correlated to their ability of eliminating tumorigenic events through apoptosis or autophagy, respectively. Irrespective of donor age, GMSCs displayed effective immunoregulation and regenerative potential in a mouse model of LPS-induced acute lung injury. Thus, we suggest the potential of GMSCs for designing cell-based immunomodulatory therapeutic approaches and their further extrapolation for acute inflammatory conditions such as acute respiratory distress syndrome and COVID-19.


Subject(s)
COVID-19 , Mesenchymal Stem Cells , Animals , Cell Differentiation , Gingiva , Humans , Mesenchymal Stem Cells/metabolism , Mice , Osteogenesis
10.
Arch Virol ; 166(8): 2285-2289, 2021 Aug.
Article in English | MEDLINE | ID: covidwho-1826502

ABSTRACT

Mesenchymal stromal cells (MSCs) are considered multipotent progenitors with the capacity to differentiate into mesoderm-like cells in many species. The immunosuppressive properties of MSCs are important for downregulating inflammatory responses. Turkey coronavirus (TCoV) is the etiological agent of a poult mortality syndrome that affects intestinal epithelial cells. In this study, poult MSCs were isolated, characterized, and infected with TCoV after in vitro culture. The poult-derived MSCs showed fibroblast-like morphology and the ability to undergo differentiation into mesodermal-derived cells and to support virus replication. Infection with TCoV resulted in cytopathic effects and the loss of cell viability. TCoV antigens and new viral progeny were detected at high levels, as were transcripts of the pro-inflammatory factors INFγ, IL-6, and IL-8. These findings suggest that the cytokine storm phenomenon is not restricted to one genus of the family Coronaviridae and that MSCs cannot always balance the process.


Subject(s)
Coronavirus, Turkey/physiology , Cytokines/metabolism , Virus Replication , Animals , Cell Differentiation , Cell Survival , Cytopathogenic Effect, Viral , Interferon-gamma/metabolism , Interleukin-6/metabolism , Interleukin-8/metabolism , Mesenchymal Stem Cells/cytology , Mesenchymal Stem Cells/metabolism , Mesenchymal Stem Cells/virology , Turkeys , Up-Regulation
11.
Cells ; 11(9)2022 04 21.
Article in English | MEDLINE | ID: covidwho-1818055

ABSTRACT

Human SARS-CoV-2 and avian infectious bronchitis virus (IBV) are highly contagious and deadly coronaviruses, causing devastating respiratory diseases in humans and chickens. The lack of effective therapeutics exacerbates the impact of outbreaks associated with SARS-CoV-2 and IBV infections. Thus, novel drugs or therapeutic agents are highly in demand for controlling viral transmission and disease progression. Mesenchymal stem cells (MSC) secreted factors (secretome) are safe and efficient alternatives to stem cells in MSC-based therapies. This study aimed to investigate the antiviral potentials of human Wharton's jelly MSC secretome (hWJ-MSC-S) against SARS-CoV-2 and IBV infections in vitro and in ovo. The half-maximal inhibitory concentrations (IC50), cytotoxic concentration (CC50), and selective index (SI) values of hWJ-MSC-S were determined using Vero-E6 cells. The virucidal, anti-adsorption, and anti-replication antiviral mechanisms of hWJ-MSC-S were evaluated. The hWJ-MSC-S significantly inhibited infection of SARS-CoV-2 and IBV, without affecting the viability of cells and embryos. Interestingly, hWJ-MSC-S reduced viral infection by >90%, in vitro. The IC50 and SI of hWJ-MSC secretome against SARS-CoV-2 were 166.6 and 235.29 µg/mL, respectively, while for IBV, IC50 and SI were 439.9 and 89.11 µg/mL, respectively. The virucidal and anti-replication antiviral effects of hWJ-MSC-S were very prominent compared to the anti-adsorption effect. In the in ovo model, hWJ-MSC-S reduced IBV titer by >99%. Liquid chromatography-tandem mass spectrometry (LC/MS-MS) analysis of hWJ-MSC-S revealed a significant enrichment of immunomodulatory and antiviral proteins. Collectively, our results not only uncovered the antiviral potency of hWJ-MSC-S against SARS-CoV-2 and IBV, but also described the mechanism by which hWJ-MSC-S inhibits viral infection. These findings indicate that hWJ-MSC-S could be utilized in future pre-clinical and clinical studies to develop effective therapeutic approaches against human COVID-19 and avian IB respiratory diseases.


Subject(s)
Bronchitis , COVID-19 , Mesenchymal Stem Cells , Wharton Jelly , Animals , Antiviral Agents/metabolism , Antiviral Agents/pharmacology , Bronchitis/metabolism , Chickens , Humans , Immunologic Factors/metabolism , Mesenchymal Stem Cells/metabolism , SARS-CoV-2 , Secretome , Wharton Jelly/metabolism
12.
Int J Mol Sci ; 23(7)2022 Mar 30.
Article in English | MEDLINE | ID: covidwho-1785735

ABSTRACT

Acute kidney injury (AKI) is a sudden decline of renal function and represents a global clinical problem due to an elevated morbidity and mortality. Despite many efforts, currently there are no treatments to halt this devastating condition. Extracellular vesicles (EVs) are nanoparticles secreted by various cell types in both physiological and pathological conditions. EVs can arise from distinct parts of the kidney and can mediate intercellular communication between various cell types along the nephron. Besides their potential as diagnostic tools, EVs have been proposed as powerful new tools for regenerative medicine and have been broadly studied as therapeutic mediators in different models of experimental AKI. In this review, we present an overview of the basic features and biological relevance of EVs, with an emphasis on their functional role in cell-to-cell communication in the kidney. We explore versatile roles of EVs in crucial pathophysiological mechanisms contributing to AKI and give a detailed description of the renoprotective effects of EVs from different origins in AKI. Finally, we explain known mechanisms of action of EVs in AKI and provide an outlook on the potential clinical translation of EVs in the setting of AKI.


Subject(s)
Acute Kidney Injury , Extracellular Vesicles , Mesenchymal Stem Cells , Acute Kidney Injury/pathology , Extracellular Vesicles/metabolism , Humans , Kidney/metabolism , Mesenchymal Stem Cells/metabolism
13.
Stem Cell Res Ther ; 13(1): 124, 2022 03 24.
Article in English | MEDLINE | ID: covidwho-1759777

ABSTRACT

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spread into more than 200 countries and infected approximately 203 million people globally. COVID-19 is associated with high mortality and morbidity in some patients, and this disease still does not have effective treatments with reproducibly appreciable outcomes. One of the leading complications associated with COVID-19 is acute respiratory distress syndrome (ARDS); this is an anti-viral host inflammatory response, and it is usually caused by a cytokine storm syndrome which may lead to multi-organ failure and death. Currently, COVID-19 patients are treated with approaches that mostly fall into two major categories: immunomodulators, which promote the body's fight against viruses efficiently, and antivirals, which slow or stop viruses from multiplying. These treatments include a variety of novel therapies that are currently being tested in clinical trials, including serum, IL-6 antibody, and remdesivir; however, the outcomes of these therapies are not consistently appreciable and remain a subject of debate. Mesenchymal stem/stromal cells (MSCs), the multipotent stem cells that have previously been used to treat viral infections and various respiratory diseases such as ARDS exhibit immunomodulatory properties and can ameliorate tissue damage. Given that SARS-CoV-2 targets the immune system and causes tissue damage, it is presumable that MSCs are being explored to treat COVID-19 patients. This review summarizes the potential mechanisms of action of MSC therapy, progress of MSC, and its related products in clinical trials for COVID-19 therapy based on the outcomes of these clinical studies.


Subject(s)
COVID-19 , Mesenchymal Stem Cells , Pneumonia , Respiratory Distress Syndrome , COVID-19/therapy , Humans , Mesenchymal Stem Cells/metabolism , SARS-CoV-2
14.
J Control Release ; 345: 214-230, 2022 05.
Article in English | MEDLINE | ID: covidwho-1747828

ABSTRACT

Mesenchymal stem cell-derived small extracellular vesicles (MSC-EVs) are promising nanotherapeutic agent for pneumonia (bacterial origin, COVID-19), but the optimal administration route and potential mechanisms of action remain poorly understood. This study compared the administration of MSC-EVs via inhalation and tail vein injection for the treatment of acute lung injury (ALI) and determined the host-derived mechanisms that may contribute to the therapeutic effects of MSC-EVs in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells (macrophage cell line) and animal models. Luminex liquid chip and hematoxylin and eosin (HE) staining revealed that, compared with the vehicle control, inhaled MSC-EVs outperformed those injected via the tail vein, by reducing the expression of pro-inflammatory cytokines, increasing the expression of anti-inflammatory cytokine, and decreasing pathological scores in ALI. MSC-EV administration promoted the polarization of macrophages towards a M2 phenotype in vitro and in vivo (via inhalation). RNA sequencing revealed that immune and redox mediators, including TLR4, Arg1, and HO-1, were associated with the activity MSC-EVs against ALI mice. Western blotting and immunofluorescence revealed that correlative inflammatory and oxidative mediators were involved in the therapeutic effects of MSC-EVs in LPS-stimulated cells and mice. Moreover, variable expression of Nrf2 was observed following treatment with MSC-EVs in cell and animal models, and knockdown of Nrf2 attenuated the anti-inflammatory and antioxidant activities of MSC-EVs in LPS-stimulated macrophages. Together, these data suggest that inhalation of MSC-EVs as a noninvasive strategy for attenuation of ALI, and the adaptive regulation of Nrf2 may contribute to their anti-inflammatory and anti-oxidant activity in mice.


Subject(s)
Acute Lung Injury , COVID-19 , Extracellular Vesicles , Mesenchymal Stem Cells , Acute Lung Injury/therapy , Animals , Anti-Inflammatory Agents/metabolism , Anti-Inflammatory Agents/therapeutic use , Antioxidants , Cytokines/metabolism , Disease Models, Animal , Extracellular Vesicles/metabolism , Lipopolysaccharides , Mesenchymal Stem Cells/metabolism , Mice , NF-E2-Related Factor 2/metabolism
15.
Cells ; 11(3)2022 01 29.
Article in English | MEDLINE | ID: covidwho-1667054

ABSTRACT

The novel pathogenic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19). Mesenchymal stem cells (MSCs) are currently utilized in clinics for pulmonary inflammatory diseases, including acute respiratory distress syndrome and acute lung injury. Given that MSCs offer a promising treatment against COVID-19, they are being used against COVID-19 in more than 70 clinical trials with promising findings. Genetically engineered MSCs offer promising therapeutic options in pulmonary diseases. However, their potential has not been explored yet. In this review, we provide perspectives on the functionally modified MSCs that can be developed and harnessed for COVID-19 therapy. Options to manage the SARS-CoV-2 infection and its variants using various bioengineering tools to increase the therapeutic efficacy of MSCs are highlighted.


Subject(s)
Bioengineering/methods , COVID-19/therapy , Mesenchymal Stem Cell Transplantation/methods , Mesenchymal Stem Cells/metabolism , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/epidemiology , COVID-19/virology , Cytokines/metabolism , Humans , Lung/metabolism , Lung/pathology , Lung/virology , Mesenchymal Stem Cells/cytology , Pandemics/prevention & control , SARS-CoV-2/physiology , Serine Endopeptidases/genetics , Serine Endopeptidases/metabolism , Treatment Outcome
16.
Front Immunol ; 12: 780900, 2021.
Article in English | MEDLINE | ID: covidwho-1662580

ABSTRACT

Mesenchymal stem cells (MSCs) are multipotent adult stem cells present in virtually all tissues; they have potent self-renewal capacity and differentiate into multiple cell types. For many reasons, these cells are a promising therapeutic alternative to treat patients with severe COVID-19 and pulmonary post-COVID sequelae. These cells are not only essential for tissue regeneration; they can also alter the pulmonary environment through the paracrine secretion of several mediators. They can control or promote inflammation, induce other stem cells differentiation, restrain the virus load, and much more. In this work, we performed single-cell RNA-seq data analysis of MSCs in bronchoalveolar lavage samples from control individuals and COVID-19 patients with mild and severe clinical conditions. When we compared samples from mild cases with control individuals, most genes transcriptionally upregulated in COVID-19 were involved in cell proliferation. However, a new set of genes with distinct biological functions was upregulated when we compared severely affected with mild COVID-19 patients. In this analysis, the cells upregulated genes related to cell dispersion/migration and induced the γ-activated sequence (GAS) genes, probably triggered by IFNGR1 and IFNGR2. Then, IRF-1 was upregulated, one of the GAS target genes, leading to the interferon-stimulated response (ISR) and the overexpression of many signature target genes. The MSCs also upregulated genes involved in the mesenchymal-epithelial transition, virus control, cell chemotaxis, and used the cytoplasmic RNA danger sensors RIG-1, MDA5, and PKR. In a non-comparative analysis, we observed that MSCs from severe cases do not express many NF-κB upstream receptors, such as Toll-like (TLRs) TLR-3, -7, and -8; tumor necrosis factor (TNFR1 or TNFR2), RANK, CD40, and IL-1R1. Indeed, many NF-κB inhibitors were upregulated, including PPP2CB, OPTN, NFKBIA, and FHL2, suggesting that MSCs do not play a role in the "cytokine storm" observed. Therefore, lung MSCs in COVID-19 sense immune danger and act protectively in concert with the pulmonary environment, confirming their therapeutic potential in cell-based therapy for COVID-19. The transcription of MSCs senescence markers is discussed.


Subject(s)
COVID-19/immunology , Cell Proliferation/physiology , Inflammation/immunology , Lung/immunology , Mesenchymal Stem Cells/immunology , Regeneration/immunology , Adult , COVID-19/metabolism , Cell Differentiation/immunology , Cell Movement/immunology , Cytoplasm/immunology , Epithelial-Mesenchymal Transition/immunology , Humans , Inflammation/metabolism , Mesenchymal Stem Cells/metabolism , SARS-CoV-2/immunology , Up-Regulation/immunology , Young Adult
17.
Int J Mol Sci ; 23(3)2022 Jan 24.
Article in English | MEDLINE | ID: covidwho-1650418

ABSTRACT

Acute Respiratory Distress Syndrome is the most common cause of respiratory failure among critically ill patients, and its importance has been heightened during the COVID-19 pandemic. Even with the best supportive care, the mortality rate in the most severe cases is 40-50%, and the only pharmacological agent shown to be of possible benefit has been steroids. Mesenchymal stromal cells (MSCs) have been tested in several pre-clinical models of lung injury and been found to have significant therapeutic benefit related to: (a) potent immunomodulation; (b) secretion of epithelial and endothelial growth factors; and (c) augmentation of host defense to infection. Initial translational efforts have shown signs of promise, but the results have not yielded the anticipated outcomes. One potential reason is the relatively low survival of MSCs in inflammatory conditions as shown in several studies. Therefore, strategies to boost the survival of MSCs are needed to enhance their therapeutic effect. Protease-activated receptors (PARs) may represent one such possibility as they are G-protein coupled receptors expressed by MSCs and control several facets of cell behavior. This review summarizes some of the existing literature about PARs and MSCs and presents possible future areas of investigation in order to develop potential, PAR-modified MSCs with enhanced therapeutic efficiency.


Subject(s)
Graft Survival/genetics , Mesenchymal Stem Cell Transplantation , Mesenchymal Stem Cells/metabolism , Receptors, Proteinase-Activated/physiology , Respiratory Distress Syndrome/therapy , Animals , COVID-19/genetics , COVID-19/pathology , COVID-19/therapy , Cell Survival/genetics , Critical Illness/therapy , Humans , Mesenchymal Stem Cells/physiology , Receptors, Proteinase-Activated/genetics , Receptors, Proteinase-Activated/metabolism , Respiratory Distress Syndrome/genetics , Respiratory Distress Syndrome/metabolism , Respiratory Distress Syndrome/virology , SARS-CoV-2/physiology , Signal Transduction/physiology , Transfection , Treatment Outcome
18.
Bull Exp Biol Med ; 172(2): 250-253, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1544492

ABSTRACT

Mesenchymal stem cells (MSC) are characterized by tolerogenic potential and therefore, are used in the treatment of autoimmune diseases such as graft-versus-host disease (GVHD) reactions after allogeneic hematopoietic cell transplantation to improve the transplant functions, as well as for the therapy and prevention of cytokine storm in COVID-19 patients and some other conditions. However, MSC can exhibit proinflammatory activity, which causes risks for their clinical use. We studied the cytokine profile of bone marrow MSC culture and demonstrate intensive production of IL-6, IL-8, and chemokine MCP-1, which participate in the pathogenesis of cytokine storm and GVHD. At the same time, no anti-inflammatory IL-4 and IL-10 were detected. To reduce the risks of MSC application in the GVHD therapeutic protocols, further studies of the conditions promoting generation of MSC with tolerogenic potential and approved clinical standards of MSC use are required.


Subject(s)
COVID-19/therapy , Cytokine Release Syndrome/prevention & control , Cytokines/analysis , Graft vs Host Disease/prevention & control , Mesenchymal Stem Cell Transplantation/adverse effects , Mesenchymal Stem Cells/immunology , Bone Marrow Cells/immunology , Bone Marrow Cells/metabolism , COVID-19/immunology , Cells, Cultured , Chemokine CCL2/analysis , Graft vs Host Disease/immunology , Hematopoietic Stem Cell Transplantation/adverse effects , Humans , Immunosuppressive Agents/therapeutic use , Interleukin-6/analysis , Interleukin-8/analysis , Mesenchymal Stem Cells/metabolism , SARS-CoV-2/immunology , Transplantation, Homologous/adverse effects
19.
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
20.
Int J Mol Sci ; 22(22)2021 Nov 17.
Article in English | MEDLINE | ID: covidwho-1524026

ABSTRACT

The rapid mutation of the SARS-CoV-2 virus is now a major concern with no effective drugs and treatments. The severity of the disease is linked to the induction of a cytokine storm that promotes extensive inflammation in the lung, leading to many acute lung injuries, pulmonary edema, and eventually death. Mesenchymal stem cells (MSCs) might prove to be a treatment option as they have immunomodulation and regenerative properties. Clinical trials utilizing MSCs in treating acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) have provided a basis in treating post-COVID-19 patients. In this review, we discussed the effects of MSCs as an immunomodulator to reduce the severity and death in patients with COVID-19, including the usage of MSCs as an alternative regenerative therapy in post-COVID-19 patients. This review also includes the current clinical trials in utilizing MSCs and their potential future utilization for long-COVID treatments.


Subject(s)
COVID-19/complications , Immunomodulation/physiology , Mesenchymal Stem Cell Transplantation , Regeneration/physiology , COVID-19/pathology , COVID-19/therapy , COVID-19/virology , Humans , Lung/pathology , Lung/physiology , Mesenchymal Stem Cells/cytology , Mesenchymal Stem Cells/metabolism , Respiratory Distress Syndrome/pathology , Respiratory Distress Syndrome/therapy , SARS-CoV-2/isolation & purification
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