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1.
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
2.
Front Biosci (Landmark Ed) ; 26(10): 948-961, 2021 10 30.
Article in English | MEDLINE | ID: covidwho-1498509

ABSTRACT

Background: Corona Virus Disease 2019 (COVID-19) is an acute respiratory infectious disease caused by severe respiratory syndrome coronavirus 2 (SARS-CoV-2). The primary pathogenesis is over-activation of the immune system. SARS-CoV-2 continues to mutate and spread rapidly and no effective treatment options are yet available. Mesenchymal stem cells (MSCs) are known to induce anti-inflammatory macrophages, regulatory T cells and dendritic cells. There are a rapidly increasing number of clinical investigations of cell-based therapy approaches for COVID-19. Objective: To summarize the pathogenic mechanism of SARS-CoV-2, and systematically formulated the immunomodulation of COVID-19 by MSCs and their exosomes, as well as research progress. Method: Searching PubMed, clinicaltrials.gov and Chictr.cn for eligible studies to be published or registered by May 2021. Main keywords and search strategies were as follows: ((Mesenchymal stem cells) OR (MSCs)) AND (COVID-19). Results: MSCs regulate the immune system to prevent cytokine release syndrome (CRS) and to promote endogenous repair by releasing various paracrine factors and exosomes. Conclusions: MSC therapy is thus a promising candidate for COVID-19.


Subject(s)
COVID-19/therapy , Exosomes/transplantation , Immunomodulation/immunology , Lung Injury/therapy , Mesenchymal Stem Cell Transplantation/methods , Mesenchymal Stem Cells/metabolism , COVID-19/epidemiology , COVID-19/virology , Clinical Trials as Topic , Exosomes/immunology , Exosomes/metabolism , Humans , Lung Injury/physiopathology , Lung Injury/virology , Mesenchymal Stem Cells/cytology , Mesenchymal Stem Cells/immunology , Outcome Assessment, Health Care/methods , Outcome Assessment, Health Care/statistics & numerical data , Pandemics , Regeneration/immunology , Regeneration/physiology , SARS-CoV-2/immunology , SARS-CoV-2/physiology
3.
Cell Transplant ; 30: 9636897211049814, 2021.
Article in English | MEDLINE | ID: covidwho-1484237

ABSTRACT

During the past 18 months as the world dealt with the COVID-19 pandemic, articles published in Cell Transplantation (CT) voiced unique perspectives on the disease which have since been supported by additional research. Intrigued by the variability in COVID-19 severity, CT authors explored the influence of variants in angiotensin-converting enzyme 2 (ACE2) and the transmembrane serine protease 2 (TMPRSS2) genes, as well as the role of androgen receptors on disease development. Mesenchymal stem cells (MSC) were offered up as a potential COVID-19 therapy because of their immune modulating characteristics and successful use in other acute respiratory diseases. Two CT author groups gave proof of principle when hospitalized COVID-19 patients were infused with MSC after no other interventions seemed to work. MSC treatment reduced disease severity and shortened hospitalization stays. Lastly, CT authors speculated why we are still in the midst of a pandemic and the consequences of disillusioned comfort as we face new emerging variants that may undermine all we have accomplished thus far.


Subject(s)
COVID-19/immunology , COVID-19/therapy , Mesenchymal Stem Cells/cytology , Serine Endopeptidases/genetics , Angiotensin-Converting Enzyme 2/metabolism , Biomedical Research , Cell Transplantation , Cytokines/metabolism , Hospitalization , Humans , Immune System , Mesenchymal Stem Cells/metabolism , Peptidyl-Dipeptidase A/genetics , Publications , Receptors, Androgen/metabolism , Retrospective Studies , SARS-CoV-2 , Severity of Illness Index
4.
Int J Mol Sci ; 22(12)2021 Jun 20.
Article in English | MEDLINE | ID: covidwho-1472414

ABSTRACT

Acute kidney injury (AKI) and chronic kidney disease (CKD) are rising in global prevalence and cause significant morbidity for patients. Current treatments are limited to slowing instead of stabilising or reversing disease progression. In this review, we describe mesenchymal stem cells (MSCs) and their constituents, extracellular vesicles (EVs) as being a novel therapeutic for CKD. MSC-derived EVs (MSC-EVs) are membrane-enclosed particles, including exosomes, which carry genetic information that mimics the phenotype of their cell of origin. MSC-EVs deliver their cargo of mRNA, miRNA, cytokines, and growth factors to target cells as a form of paracrine communication. This genetically reprograms pathophysiological pathways, which are upregulated in renal failure. Since the method of exosome preparation significantly affects the quality and function of MSC-exosomes, this review compares the methodologies for isolating exosomes from MSCs and their role in tissue regeneration. More specifically, it summarises the therapeutic efficacy of MSC-EVs in 60 preclinical animal models of AKI and CKD and the cargo of biomolecules they deliver. MSC-EVs promote tubular proliferation and angiogenesis, and inhibit apoptosis, oxidative stress, inflammation, the epithelial-to-mesenchymal transition, and fibrosis, to alleviate AKI and CKD. By reprogramming these pathophysiological pathways, MSC-EVs can slow or even reverse the progression of AKI to CKD, and therefore offer potential to transform clinical practice.


Subject(s)
Biological Therapy , Extracellular Vesicles/metabolism , Extracellular Vesicles/transplantation , Kidney Diseases/therapy , Mesenchymal Stem Cells/metabolism , Acute Kidney Injury/diagnosis , Acute Kidney Injury/etiology , Acute Kidney Injury/metabolism , Acute Kidney Injury/therapy , Animals , Apoptosis/drug effects , Biological Therapy/methods , Cell Differentiation , Cell Proliferation/drug effects , Cell Self Renewal , Chemical Fractionation , Disease Management , Disease Susceptibility , Exosomes/metabolism , Humans , Kidney Diseases/etiology , Kidney Diseases/pathology , Mesenchymal Stem Cells/cytology , Protective Agents , Renal Insufficiency/diagnosis , Renal Insufficiency/etiology , Renal Insufficiency, Chronic/diagnosis , Renal Insufficiency, Chronic/etiology , Renal Insufficiency, Chronic/metabolism , Renal Insufficiency, Chronic/therapy
5.
Cells ; 10(10)2021 10 03.
Article in English | MEDLINE | ID: covidwho-1444118

ABSTRACT

The PD-L1/PD-1 immune checkpoint axis is the strongest T cell exhaustion inducer. As immune dysfunction occurs during obesity, we analyzed the impact of obesity on PD-L1/PD-1 expression in white adipose tissue (WAT) in mice and in human white adipocytes. We found that PD-L1 was overexpressed in WAT of diet-induced obese mice and was associated with increased expression of PD-1 in visceral but not subcutaneous WAT. Human in vitro cocultures with adipose-tissue-derived mesenchymal stem cells (ASC) and mononuclear cells demonstrated that the presence of ASC harvested from obese WAT (i) enhanced PD-L1 expression as compared with ASC from lean WAT, (ii) decreased Th1 cell cytokine secretion, and (iii) resulted in decreased cytolytic activity towards adipocytes. Moreover, (iv) the implication of PD-L1 in obese ASC-mediated T cell dysfunction was demonstrated through PD-L1 blockade. Finally, (v) conditioned media gathered from these cocultures enhanced PD-L1 expression in freshly differentiated adipocytes, depending on IFNγ. Altogether, our results suggest that PD-L1 is overexpressed in the WAT of obese individuals during IFNγ secretion, leading to T cell dysfunction and notably reduced cytolytic activity. Such a mechanism could shed light on why adipose-tissue-infiltrating viruses, such as SARS-CoV-2, can worsen disease in obese individuals.


Subject(s)
Adipose Tissue, White/metabolism , B7-H1 Antigen/biosynthesis , Gene Expression Regulation , Mesenchymal Stem Cells/cytology , Obesity/metabolism , T-Lymphocytes/immunology , Animals , COVID-19/immunology , Cell Differentiation , Coculture Techniques , Humans , Immunohistochemistry , Inflammation , Interferon-gamma/metabolism , Leukocytes, Mononuclear/cytology , Male , Mice , Mice, Inbred C57BL , Obesity/immunology , SARS-CoV-2 , T-Lymphocytes/cytology
6.
Cells ; 10(10)2021 09 29.
Article in English | MEDLINE | ID: covidwho-1444117

ABSTRACT

Mesenchymal stem cells (MSCs) are multipotent adult stem cells present in virtually all tissues; they have a potent self-renewal capacity and can differentiate into multiple cell types. They also affect the ambient tissue by the paracrine secretion of numerous factors in vivo, including the induction of other stem cells' differentiation. In vitro, the culture media supernatant is named secretome and contains soluble molecules and extracellular vesicles that retain potent biological function in tissue regeneration. MSCs are considered safe for human treatment; their use does not involve ethical issues, as embryonic stem cells do not require genetic manipulation as induced pluripotent stem cells, and after intravenous injection, they are mainly found in the lugs. Therefore, these cells are currently being tested in various preclinical and clinical trials for several diseases, including COVID-19. Several affected COVID-19 patients develop induced acute respiratory distress syndrome (ARDS) associated with an uncontrolled inflammatory response. This condition causes extensive damage to the lungs and may leave serious post-COVID-19 sequelae. As the disease may cause systemic alterations, such as thromboembolism and compromised renal and cardiac function, the intravenous injection of MSCs may be a therapeutic alternative against multiple pathological manifestations. In this work, we reviewed the literature about MSCs biology, focusing on their function in pulmonary regeneration and their use in COVID-19 treatment.


Subject(s)
COVID-19/blood , COVID-19/therapy , Lung/physiology , Mesenchymal Stem Cell Transplantation/methods , Mesenchymal Stem Cells/cytology , Regeneration/physiology , Animals , COVID-19/drug therapy , Cell Differentiation , Cell- and Tissue-Based Therapy , Culture Media , Extracellular Vesicles , Humans , Inflammation , Mice , Mice, SCID , Phenotype , Pneumonia/blood , Pneumonia/immunology , Pneumonia/therapy , Respiratory Distress Syndrome , SARS-CoV-2 , Thromboembolism/blood , Thromboembolism/immunology , Thromboembolism/therapy
7.
Curr Stem Cell Res Ther ; 16(4): 465-480, 2021.
Article in English | MEDLINE | ID: covidwho-1435707

ABSTRACT

The cause of Coronavirus Disease 2019 (COVID-19) known as the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2, formerly designated 2019-nCoV) was first discovered in December 2019 in Wuhan, China. It then spread rapidly worldwide. Investigation for the discovery of drugs to cure this disease continues. The currently accepted treatments are supportive, but there is no specific disease curing intervention found yet. Since mid-February, therapies involving Mesenchymal Stem/Stromal Cells (MSCs) have been proposed for the treatment of patients with COVID-19. In light of these recent developments, this review will focus on: i) the mechanism of SARS-CoV-2 action and the subsequent pathology in COVID-19, ii) the proposed mechanism( s) of outcome-improving action of MSCs or MSC-derived extracellular vesicles in COVID-19 pneumonia, iii) registered MSC-based clinical trials and interventions for the treatment of COVID-19, iv) published case studies/series/trials reporting the use of MSC-based treatments in COVID-19 cases, and finally v) the need for authority regulations and clinical guidelines for MSCbased treatment strategies for COVID-19.


Subject(s)
COVID-19/therapy , Mesenchymal Stem Cell Transplantation/standards , Mesenchymal Stem Cells/cytology , Practice Guidelines as Topic , Extracellular Vesicles/metabolism , Humans , SARS-CoV-2/pathogenicity
8.
Life Sci ; 284: 119901, 2021 Nov 01.
Article in English | MEDLINE | ID: covidwho-1370629

ABSTRACT

COVID-19 is a serious viral infection that struck the world in December 2019 starting from Wuhan in China, spreading subsequently to all over the world. The disease has baffled scientists and doctors worldwide in terms of its presentation, behaviour, and treatment options till now. A low mortality rate is the only relief we get so far from COVID-19 in terms of numbers. Treatment options have gradually streamlined to steroids and very few FDA approved antiviral as well as plasma therapy and supportive treatment. Monoclonal antibodies are used to tide over any impending cytokine storm but are not equally effective in all patients. Ventilation support is invariably required for moderate to severe disease varying from a simple High Flow non-rebreathing mask to BiPAP (Bilevel Positive Airway Pressure) and HFNO (High-Flow Nasal Oxygen) extending to full-fledge ventilation via a Mechanical Ventilator. Because of the non-availability of satisfactory treatment so far, many researchers from different biomedical fields are looking for alternative therapeutic strategies to manage the pandemic. One such therapeutic approach showing a ray of hope to combat COVID-19 infection is Mesenchymal stem cell therapy. Mesenchymal cells have immunomodulatory, anti-inflammatory as well as regenerative properties and various preliminary studies have shown that MSCs can reverse the lung damage and overcome the cytokine storm incited by COVID-19 infection. Also, it has improved the recovery rate of critically ill patients on mechanical ventilation. In this review, we will discuss the possibility and relevance of MSCs in COVID-19 treatment and preview of various MSCs clinical trials.


Subject(s)
COVID-19/therapy , Mesenchymal Stem Cell Transplantation , Mesenchymal Stem Cells/cytology , SARS-CoV-2/physiology , COVID-19/immunology , COVID-19/prevention & control , COVID-19/virology , Clinical Trials as Topic , Humans , Immunity
9.
Biomolecules ; 10(10)2020 09 27.
Article in English | MEDLINE | ID: covidwho-1295752

ABSTRACT

Acute and chronic skin wounds due to burns, pressure injuries, and trauma represent a substantial challenge to healthcare delivery with particular impacts on geriatric, paraplegic, and quadriplegic demographics worldwide. Nevertheless, the current standard of care relies extensively on preventive measures to mitigate pressure injury, surgical debridement, skin flap procedures, and negative pressure wound vacuum measures. This article highlights the potential of adipose-, blood-, and cellulose-derived products (cells, decellularized matrices and scaffolds, and exosome and secretome factors) as a means to address this unmet medical need. The current status of this research area is evaluated and discussed in the context of promising avenues for future discovery.


Subject(s)
Burns/therapy , Exosomes/transplantation , Hydrogels/therapeutic use , Wound Healing/genetics , Burns/pathology , Cell- and Tissue-Based Therapy/trends , Cellulose/therapeutic use , Exosomes/genetics , Humans , Hydrogels/chemistry , Mesenchymal Stem Cell Transplantation/trends , Mesenchymal Stem Cells/cytology , Skin/growth & development , Skin/injuries , Skin/metabolism
10.
Cell Transplant ; 30: 9636897211024942, 2021.
Article in English | MEDLINE | ID: covidwho-1285159

ABSTRACT

The aim of this clinical trial was to control the cytokine storm by administering mesenchymal stem cells (MSCs) to critically-ill COVID-19 patients, to evaluate the healing effect, and to systematically investigate how the treatment works. Patients with moderate and critical COVID-19 clinical manifestations were separated as Group 1 (moderate cases, n = 10, treated conventionally), Group 2 (critical cases, n = 10, treated conventionally), and Group 3 (critical cases, n = 10, treated conventionally plus MSCs transplantation therapy of three consecutive doses on treatment days 0, 3, and 6, (as 3 × 106 cells/kg, intravenously). The treatment mechanism of action was investigated with evaluation markers of the cytokine storm, via biochemical parameters, levels of proinflammatory and anti-inflammatory cytokines, analyses of tissue regeneration via the levels of growth factors, apoptosis markers, chemokines, matrix metalloproteinases, and granzyme-B, and by the assessment of the immunomodulatory effects via total oxidant/antioxidant status markers and the levels of lymphocyte subsets. In the assessment of the overall mortality rates of all the cases, six patients in Group-2 and three patients in Group-3 died, and there was no loss in Group-1. Proinflammatory cytokines IFNγ, IL-6, IL-17A, IL-2, IL-12, anti-inflammatory cytokines IL-10, IL-13, IL-1ra, and growth factors TGF-ß, VEGF, KGF, and NGF levels were found to be significant in Group-3. When Group-2 and Group-3 were compared, serum ferritin, fibrinogen and CRP levels in Group-3 had significantly decreased. CD45 +, CD3 +, CD4 +, CD8 +, CD19 +, HLA-DR +, and CD16 + / CD56 + levels were evaluated. In the statistical comparison of the groups, significance was only determined in respect of neutrophils. The results demonstrated the positive systematic and cellular effects of MSCs application on critically ill COVID-19 patients in a versatile way. This effect plays an important role in curing and reducing mortality in critically ill patients.


Subject(s)
COVID-19/therapy , Mesenchymal Stem Cell Transplantation , Adult , C-Reactive Protein/analysis , COVID-19/pathology , COVID-19/virology , Critical Illness , Cytokines/blood , Female , Humans , Interferon-gamma/blood , Interleukin-10/blood , Interleukin-8/blood , Leukocyte Common Antigens/metabolism , Lymphocytes/cytology , Lymphocytes/metabolism , Male , Mesenchymal Stem Cells/cytology , Mesenchymal Stem Cells/metabolism , Middle Aged , Prospective Studies , SARS-CoV-2/isolation & purification , Severity of Illness Index , Treatment Outcome
11.
Eur J Pediatr Surg ; 31(4): 326-334, 2021 Aug.
Article in English | MEDLINE | ID: covidwho-1279928

ABSTRACT

The novel coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), continues to be a major health concern. In search for novel treatment strategies against COVID-19, exosomes have attracted the attention of scientists and pharmaceutical companies worldwide. Exosomes are small extracellular vesicles, secreted by all types of cells, and considered as key mediators of intercellular communication and stem-cell paracrine signaling. Herein, we reviewed the most recent literature about the role of exosomes as potential agents for treatment, prevention, diagnosis, and pathogenesis of COVID-19. Several studies and ongoing clinical trials have been investigating the anti-inflammatory, immunomodulatory, and reparative effects of exosomes derived from mesenchymal stem/stromal cells for COVID-19-related acute lung injury. Other studies reported that exosomes play a key role in convalescent plasma therapy for COVID-19, and that they could be of use for the treatment of COVID-19 Kawasaki's-like multisystem inflammatory syndrome and as drug delivery nanocarriers for antiviral therapy. Harnessing some advantageous aspects of exosome biology, such as their endogenous origin, capability of crossing biological barriers, high stability in circulation, and low toxicity and immunogenicity, several companies have been testing exosome-based vaccines against SARS-CoV-2. As they carry cargos that mimic the status of parent cells, exosomes can be isolated from a variety of sources, including plasma, and employed as biomarkers of COVID-19. Lastly, there is growing evidence supporting the role of exosomes in COVID-19 infection, spread, reactivation, and reinfection. The lessons learned using exosomes for COVID-19 will help determine their efficacy and applicability in other clinical conditions.


Subject(s)
COVID-19/therapy , Exosomes/immunology , COVID-19/diagnosis , COVID-19/prevention & control , COVID-19 Vaccines , Drug Carriers , Humans , Immunization, Passive , Mesenchymal Stem Cells/cytology
12.
PLoS One ; 16(6): e0252302, 2021.
Article in English | MEDLINE | ID: covidwho-1278172

ABSTRACT

A potent therapy for the infectious coronavirus disease COVID-19 is urgently required with, at the time of writing, research in this area still ongoing. This study aims to evaluate the in vitro anti-viral activities of combinations of certain commercially available drugs that have recently formed part of COVID-19 therapy. Dual combinatory drugs, namely; Lopinavir-Ritonavir (LOPIRITO)-Clarithromycin (CLA), LOPIRITO-Azithromycin (AZI), LOPIRITO-Doxycycline (DOXY), Hydroxychloroquine (HCQ)-AZI, HCQ-DOXY, Favipiravir (FAVI)-AZI, HCQ-FAVI, and HCQ-LOPIRITO, were prepared. These drugs were mixed at specific ratios and evaluated for their safe use based on the cytotoxicity concentration (CC50) values of human umbilical cord mesenchymal stem cells. The anti-viral efficacy of these combinations in relation to Vero cells infected with SARS-CoV-2 virus isolated from a patient in Universitas Airlangga hospital, Surabaya, Indonesia and evaluated for IC50 24, 48, and 72 hours after viral inoculation was subsequently determined. Observation of the viral load in qRT-PCR was undertaken, the results of which indicated the absence of high levels of cytotoxicity in any samples and that dual combinatory drugs produced lower cytotoxicity than single drugs. In addition, these combinations demonstrated considerable effectiveness in reducing the copy number of the virus at 48 and 72 hours, while even at 24 hours, post-drug incubation resulted in low IC50 values. Most combination drugs reduced pro-inflammatory markers, i.e. IL-6 and TNF-α, while increasing the anti-inflammatory response of IL-10. According to these results, the descending order of effective dual combinatory drugs is one of LOPIRITO-AZI>LOPIRITO-DOXY>HCQ-AZI>HCQ-FAVI>LOPIRITO-CLA>HCQ-DOX. It can be suggested that dual combinatory drugs, e.g. LOPIRITO-AZI, can potentially be used in the treatment of COVID-19 infectious diseases.


Subject(s)
Anti-Bacterial Agents/pharmacology , Antiviral Agents/pharmacology , COVID-19/drug therapy , Hydroxychloroquine/pharmacology , SARS-CoV-2/drug effects , Animals , Anti-Bacterial Agents/therapeutic use , Antiviral Agents/therapeutic use , COVID-19/virology , Cell Survival/drug effects , Cells, Cultured , Chlorocebus aethiops , Drug Combinations , Hospitalization , Host-Pathogen Interactions/drug effects , Humans , Hydroxychloroquine/therapeutic use , Indonesia , Inhibitory Concentration 50 , Inpatients , Mesenchymal Stem Cells/cytology , Mesenchymal Stem Cells/drug effects , SARS-CoV-2/isolation & purification , SARS-CoV-2/physiology , Time Factors , Vero Cells , Viral Load/drug effects
13.
Stem Cells Transl Med ; 10(9): 1279-1287, 2021 09.
Article in English | MEDLINE | ID: covidwho-1260571

ABSTRACT

One of the main causes of acute respiratory distress syndrome in coronavirus disease 2019 (COVID-19) is cytokine storm, although the exact cause is still unknown. Umbilical cord mesenchymal stromal cells (UC-MSCs) influence proinflammatory T-helper 2 (Th2 ) cells to shift to an anti-inflammatory agent. To investigate efficacy of UC-MSC administration as adjuvant therapy in critically ill patients with COVID-19, we conducted a double-blind, multicentered, randomized controlled trial at four COVID-19 referral hospitals in Jakarta, Indonesia. This study included 40 randomly allocated critically ill patients with COVID-19; 20 patients received an intravenous infusion of 1 × 106 /kg body weight UC-MSCs in 100 ml saline (0.9%) solution (SS) and 20 patients received 100 ml 0.9% SS as the control group. All patients received standard therapy. The primary outcome was measured by survival rate and/or length of ventilator usage. The secondary outcome was measured by clinical and laboratory improvement, with serious adverse events. Our study showed the survival rate in the UC-MSCs group was 2.5 times higher than that in the control group (P = .047), which is 10 patients and 4 patients in the UC-MSCs and control groups, respectively. In patients with comorbidities, UC-MSC administration increased the survival rate by 4.5 times compared with controls. The length of stay in the intensive care unit and ventilator usage were not statistically significant, and no adverse events were reported. The application of infusion UC-MSCs significantly decreased interleukin 6 in the recovered patients (P = .023). Therefore, application of intravenous UC-MSCs as adjuvant treatment for critically ill patients with COVID-19 increases the survival rate by modulating the immune system toward an anti-inflammatory state.


Subject(s)
Mesenchymal Stem Cells/cytology , SARS-CoV-2/growth & development , SARS-CoV-2/physiology , Umbilical Cord/cytology , COVID-19 , Double-Blind Method , Humans , Male , Middle Aged , Severity of Illness Index
14.
Cell Transplant ; 30: 9636897211021008, 2021.
Article in English | MEDLINE | ID: covidwho-1255859

ABSTRACT

The coronavirus pandemic is one of the most significant public health events in recent history. Currently, no specific treatment is available. Some drugs and cell-based therapy have been tested as alternatives to decrease the disease's symptoms, length of hospital stay, and mortality. We reported the case of a patient with a severe manifestation of COVID-19 in critical condition who did not respond to the standard procedures used, including six liters of O2 supplementation under a nasal catheter and treatment with dexamethasone and enoxaparin in prophylactic dose. The patient was treated with tocilizumab and an advanced therapy product based on umbilical cord-derived mesenchymal stromal cells (UC-MSC). The combination of tocilizumab and UC-MSC proved to be safe, with no adverse effects, and the results of this case report prove to be a promising alternative in the treatment of patients with severe acute respiratory syndrome due to SARS-CoV-2.


Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , COVID-19/therapy , Mesenchymal Stem Cell Transplantation , COVID-19/drug therapy , COVID-19/virology , Combined Modality Therapy , Humans , Immunophenotyping , Karyotyping , Mesenchymal Stem Cells/cytology , Mesenchymal Stem Cells/metabolism , Middle Aged , RNA, Viral/analysis , SARS-CoV-2/genetics , SARS-CoV-2/isolation & purification , Thorax/diagnostic imaging , Tomography, X-Ray Computed , Umbilical Cord/cytology , Viral Load
15.
Stem Cells Dev ; 30(15): 758-772, 2021 08 01.
Article in English | MEDLINE | ID: covidwho-1254367

ABSTRACT

Cytokine storm is recognized as one of the factors contributing to organ failures and mortality in patients with COVID-19. Due to chronic inflammation, COVID-19 patients with diabetes mellitus (DM) or renal disease (RD) have more severe symptoms and higher mortality. However, the factors that contribute to severe outcomes of COVID-19 patients with DM and RD have received little attention. In an effort to investigate potential treatments for COVID-19, recent research has focused on the immunomodulation functions of mesenchymal stem cells (MSCs). In this study, the correlation between DM and RD and the severity of COVID-19 was examined by a combined approach with a meta-analysis and experimental research. The results of a systematic review and meta-analysis suggested that the odd of mortality in patients with both DM and RD was increased in comparison to those with a single comorbidity. In addition, in the experimental research, the data showed that high glucose and uremic toxins contributed to the induction of cytokine storm in human lung adenocarcinoma epithelial cells (Calu-3 cells) in response to SARS-CoV Peptide Pools. Of note, the incorporation of Wharton's jelly MSC-derived extracellular vesicles (WJ-EVs) into SARS-CoV peptide-induced Calu-3 resulted in a significant decrease in nuclear NF-κB p65 and the downregulation of the cytokine storm under high concentrations of glucose and uremic toxins. This clearly suggests the potential for WJ-EVs to reduce cytokine storm reactions in patients with both chronic inflammation diseases and viral infection.


Subject(s)
Cytokine Release Syndrome/prevention & control , Extracellular Vesicles/physiology , Mesenchymal Stem Cells/cytology , SARS-CoV-2/physiology , Wharton Jelly/cytology , Adult , Aged , COVID-19/blood , COVID-19/complications , COVID-19/metabolism , COVID-19/therapy , Cells, Cultured , Coculture Techniques , Cytokine Release Syndrome/genetics , Cytokine Release Syndrome/metabolism , Cytokine Release Syndrome/virology , Cytokines/genetics , Cytokines/metabolism , Diabetes Complications/blood , Diabetes Complications/metabolism , Diabetes Complications/therapy , Diabetes Complications/virology , Diabetes Mellitus/blood , Diabetes Mellitus/metabolism , Diabetes Mellitus/therapy , Diabetes Mellitus/virology , Dose-Response Relationship, Drug , Female , Gene Expression Regulation/drug effects , Glucose/metabolism , Glucose/pharmacology , Humans , Inflammation Mediators/metabolism , Male , Mesenchymal Stem Cell Transplantation , Mesenchymal Stem Cells/physiology , Pregnancy , Toxins, Biological/metabolism , Toxins, Biological/pharmacology , Umbilical Cord/cytology , Uremia/blood , Uremia/complications , Uremia/metabolism , Uremia/therapy
16.
Arch Virol ; 166(8): 2285-2289, 2021 Aug.
Article in English | MEDLINE | ID: covidwho-1245240

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
17.
Stem Cells Transl Med ; 10(9): 1288-1303, 2021 09.
Article in English | MEDLINE | ID: covidwho-1233233

ABSTRACT

Mesenchymal stem cell therapy (MSCT) for immune and inflammatory diseases continues to be popular based on progressive accumulation of preclinical mechanistic evidence. This has led to further expansion in clinical indications from graft rejection, autoimmune diseases, and osteoarthritis, to inflammatory liver and pulmonary diseases including COVID-19. A clear trend is the shift from using autologous to allogeneic MSCs, which can be immediately available as off-the-shelf products. In addition, new products such as cell-free exosomes and human pluripotent stem cell (hPSC)-derived MSCs are exciting developments to further prevalent use. Increasing numbers of trials have now published results in which safety of MSCT has been largely demonstrated. While reports of therapeutic endpoints are still emerging, efficacy can be seen for specific indications-including graft-vs-host-disease, strongly Th17-mediated autoimmune diseases, and osteoarthritis-which are more robustly supported by mechanistic preclinical evidence. In this review, we update and discuss outcomes in current MSCT clinical trials for immune and inflammatory disease, as well as new innovation and emerging trends in the field.


Subject(s)
COVID-19/therapy , Mesenchymal Stem Cell Transplantation , Mesenchymal Stem Cells/cytology , SARS-CoV-2/drug effects , Graft vs Host Disease/therapy , Humans , Mesenchymal Stem Cell Transplantation/methods , Mesenchymal Stem Cells/immunology , Pluripotent Stem Cells/classification
18.
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
19.
Eur Rev Med Pharmacol Sci ; 25(6): 2748-2751, 2021 Mar.
Article in English | MEDLINE | ID: covidwho-1173126

ABSTRACT

COVID-19 is an acute respiratory infectious disease caused by SARS-COV 2 (Severe Acute Respiratory Syndrome Coronavirus) that has become a global pandemic. COVID-19 mainly causes the respiratory complications of Acute Respiratory Distress Syndrome (ARDS), cytokine storm, and severe immune disruptions. The assays depict that though people recuperate from COVID-19, there are still symptoms that persists in the body causing discomfort, which is the consequence of the viral infection due to severe immune disruptions. Upon various difficulties of post COVID-19, the pulmonary fibrosis is the stumbling block in the lungs causing severe damage. In this review, we have shown the effectiveness and importance of the Hepatocyte Growth Factor (HGF) secreted by Mesenchymal Stem Cell (MSC) therapy on selective stoppage of the Transforming Growth Factor-Beta (TGF-ß) signalling pathway by causing immunomodulatory effects that ameliorate the pulmonary fibrosis through paracrine signalling. However, more pilot studies have to be carried out to determine the efficacy and outcomes of the re-emerging complication.


Subject(s)
COVID-19/epidemiology , Mesenchymal Stem Cell Transplantation/methods , Mesenchymal Stem Cells/cytology , Pulmonary Fibrosis/therapy , Pulmonary Fibrosis/virology , COVID-19/transmission , COVID-19/virology , Global Health , Humans , Pulmonary Fibrosis/epidemiology , SARS-CoV-2/isolation & purification
20.
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
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