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Open accessJournal ArticleDOI: 10.1080/17476348.2021.1848555

Mesenchymal stromal cells for acute respiratory distress syndrome (ARDS), sepsis, and COVID-19 infection: optimizing the therapeutic potential.

04 Mar 2021-Expert Review of Respiratory Medicine (Expert Reviews Ltd.)-Vol. 15, Iss: 3, pp 301-324
Abstract: Introduction: Mesenchymal stromal (stem) cell (MSC) therapies are emerging as a promising therapeutic intervention in patients with Acute Respiratory Distress Syndrome (ARDS) and sepsis due to their reparative, immunomodulatory, and antimicrobial properties.Areas covered: This review provides an overview of Mesenchymal stromal cells (MSCs) and their mechanisms of effect in ARDS and sepsis. The preclinical and clinical evidence to support MSC therapy in ARDS and sepsis is discussed. The potential for MSC therapy in COVID-19 ARDS is discussed with insights from respiratory viral models and early clinical reports of MSC therapy in COVID-19. Strategies to optimize the therapeutic potential of MSCs in ARDS and sepsis are considered including preconditioning, altered gene expression, and alternative cell-free MSC-derived products, such as extracellular vesicles and conditioned medium.Expert opinion: MSC products present considerable therapeutic promise for ARDS and sepsis. Preclinical investigations report significant benefits and early phase clinical studies have not highlighted safety concerns. Optimization of MSC function in preclinical models of ARDS and sepsis has enhanced their beneficial effects. MSC-derived products, as cell-free alternatives, may provide further advantages in this field. These strategies present opportunity for the clinical development of MSCs and MSC-derived products with enhanced therapeutic efficacy.

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Topics: ARDS (56%), Sepsis (51%)
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7 results found


Open accessJournal ArticleDOI: 10.1096/FASEBJ.23.1_SUPPLEMENT.771.1
01 Apr 2009-The FASEB Journal
Abstract: Recent studies have suggested that bone marrow-derived multipotent mesenchymal stem cells (MSCs) may have therapeutic applications in multiple clinical disorders including myocardial infarction, diabetes, sepsis, and hepatic and acute renal failure. Here, we tested the therapeutic capacity of human MSCs to restore alveolar epithelial fluid transport and lung fluid balance from acute lung injury (ALI) in an ex vivo perfused human lung preparation injured by E. coli endotoxin. Intra-bronchial instillation of endotoxin into the distal airspaces resulted in pulmonary edema with the loss of alveolar epithelial fluid transport measured as alveolar fluid clearance. Treatment with allogeneic human MSCs or its conditioned medium given 1 h following endotoxin-induced lung injury reduced extravascular lung water, improved lung endothelial barrier permeability and restored alveolar fluid clearance. Using siRNA knockdown of potential paracrine soluble factors, secretion of keratinocyte growth factor was essential for the beneficial effect of MSCs on alveolar epithelial fluid transport, in part by restoring amiloride-dependent sodium transport. In summary, treatment with allogeneic human MSCs or the conditioned medium restores normal fluid balance in an ex vivo perfused human lung injured by E. coli endotoxin.

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Topics: Lung injury (71%), Ex vivo (60%), Mesenchymal stem cell (55%)

460 Citations


Open accessJournal ArticleDOI: 10.1186/S13287-021-02334-5
Birbal Singh1, Gorakh Mal1, Vinod Verma2, Ruchi Tiwari  +7 moreInstitutions (8)
Abstract: The global health emergency of COVID-19 has necessitated the development of multiple therapeutic modalities including vaccinations, antivirals, anti-inflammatory, and cytoimmunotherapies, etc. COVID-19 patients suffer from damage to various organs and vascular structures, so they present multiple health crises. Mesenchymal stem cells (MSCs) are of interest to treat acute respiratory distress syndrome (ARDS) caused by SARS-CoV-2 infection. Stem cell-based therapies have been verified for prospective benefits in copious preclinical and clinical studies. MSCs confer potential benefits to develop various cell types and organoids for studying virus-human interaction, drug testing, regenerative medicine, and immunomodulatory effects in COVID-19 patients. Apart from paving the ways to augment stem cell research and therapies, somatic cell nuclear transfer (SCNT) holds unique ability for a wide range of health applications such as patient-specific or isogenic cells for regenerative medicine and breeding transgenic animals for biomedical applications. Being a potent cell genome-reprogramming tool, the SCNT has increased prominence of recombinant therapeutics and cellular medicine in the current era of COVID-19. As SCNT is used to generate patient-specific stem cells, it avoids dependence on embryos to obtain stem cells. The nuclear transfer cloning, being an ideal tool to generate cloned embryos, and the embryonic stem cells will boost drug testing and cellular medicine in COVID-19.

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Topics: Stem cell (64%), Somatic cell nuclear transfer (63%), Embryonic stem cell (57%) ... read more

1 Citations


Journal ArticleDOI: 10.1080/21688370.2021.1929787
20 Jun 2021-Tissue barriers
Abstract: Endothelial barrier dysfunction (EBD) is the hallmark of Acute Respiratory Distress Syndrome (ARDS), a potentially lethal respiratory disorder associated with the COVID-19 - related deaths. Herein, we employed a cecal ligation and puncture (CLP) murine model of sepsis, to evaluate the effects of sepsis-induced EBD in the expression of the never in mitosis A (NIMA)-related kinases (NEKs). Members of that family of kinases regulate the activity and expression of the tumor suppressor P53, previously shown to modulate the actin cytoskeleton remodeling. Our results introduce the induction of NEK2, NEK3, NEK4, NEK7, and NEK9 in a CLP model of sepsis. Hence, we suggest that NEKs are involved in inflammatory processes and are holding the potential to serve as novel therapeutic targets for pathologies related to EBD, including ARDS and sepsis. Further studies will delineate the underlying molecular events and their interrelations with P53.

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Topics: ARDS (53%), Sepsis (52%)

1 Citations


Open accessJournal ArticleDOI: 10.37349/EI.2021.00010
30 Jun 2021-
Abstract: Mesenchymal stromal cells (MSCs) are a mesodermal stem cell population, with known self-renewal and multilineage differentiation properties. In the last century, MSCs have been widely used in regenerative medicine and tissue engineering approaches. MSCs initially were isolated from bone marrow aspirates, but currently have been identified in a great number of tissues of the human body. Besides their utilization in regenerative medicine, MSCs possess significant immunoregulatory/immunosuppressive properties, through interaction with the cells of innate and adaptive immunity. MSCs can exert their immunomodulatory properties with either cell-cell contact or via paracrine secretion of molecules, such as cytokines, growth factors and chemokines. Of particular importance, the MSCs’ immunomodulatory properties are explored as promising therapeutic strategies in immune-related disorders, such as autoimmune diseases, graft versus host disease, cancer. MSCs may also have an additional impact on coronavirus disease-19 (COVID-19), by attenuating the severe symptoms of this disorder. Nowadays, a great number of clinical trials, of MSC-mediated therapies are evaluated for their therapeutic potential. In this review, the current knowledge on cellular and molecular mechanisms involved in MSC-mediated immunomodulation were highlighted. Also, the most important aspects, regarding their potential application in immune-related diseases, will be highlighted. The broad application of MSCs has emerged their role as key immunomodulatory players, therefore their utilization in many disease situations is full of possibilities for future clinical treatment.

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Topics: Immune system (60%), Mesenchymal stem cell (56%)

1 Citations


Journal ArticleDOI: 10.1128/CMR.00064-21
Abstract: There is an urgent need for new antimicrobial strategies for treating complex infections and emerging pathogens. Human mesenchymal stromal cells (MSCs) are adult multipotent cells with antimicrobial properties, mediated through direct bactericidal activity and modulation of host innate and adaptive immune cells. More than 30 in vivo studies have reported on the use of human MSCs for the treatment of infectious diseases, with many more studies of animal MSCs in same-species models of infection. MSCs demonstrate potent antimicrobial effects against the major classes of human pathogens (bacteria, viruses, fungi, and parasites) across a wide range of infection models. Mechanistic studies have yielded important insight into their immunomodulatory and bactericidal activity, which can be enhanced through various forms of preconditioning. MSCs are being investigated in over 80 clinical trials for difficult-to-treat infectious diseases, including sepsis and pulmonary, intra-abdominal, cutaneous, and viral infections. Completed trials consistently report MSCs to be safe and well tolerated, with signals of efficacy against some infectious diseases. Although significant obstacles must be overcome to produce a standardized, affordable, clinical-grade cell therapy, these studies suggest that MSCs may have particular potential as an adjunct therapy in complex or resistant infections.

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Topics: Mesenchymal stem cell (52%), Antimicrobial (52%), Immune system (51%)

References
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167 results found


Journal ArticleDOI: 10.1080/14653240600855905
01 Jan 2006-Cytotherapy
Abstract: The considerable therapeutic potential of human multipotent mesenchymal stromal cells (MSC) has generated markedly increasing interest in a wide variety of biomedical disciplines. However, investig...

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12,805 Citations


Open accessJournal ArticleDOI: 10.1001/JAMA.2016.0287
23 Feb 2016-JAMA
Abstract: Importance Definitions of sepsis and septic shock were last revised in 2001. Considerable advances have since been made into the pathobiology (changes in organ function, morphology, cell biology, biochemistry, immunology, and circulation), management, and epidemiology of sepsis, suggesting the need for reexamination. Objective To evaluate and, as needed, update definitions for sepsis and septic shock. Process A task force (n = 19) with expertise in sepsis pathobiology, clinical trials, and epidemiology was convened by the Society of Critical Care Medicine and the European Society of Intensive Care Medicine. Definitions and clinical criteria were generated through meetings, Delphi processes, analysis of electronic health record databases, and voting, followed by circulation to international professional societies, requesting peer review and endorsement (by 31 societies listed in the Acknowledgment). Key Findings From Evidence Synthesis Limitations of previous definitions included an excessive focus on inflammation, the misleading model that sepsis follows a continuum through severe sepsis to shock, and inadequate specificity and sensitivity of the systemic inflammatory response syndrome (SIRS) criteria. Multiple definitions and terminologies are currently in use for sepsis, septic shock, and organ dysfunction, leading to discrepancies in reported incidence and observed mortality. The task force concluded the term severe sepsis was redundant. Recommendations Sepsis should be defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. For clinical operationalization, organ dysfunction can be represented by an increase in the Sequential [Sepsis-related] Organ Failure Assessment (SOFA) score of 2 points or more, which is associated with an in-hospital mortality greater than 10%. Septic shock should be defined as a subset of sepsis in which particularly profound circulatory, cellular, and metabolic abnormalities are associated with a greater risk of mortality than with sepsis alone. Patients with septic shock can be clinically identified by a vasopressor requirement to maintain a mean arterial pressure of 65 mm Hg or greater and serum lactate level greater than 2 mmol/L (>18 mg/dL) in the absence of hypovolemia. This combination is associated with hospital mortality rates greater than 40%. In out-of-hospital, emergency department, or general hospital ward settings, adult patients with suspected infection can be rapidly identified as being more likely to have poor outcomes typical of sepsis if they have at least 2 of the following clinical criteria that together constitute a new bedside clinical score termed quickSOFA (qSOFA): respiratory rate of 22/min or greater, altered mentation, or systolic blood pressure of 100 mm Hg or less. Conclusions and Relevance These updated definitions and clinical criteria should replace previous definitions, offer greater consistency for epidemiologic studies and clinical trials, and facilitate earlier recognition and more timely management of patients with sepsis or at risk of developing sepsis.

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Topics: Sepsis Six (75%), Surviving Sepsis Campaign (73%), Septic shock (63%) ... read more

9,896 Citations


Journal ArticleDOI: 10.1001/JAMA.2012.5669
20 Jun 2012-JAMA
Abstract: The acute respiratory distress syndrome (ARDS) was defined in 1994 by the American-European Consensus Conference (AECC); since then, issues regarding the reliability and validity of this definition have emerged. Using a consensus process, a panel of experts convened in 2011 (an initiative of the European Society of Intensive Care Medicine endorsed by the American Thoracic Society and the Society of Critical Care Medicine) developed the Berlin Definition, focusing on feasibility, reliability, validity, and objective evaluation of its performance. A draft definition proposed 3 mutually exclusive categories of ARDS based on degree of hypoxemia: mild (200 mm Hg < PaO2/FIO2 ≤ 300 mm Hg), moderate (100 mm Hg < PaO2/FIO2 ≤ 200 mm Hg), and severe (PaO2/FIO2 ≤ 100 mm Hg) and 4 ancillary variables for severe ARDS: radiographic severity, respiratory system compliance (≤40 mL/cm H2O), positive end-expiratory pressure (≥10 cm H2O), and corrected expired volume per minute (≥10 L/min). The draft Berlin Definition was empirically evaluated using patient-level meta-analysis of 4188 patients with ARDS from 4 multicenter clinical data sets and 269 patients with ARDS from 3 single-center data sets containing physiologic information. The 4 ancillary variables did not contribute to the predictive validity of severe ARDS for mortality and were removed from the definition. Using the Berlin Definition, stages of mild, moderate, and severe ARDS were associated with increased mortality (27%; 95% CI, 24%-30%; 32%; 95% CI, 29%-34%; and 45%; 95% CI, 42%-48%, respectively; P < .001) and increased median duration of mechanical ventilation in survivors (5 days; interquartile [IQR], 2-11; 7 days; IQR, 4-14; and 9 days; IQR, 5-17, respectively; P < .001). Compared with the AECC definition, the final Berlin Definition had better predictive validity for mortality, with an area under the receiver operating curve of 0.577 (95% CI, 0.561-0.593) vs 0.536 (95% CI, 0.520-0.553; P < .001). This updated and revised Berlin Definition for ARDS addresses a number of the limitations of the AECC definition. The approach of combining consensus discussions with empirical evaluation may serve as a model to create more accurate, evidence-based, critical illness syndrome definitions and to better inform clinical care, research, and health services planning.

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6,097 Citations


Journal ArticleDOI: 10.1002/JOR.1100090504
Arnold I. Caplan1Institutions (1)
Abstract: Bone and cartilage formation in the embryo and repair and turnover in the adult involve the progeny of a small number of cells called mesenchymal stem cells. These cells divide, and their progeny become committed to a specific and distinctive phenotypic pathway, a lineage with discrete steps and, finally, end-stage cells involved with fabrication of a unique tissue type, e.g., cartilage or bone. Local cuing (extrinsic factors) and the genomic potential (intrinsic factors) interact at each lineage step to control the rate and characteristic phenotype of the cells in the emerging tissue. The study of these mesenchymal stem cells, whether isolated from embryos or adults, provides the basis for the emergence of a new therapeutic technology of self-cell repair. The isolation, mitotic expansion, and site-directed delivery of autologous stem cells can govern the rapid and specific repair of skeletal tissues.

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4,574 Citations


Open accessJournal ArticleDOI: 10.1056/NEJMOA2021436
Abstract: BackgroundCoronavirus disease 2019 (Covid-19) is associated with diffuse lung damage. Glucocorticoids may modulate inflammation-mediated lung injury and thereby reduce progression to respiratory failure and death.MethodsIn this controlled, open-label trial comparing a range of possible treatments in patients who were hospitalized with Covid-19, we randomly assigned patients to receive oral or intravenous dexamethasone (at a dose of 6 mg once daily) for up to 10 days or to receive usual care alone. The primary outcome was 28-day mortality. Here, we report the final results of this assessment.ResultsA total of 2104 patients were assigned to receive dexamethasone and 4321 to receive usual care. Overall, 482 patients (22.9%) in the dexamethasone group and 1110 patients (25.7%) in the usual care group died within 28 days after randomization (age-adjusted rate ratio, 0.83; 95% confidence interval [CI], 0.75 to 0.93; P<0.001). The proportional and absolute between-group differences in mortality varied considerably according to the level of respiratory support that the patients were receiving at the time of randomization. In the dexamethasone group, the incidence of death was lower than that in the usual care group among patients receiving invasive mechanical ventilation (29.3% vs. 41.4%; rate ratio, 0.64; 95% CI, 0.51 to 0.81) and among those receiving oxygen without invasive mechanical ventilation (23.3% vs. 26.2%; rate ratio, 0.82; 95% CI, 0.72 to 0.94) but not among those who were receiving no respiratory support at randomization (17.8% vs. 14.0%; rate ratio, 1.19; 95% CI, 0.92 to 1.55).ConclusionsIn patients hospitalized with Covid-19, the use of dexamethasone resulted in lower 28-day mortality among those who were receiving either invasive mechanical ventilation or oxygen alone at randomization but not among those receiving no respiratory support. (Funded by the Medical Research Council and National Institute for Health Research and others; RECOVERY ClinicalTrials.gov number, NCT04381936. opens in new tab; ISRCTN number, 50189673. opens in new tab.)

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Topics: Lung injury (55%), Mechanical ventilation (52%), Randomized controlled trial (52%) ... read more

4,501 Citations