Strategies to Enhance Mesenchymal Stem Cell-Based Therapies for Acute Respiratory Distress Syndrome.
TL;DR: A large body of experimental evidence for a variety of strategies directed towards strengthening the therapeutic potential of MSCs in ARDS is summarized to provide a comprehensive and updated view.
Abstract: Acute respiratory distress syndrome (ARDS) is a multifaced disease characterized by the acute onset of hypoxemia, worsened pulmonary compliance, and noncardiogenic pulmonary edema. Despite over five decades of research, specific treatments for established ARDS are still lacking. MSC-based therapies have the advantage of targeting nearly all pathophysiological components of ARDS by means of a variety of secreted trophic factors, exerting anti-inflammatory, antioxidative, immunomodulatory, antiapoptotic, and proangiogenic effects, resulting in significant structural and functional recovery following ARDS in various preclinical models. However, the therapeutic efficacy of transplanted MSCs is limited by their poor engraftment and low survival rate in the injured tissues, major barriers to clinical translation. Accordingly, several strategies have been explored to improve MSC retention in the lung and enhance the innate properties of MSCs in preclinical models of ARDS. To provide a comprehensive and updated view, we summarize a large body of experimental evidence for a variety of strategies directed towards strengthening the therapeutic potential of MSCs in ARDS.
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TL;DR: It is imperative to better comprehend the rationale and underlying data that both support and refute effectiveness of MSCs in respiratory virus infections, and to define the targeted patient population and potential cell therapy approaches for COVID-19.
Abstract: The severe respiratory consequences of the coronavirus disease 2019 (COVID-19) pandemic have prompted urgent need for novel therapies. Cell-based approaches, primarily using mesenchymal stem (stromal) cells (MSCs), have demonstrated safety and possible efficacy in patients with acute respiratory distress syndrome (ARDS), although they are not yet well studied in respiratory virus-induced ARDS. Limited pre-clinical data suggest that systemic MSC administration can significantly reduce respiratory virus (influenza strains H5N1 and H9N2)-induced lung injury; however, there are no available data in models of coronavirus respiratory infection.There is a rapidly increasing number of clinical investigations of cell-based therapy approaches for COVID-19. These utilise a range of different cell sources, doses, dosing strategies and targeted patient populations. To provide a rational strategy to maximise potential therapeutic use, it is critically important to understand the relevant pre-clinical studies and postulated mechanisms of MSC actions in respiratory virus-induced lung injuries. This review presents these, along with consideration of current clinical investigations.
196 citations
Cites background from "Strategies to Enhance Mesenchymal S..."
...Conversely, ACE2 was reported to protect against non-viral lung injury by degrading the profibrotic peptide angiotensin (Ang) II[31]....
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TL;DR: A comprehensive review of the mechanisms and optimization of MSC therapy in ARDS is provided and the potentials and possible barriers of M SC therapy for COVID-19 patients with ARDS are highlighted.
Abstract: The 2019 novel coronavirus disease (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has occurred in China and around the world. SARS-CoV-2-infected patients with severe pneumonia rapidly develop acute respiratory distress syndrome (ARDS) and die of multiple organ failure. Despite advances in supportive care approaches, ARDS is still associated with high mortality and morbidity. Mesenchymal stem cell (MSC)-based therapy may be an potential alternative strategy for treating ARDS by targeting the various pathophysiological events of ARDS. By releasing a variety of paracrine factors and extracellular vesicles, MSC can exert anti-inflammatory, anti-apoptotic, anti-microbial, and pro-angiogenic effects, promote bacterial and alveolar fluid clearance, disrupt the pulmonary endothelial and epithelial cell damage, eventually avoiding the lung and distal organ injuries to rescue patients with ARDS. An increasing number of experimental animal studies and early clinical studies verify the safety and efficacy of MSC therapy in ARDS. Since low cell engraftment and survival in lung limit MSC therapeutic potentials, several strategies have been developed to enhance their engraftment in the lung and their intrinsic, therapeutic properties. Here, we provide a comprehensive review of the mechanisms and optimization of MSC therapy in ARDS and highlighted the potentials and possible barriers of MSC therapy for COVID-19 patients with ARDS.
95 citations
Cites background or methods from "Strategies to Enhance Mesenchymal S..."
...…on the therapeutic effects of mesenchymal stem cells (MSCs), although some studies have also investigated the possible applications of pluripotent stem cells, pulmonary epithelial progenitors, and endothelial progenitor cells (Laffey and Matthay, 2017; Han et al., 2019; Lopes-Pacheco et al., 2019)....
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...MSCs overexpressing EP2 increase their migration to the sites of lung injury in the mouse model of LPS-ALI (Han et al., 2019)....
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...The strategies using genetic modification to overexpress beneficial genes on MSCs have enhanced the migration, survival, and therapeutic potential of MSCs transfer in the models of ARDS (Han et al., 2019)....
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TL;DR: In this paper, mesenchymal stem cells (MSCs) were administered to critically ill COVID-19 patients to evaluate the healing effect, and to systematically investigate how the treatment works.
62 citations
TL;DR: In this review, the rationale and possible outcomes of compassionate use of MSCs, particularly in patients with SARS‐CoV‐2 infections, toward proving or disproving the efficacy of this approach in the near future are documented.
Abstract: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-caused coronavirus disease 2019 (COVID-19) pandemic has become a global health crisis with an extremely rapid progress resulting in thousands of patients who may develop acute respiratory distress syndrome (ARDS) requiring intensive care unit (ICU) treatment. So far, no specific antiviral therapeutic agent has been demonstrated to be effective for COVID-19; therefore, the clinical management is largely supportive and depends on the patients' immune response leading to a cytokine storm followed by lung edema, dysfunction of air exchange, and ARDS, which could lead to multiorgan failure and death. Given that human mesenchymal stem cells (MSCs) from various tissue sources have revealed successful clinical outcomes in many immunocompromised disorders by inhibiting the overactivation of the immune system and promoting endogenous repair by improving the microenvironment, there is a growing demand for MSC infusions in patients with COVID-19-related ARDS in the ICU. In this review, we have documented the rationale and possible outcomes of compassionate use of MSCs, particularly in patients with SARS-CoV-2 infections, toward proving or disproving the efficacy of this approach in the near future. Many centers have registered and approved, and some already started, single-case or phase I/II trials primarily aiming to rescue their critical patients when no other therapeutic approach responds. On the other hand, it is also very important to mention that there is a good deal of concern about clinics offering unproven stem cell treatments for COVID-19. The reviewers and oversight bodies will be looking for a balanced but critical appraisal of current trials.
43 citations
Cites background from "Strategies to Enhance Mesenchymal S..."
...In addition, low mobilization of MSCs to the sites of injury and poor survival of transplanted MSCs in the harsh microenvironment are obstacles faced by clinical translation.(111) MSCs IN COVID-19-RELATED ARDS 9...
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TL;DR: In this article, the authors reviewed the latest applications of nanomedicine in pre-clinical acute respiratory distress syndrome (ARDS) therapy, highlights the strategies for targeted treatment of lung inflammation, presents the innovative drug delivery systems, and provides inspiration for strengthening the therapeutic effect of nanomedical-based treatment.
41 citations
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TL;DR: The Mesenchymal and Tissue Stem Cell Committee of the International Society for Cellular Therapy proposes minimal criteria to define human MSC, believing this minimal set of standard criteria will foster a more uniform characterization of MSC and facilitate the exchange of data among investigators.
14,724 citations
TL;DR: In patients with acute lung injury and the acute respiratory distress syndrome, mechanical ventilation with a lower tidal volume than is traditionally used results in decreased mortality and increases the number of days without ventilator use.
Abstract: Background Traditional approaches to mechanical ventilation use tidal volumes of 10 to 15 ml per kilogram of body weight and may cause stretch-induced lung injury in patients with acute lung injury and the acute respiratory distress syndrome. We therefore conducted a trial to determine whether ventilation with lower tidal volumes would improve the clinical outcomes in these patients. Methods Patients with acute lung injury and the acute respiratory distress syndrome were enrolled in a multicenter, randomized trial. The trial compared traditional ventilation treatment, which involved an initial tidal volume of 12 ml per kilogram of predicted body weight and an airway pressure measured after a 0.5-second pause at the end of inspiration (plateau pressure) of 50 cm of water or less, with ventilation with a lower tidal volume, which involved an initial tidal volume of 6 ml per kilogram of predicted body weight and a plateau pressure of 30 cm of water or less. The primary outcomes were death before a patient was discharged home and was breathing without assistance and the number of days without ventilator use from day 1 to day 28. Results The trial was stopped after the enrollment of 861 patients because mortality was lower in the group treated with lower tidal volumes than in the group treated with traditional tidal volumes (31.0 percent vs. 39.8 percent, P=0.007), and the number of days without ventilator use during the first 28 days after randomization was greater in this group (mean [+/-SD], 12+/-11 vs. 10+/-11; P=0.007). The mean tidal volumes on days 1 to 3 were 6.2+/-0.8 and 11.8+/-0.8 ml per kilogram of predicted body weight (P Conclusions In patients with acute lung injury and the acute respiratory distress syndrome, mechanical ventilation with a lower tidal volume than is traditionally used results in decreased mortality and increases the number of days without ventilator use.
11,028 citations
"Strategies to Enhance Mesenchymal S..." refers background in this paper
...It is well established that mechanical ventilation with a lower tidal volume shortened the duration of mechanical ventilation and significantly decreased 28-day mortality [4]....
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TL;DR: The data support the hypothesis that a human lipoaspirate contains multipotent cells and may represent an alternative stem cell source to bone marrow-derived MSCs.
Abstract: Future cell-based therapies such as tissue engineering will benefit from a source of autologous pluripotent stem cells. For mesodermal tissue engineering, one such source of cells is the bone marrow stroma. The bone marrow compartment contains several cell populations, including mesenchymal stem cells (MSCs) that are capable of differentiating into adipogenic, osteogenic, chondrogenic, and myogenic cells. However, autologous bone marrow procurement has potential limitations. An alternate source of autologous adult stem cells that is obtainable in large quantities, under local anesthesia, with minimal discomfort would be advantageous. In this study, we determined if a population of stem cells could be isolated from human adipose tissue. Human adipose tissue, obtained by suction-assisted lipectomy (i.e., liposuction), was processed to obtain a fibroblast-like population of cells or a processed lipoaspirate (PLA). These PLA cells can be maintained in vitro for extended periods with stable population doubling and low levels of senescence. Immunofluorescence and flow cytometry show that the majority of PLA cells are of mesodermal or mesenchymal origin with low levels of contaminating pericytes, endothelial cells, and smooth muscle cells. Finally, PLA cells differentiate in vitro into adipogenic, chondrogenic, myogenic, and osteogenic cells in the presence of lineage-specific induction factors. In conclusion, the data support the hypothesis that a human lipoaspirate contains multipotent cells and may represent an alternative stem cell source to bone marrow-derived MSCs.
7,402 citations
"Strategies to Enhance Mesenchymal S..." refers background in this paper
...Apart from the bone marrow, MSCs can be harvested from a variety of sources, including adipose tissues and umbilical cord blood [17, 18]....
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TL;DR: It is estimated that each year in the United States there are 190,600 cases of acute lung injury, which are associated with 74,500 deaths and 3.6 million hospital days, considerably higher than previous reports have suggested.
Abstract: BACKGROUND Acute lung injury is a critical illness syndrome consisting of acute hypoxemic respiratory failure with bilateral pulmonary infiltrates that are not attributed to left atrial hypertension. Despite recent advances in our understanding of the mechanism and treatment of acute lung injury, its incidence and outcomes in the United States have been unclear. METHODS We conducted a prospective, population-based, cohort study in 21 hospitals in and around King County, Washington, from April 1999 through July 2000, using a validated screening protocol to identify patients who met the consensus criteria for acute lung injury. RESULTS A total of 1113 King County residents undergoing mechanical ventilation met the criteria for acute lung injury and were 15 years of age or older. On the basis of this figure, the crude incidence of acute lung injury was 78.9 per 100,000 person-years and the age-adjusted incidence was 86.2 per 100,000 person-years. The in-hospital mortality rate was 38.5 percent. The incidence of acute lung injury increased with age from 16 per 100,000 person-years for those 15 through 19 years of age to 306 per 100,000 person-years for those 75 through 84 years of age. Mortality increased with age from 24 percent for patients 15 through 19 years of age to 60 percent for patients 85 years of age or older (P<0.001). We estimate that each year in the United States there are 190,600 cases of acute lung injury, which are associated with 74,500 deaths and 3.6 million hospital days. CONCLUSIONS Acute lung injury has a substantial impact on public health, with an incidence in the United States that is considerably higher than previous reports have suggested.
3,358 citations
"Strategies to Enhance Mesenchymal S..." refers background in this paper
...Although comprehensive research has enabled clinicians to gain deep insight into the complex pathogenesis of ARDS, its incidence is still increasing [1]....
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University of Milan1, St. Michael's GAA, Sligo2, University of Toronto3, University of Paris4, Paris Diderot University5, University Health Network6, St. Michael's Hospital7, Australian National University8, Uppsala University9, Queen's University Belfast10, Sapienza University of Rome11, Sunnybrook Health Sciences Centre12, Harvard University13, Leipzig University14
TL;DR: Clinician recognition of ARDS was associated with higher PEEP, greater use of neuromuscular blockade, and prone positioning, which indicates the potential for improvement in the management of patients with ARDS.
Abstract: IMPORTANCE Limited information exists about the epidemiology, recognition, management, and outcomes of patients with the acute respiratory distress syndrome (ARDS). OBJECTIVES To evaluate intensive ...
3,259 citations