RUNX1 mediates the therapeutic effects of mesenchymal stem cells-derived microparticles in acute respiratory distress syndrome.
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ABSTRACT:
SUBMITTER: Predescu D
PROVIDER: S-EPMC10641787 | biostudies-literature | 2023 Nov
REPOSITORIES: biostudies-literature
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RUNX1 mediates the therapeutic effects of mesenchymal stem cells-derived microparticles in acute respiratory distress syndrome.
Predescu Dan D Qin Shanshan S Stefanis Vasilios V Carman Brandon B Ganesh Balaji B Sharma Kanika K Mokhlesi Babak B Predescu Sanda S
Clinical and translational medicine 20231101 11
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Project description: Not available
| S-EPMC7706158 | biostudies-literature
Project description:Acute respiratory distress syndrome (ARDS) is a serious and potentially fatal acute inflammatory lung condition which currently has no specific treatments targeting its pathophysiology. However, mesenchymal stem cells have been shown to have very promising therapeutic potential, and recently, it has been established that their effect is largely due to the transfer of extracellular vesicles (EVs). EVs have been shown to transfer a variety of substances such as mRNA, miRNA, and even organelles such as mitochondria in order to ameliorate ARDS in preclinical models. In addition, the fact that they have been proven to have the same effect as their parent cells combined with their numerous advantages over whole cell administration means that they are a promising candidate for clinical application that merits further research.
| S-EPMC6954712 | biostudies-literature
Project description:The acute respiratory distress syndrome (ARDS) is a multifaceted lung disorder in which no specific therapeutic intervention is able to effectively improve clinical outcomes. Despite an improved understanding of molecular mechanisms and advances in supportive care strategies, ARDS remains associated with high mortality, and survivors usually face long-term morbidity. In recent years, preclinical studies have provided mounting evidence of the potential of mesenchymal stem cell (MSC)-based therapies in lung diseases and critical illnesses. In several models of ARDS, MSCs have been demonstrated to induce anti-inflammatory and anti-apoptotic effects, improve epithelial and endothelial cell recovery, and enhance microbial and alveolar fluid clearance, thus resulting in improved lung and distal organ function and survival. Early-stage clinical trials have also demonstrated the safety of MSC administration in patients with ARDS, but further, large-scale investigations are required to assess the safety and efficacy profile of these therapies. In this review, we summarize the main mechanisms whereby MSCs have been shown to exert therapeutic effects in experimental ARDS. We also highlight questions that need to be further elucidated and barriers that must be overcome in order to efficiently translate MSC research into clinical practice.
| S-EPMC7222160 | biostudies-literature
Project description:In different preclinical studies, different sources of MSCs derived from adipose tissue, bone marrow, placenta, umbilical cord have shown effectiveness in treating ARDS. However, their clinical translation has not been effective as demonstrated by variable outcomes from clinical trials. One reason for this could be the MSC source chosen for clinical translation as there is lack of study comparing the different sources of MSCs. In previous work, we performed a “head-to-head” comparison between different sources of MSCs and showed that each source had a unique genomic and proteomic “signature”. Hence, in this current study, we investigated the choice of MSC source best suited for therapy in an LPS-induced mouse model of ARDS. We compare the 3 most commonly used MSC sources: bone marrow derived-MSCs (BM-MSCs), adipose tissue derived-MSCs (AD-MSCs) and umbilical cord derived-MSCs (UC-MSCs) therapy in LPS-induced ARDS model where we did bulk RNA sequencing of the lungs to validate the efficacy of therapy in terms of different changes in gene label and different pathways involved.
2023-08-23 | GSE241186 | GEO
Project description:BackgroundMesenchymal stem/stromal cells (MSCs) have attracted interest as a potential therapy given their anti-inflammatory and immunomodulatory properties. However, clinical trials using MSCs for acute respiratory distress syndrome (ARDS) have produced mixed and inconclusive data. In previous work, we performed a "head-to-head" comparison between different sources of MSCs and showed that each source had a unique genomic and proteomic "signature".MethodThis study investigated which sources of MSC: bone marrow derived-MSCs (BM-MSCs), adipose tissue derived-MSCs (AD-MSCs) and umbilical cord derived-MSCs (UC-MSCs) would be the optimal candidate to be used as a therapy in an LPS-induced mouse model of ARDS. Immune cells assessment, tissue transcriptomics, animal survival, and endothelial-epithelial barrier assessment were used to evaluate their effects.ResultsWhen comparing the three most commonly used MSC sources, we found that UC-MSCs exhibited greater efficacy compared to other MSCs in improving animal survival, mitigating epithelial/endothelial damage, decreasing lung inflammation via reducing neutrophil infiltration, T cell proliferation, and M1 polarization. Bulk RNA sequencing of lung tissue also showed that UC-MSCs have the capability to downregulate extracellular trap formation, by the downregulation of key genes like Elane and Padi4. Notably, treatment with UC-MSCs demonstrated a significant reduction in Fc-γ R mediated phagocytosis, which has been associated with monocyte pyroptosis and intense inflammation in the context of COVID-19.ConclusionOur findings suggest that UC-MSCs are an optimal source of MSC to treat acute inflammatory conditions in the lungs, such as ARDS.
| S-EPMC11520775 | biostudies-literature
Project description:Based on preclinical data, cell-based therapy with bone marrow-derived mesenchymal stem (stromal) cells (MSCs) is a potentially attractive new therapeutic option for treating patients with the acute respiratory distress syndrome. Small and large animal models of acute lung injury from endotoxin, live bacteria, and sepsis have shown that MSCs can decrease lung injury and increase survival. The mechanisms for benefit are mediated in part by paracrine release of several antiinflammatory cytokines, keratinocyte growth factor, angiopoietin-1, as well as the release of antimicrobial peptides. There is also evidence that MSCs can transfer mitochondria and restore normal bioenergetics to injured alveolar epithelium. Some of the beneficial effects are mediated by microvesicles. A phase 1 safety and dose-escalation trial was completed and a randomized, double-blind clinical trial is currently underway.
| S-EPMC4430975 | biostudies-literature
Project description:Acute respiratory distress syndrome (ARDS) is a severe respiratory disease associated with high morbidity and mortality in the clinic. In the face of limited treatment options for ARDS, extracellular vesicles derived from mesenchymal stem cells (MSC-EVs) have recently shown promise. They regulate levels of growth factors, cytokines, and other internal therapeutic molecules. The possible therapeutic mechanisms of MSC-EVs include anti-inflammatory, cell injury repair, alveolar fluid clearance, and microbe clearance. The potent therapeutic ability and biocompatibility of MSC-EVs have enabled them as an alternative option to ameliorate ARDS. In this review, recent advances, therapeutic mechanisms, advantages and limitations, as well as improvements of using MSC-EVs to treat ARDS are summarized. This review is expected to provide a brief view of the potential applications of MSC-EVs as novel biodrugs to treat ARDS.
| S-EPMC9463673 | biostudies-literature
Project description:The mortality rate of critically ill patients with acute respiratory distress syndrome (ARDS) is 30.9% to 46.1%. The emergence of the coronavirus disease 2019 (Covid-19) has become a global issue with raising dire concerns. Patients with severe Covid-19 may progress toward ARDS. Mesenchymal stem cells (MSCs) can be derived from bone marrow, umbilical cord, adipose tissue and so on. The easy accessibility and low immunogenicity enable MSCs for allogeneic administration, and thus they were widely used in animal and clinical studies. Accumulating evidence suggests that mesenchymal stem cell infusion can ameliorate ARDS. However, the underlying mechanisms of MSCs need to be discussed. Recent studies showed MSCs can modulate immune/inflammatory cells, attenuate endoplasmic reticulum stress, and inhibit pulmonary fibrosis. The paracrine cytokines and exosomes may account for these beneficial effects. In this review, we summarize the therapeutic mechanisms of MSCs in ARDS, analyzed the most recent animal experiments and Covid-19 clinical trial results, discussed the adverse effects and prospects in the recent studies, and highlight the potential roles of MSC therapy for Covid-19 patients with ARDS.
| S-EPMC8107778 | biostudies-literature
Project description:Acute respiratory distress syndrome (ARDS) is a devastating hypoxemic respiratory failure, characterized by disruption of the alveolar-capillary membrane barrier. Current management for ARDS remains supportive, including lung-protective ventilation and a conservative fluid strategy. Mesenchymal stem cells (MSCs) have emerged as a potentially attractive candidate for the management of ARDS through facilitating lung tissue regeneration and repair by releasing paracrine soluble factors. Over the last decade, a variety of strategies have emerged to optimize MSC-based therapy. Among these, the strategy using genetically modified MSCs has received increased attention recently due to its distinct advantage, in conferring incremental migratory capacity and, enhancing the anti-inflammatory, immunomodulatory, angiogenic, and antifibrotic effects of these cells in numerous preclinical ARDS models, which may in turn provide additional benefits in the management of ARDS. Here, we provide an overview of recent studies testing the efficacy of genetically modified MSCs using preclinical models of ARDS.
| S-EPMC6915956 | biostudies-literature
Project description:Background Injury of alveolar epithelial cells and capillary endothelial cells is crucial in the pathogenesis of acute lung injury/acute respiratory distress syndrome (ALI/ARDS). Mesenchymal stem cells (MSCs) are a promising cell source for ALI/ARDS treatment. Overexpression of Fork head box protein M1 (FoxM1) facilitates MSC differentiation into alveolar type II (AT II) cells in vitro. Moreover, FoxM1 has been shown to repair the endothelial barrier. Therefore, this study explored whether overexpression of FoxM1 promotes the therapeutic effect of bone marrow-derived MSCs (BMSCs) on ARDS by differentiation of BMSCs into AT II cells or a paracrine mechanism. Methods A septic ALI model was established in mice by intraperitoneal administration of lipopolysaccharide. The protective effect of BMSCs-FoxM1 on ALI was explored by detecting pathological variations in the lung, total protein concentration in bronchoalveolar lavage fluid (BALF), wet/dry (W/D) lung weight ratio, oxidative stress levels, cytokine levels, and retention of BMSCs in the lung. In addition, we assessed whether FoxM1 overexpression promoted the therapeutic effect of BMSCs on ALI/ARDS by differentiating into AT II cells using SPC−/− mice. Furthermore, the protective effect of BMSCs-FoxM1 on lipopolysaccharide-induced endothelial cell (EC) injury was explored by detecting EC proliferation, apoptosis, scratch wounds, tube formation, permeability, and oxidative stress, and analyzing whether the Wnt/β-catenin pathway contributes to the regulatory mechanism in vitro using a pathway inhibitor. Results Compared with BMSCs-Vector, treatment with BMSCs-FoxM1 significantly decreased the W/D lung weight ratio, total BALF protein level, lung injury score, oxidative stress, and cytokine levels. With the detected track of BMSCs-FoxM1, we observed a low residency rate and short duration of residency in the lung. Notably, SPC was not expressed in SPC−/− mice injected with BMSCs-FoxM1. Furthermore, BMSCs-FoxM1 enhanced EC proliferation, migration, and tube formation; inhibited EC apoptosis and inflammation; and maintained vascular integrity through activation of the Wnt/β-catenin pathway, which was partially reversed by XAV-939. Conclusion Overexpression of FoxM1 enhanced the therapeutic effect of BMSCs on ARDS, possibly through a paracrine mechanism rather than by promoting BMSC differentiation into AT II cells in vivo, and prevented LPS-induced EC barrier disruption partially through activating the Wnt/β-catenin signaling pathway in vitro. Supplementary Information The online version contains supplementary material available at 10.1186/s13287-023-03240-8.
| S-EPMC9926819 | biostudies-literature