Therapeutic Potential of Mesenchymal Stromal Cells for Acute Respiratory Distress Syndrome

Abstract

Based on preclinical data, cell-based therapy with bone marrowderived 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.Keywords: pulmonary edema; acute lung injury; mesenchymal stem cells; acute respiratory failure Correspondence and requests for reprints should be addressed to Michael A. Matthay, M.D.,

Mesenchymal Stem Cells Modified with Heme Oxygenase-1 Have Enhanced Paracrine Function and Attenuate Lipopolysaccharide-Induced Inflammatory and Oxidative Damage in Pulmonary Microvascular Endothelial Cells

“…MSCs have the ability to release multiple soluble factors, such as growth factors, antiinflammatory cytokines, and antimicrobial peptides, which can improve endothelial and epithelial permeability, modulate innate and adaptive immunity, and protect against oxidative damage-induced apoptosis [50]. In our present study, we also found that the stem cells had a protective effect on endothelial cells, in line with previous reports [12,17,18,20,51]. Because the indirect co-culture system was adopted during our experiment, we think that the immunomodulatory effect of MSCs on inflammation and oxidative stress can be ascribed to a paracrine mechanism.…”

“…As we found that the cell growth curve of MSCs was similar to that of MSCs-HO-1 it suggests that the additional protective effect of MSCs-HO-1 was not associated with cell viability. Accumulating evidence using different preclinical animal models, including endotoxin-induced, live bacteria-induced, sepsis-associated, and pancreatitis-associated lung injury, has shown that cell-based therapy with MSCs is a potentially attractive option for treating ALI/ARDS [18]. The mechanisms of MSC protection against ALI/ARDS include multilineage differentiation potential (e.g., cell replacement and tissue regeneration), paracrine (e.g., secretion of antimicrobial and repair factors), and cell-cell contactdependent (e.g., transfer of nucleic acids and organelles) mechanisms [17].…”

Extracellular vesicles in lung microenvironment and pathogenesis

“…MSCs have potential in tissue regeneration because of their anti-inflammatory and immunosuppressive properties [93]. To date, there have been many extensive studies and clinical trials examining the use of MSC-based therapy as a regenerative tool in many clinical disorders, including lung tissue repair and regeneration after acute respiratory distress syndrome (ARDS) [94]. The repair mechanisms are partly mediated by the paracrine secretion of cytokines and growth factors by MSCs, and in many cases these paracrine factors are packaged within EVs.…”

AMP-Activated Protein Kinase and Glycogen Synthase Kinase 3β Modulate the Severity of Sepsis-induced Lung injury

“…W-peptide (chemoattractant) was Of note, the extent of mitochondrial dysfunction in the lungs has been shown to correlate with mortality in sepsis (19,20). Approaches to prevent mitochondrial dysfunction or to restore mitochondrial bioenergetics may diminish the severity of sepsis-associated lung injury (21)(22)(23).…”