Mesenchymal stromal cell extracellular vesicles rescue mitochondrial dysfunction and improve barrier integrity in clinically relevant models of ARDS

Abstract

Alveolar epithelial-capillary barrier disruption is a hallmark of Acute Respiratory Distress Syndrome (ARDS). Contribution of mitochondrial dysfunction to the compromised alveolar-capillary barrier in ARDS remains unclear. Mesenchymal stromal cells-derived extracellular vesicles (MSC EVs) are considered as a cell free therapy for ARDS. Mitochondrial transfer was shown to be important for the therapeutic effects of MSCs and MSC EVs. Here we investigated the contribution of mitochondrial dysfunction to the injury of alveolar epithelial and endothelial barriers in ARDS and the ability of MSC EVs to modulate alveolar-capillary barrier integrity through mitochondrial transfer.Primary human small airway epithelial and pulmonary microvascular endothelial cells and human precision cut lung slices (PCLSs) were stimulated with endotoxin or plasma samples from patients with ARDS and treated with MSC EVs, barrier properties and mitochondrial functions were evaluated. LPS-injured mice were treated with MSC EVs and degree of lung injury and mitochondrial respiration of the lung tissue were assessed.Inflammatory stimulation resulted in increased permeability coupled with pronounced mitochondrial dysfunction in both types of primary cells and PCLSs. EVs derived from normal MSCs restored barrier integrity and normal levels of oxidative phosphorylation while EV preparation which did not contain mitochondria was not effective. In vivo, presence of mitochondria was critical for EV ability to reduce lung injury and restore mitochondrial respiration in the lung tissue.In the ARDS environment MSC-EVs improve alveolar-capillary barrier properties through restoration of mitochondrial functions at least partially via mitochondrial transfer.

[Retracted] Mesenchymal Stem Cell‐Derived Exosomes and Their Potential Agents in Hematological Diseases

“…Oxidative stress, as was reflected by levels of reactive oxygen species (ROS), mitochondrial dysfunction, and aberrant calcium signaling [ 82 ], has been recognized as a contributing factor in tumorigenesis and involved in the progression of multiple diseases including myeloid leukemia, abnormal hematopoiesis, colon inflammation, and liver fibrosis [ 34 , 79 , 83 ] ( Figure 2(b) ). Nowadays, MSC-exosomes, as a cell-free strategy, have attracted considerable attention due to their robust antioxidative capacities [ 34 , 35 , 82 , 84 ]. They were reported to reduced ROS generation, DNA damage, aberrant calcium signaling, and mitochondrial changes via regulation of the NRF2 system in oxidative stress-induced skin injury [ 35 ].…”

A crosstalk between type 2 innate lymphoid cells and alternative macrophages in lung development and lung diseases (Review)

“…The arrest of alveolar development or disruption of alveolar structure is not only associated with neonatal respiratory distress syndrome, bronchopulmonary dysplasia and persistent pulmonary hypertension, but also chronic lung diseases, such as asthma, allergic diseases and chronic obstructive pulmonary emphysema (2)(3)(4). Pulmonary epithelial barrier dysfunction is an important pathological component of lung injury, which is mainly caused by damage of epithelial cell migration (96). ILC2s participate in the regulation of AEC2 and different lung diseases (37).…”

Mesenchymal stromal cells reduce evidence of lung injury in patients with ARDS

“…Mesenchymal stromal cells (MSCs) have been investigated as a novel therapeutic for ARDS because of their potential to act on many of the key pathways implicated in the pathogenesis of lung injury ( 11 ). MSCs promote a proresolving macrophage phenotype ( 12 ), enhance alveolar fluid clearance ( 13 , 14 ), restore epithelial and endothelial barrier integrity ( 15 ), and reduce lung injury severity in preclinical models ( 16 ). The trial of treatment with allogeneic MSCs for moderate-to-severe ARDS (START trial, ClinicalTrials.gov NCT02097641) demonstrated the safety of MSCs in ARDS ( 17 ), but their efficacy in a clinical population has not definitively been proven.…”