Mesenchymal Stem Cell Microvesicles Restore Protein Permeability Across Primary Cultures of Injured Human Lung Microvascular Endothelial Cells

Abstract

Our previous study demonstrated that mesenchymal stem cell (MSC) microvesicles (MV) reduced lung inflammation, protein permeability, and pulmonary edema in endotoxin‐induced acute lung injury in mice. However, the underlying mechanisms for restoring lung protein permeability were not fully understood. In this current study, we hypothesized that MSC MV would restore protein permeability across injured human lung microvascular endothelial cells (HLMVEC) in part through the transfer of angiopoietin‐1 (Ang1) mRNA to the injured endothelium. A transwell coculture system was used to study the effect of MSC MV on protein permeability across HLMVECs injured by cytomix, a mixture of IL‐1β, TNF‐α, and IFN‐γ (50 ng/ml). Our result showed that cytomix significantly increased permeability to FITC‐dextran (70 kDa) across HLMVECs over 24 hours. Administration of MSC MVs restored this permeability in a dose dependent manner, which was associated with an increase in Ang1 mRNA and protein secretion in the injured endothelium. This beneficial effect was diminished when MSC MV was pretreated with an anti‐CD44 antibody, suggesting that internalization of MV into the HLMVEC was required for the therapeutic effect. Fluorescent microscopy showed that MSC MV largely prevented the reorganization of cytoskeleton protein F‐actin into “actin stress fiber” and restored the location of the tight junction protein ZO‐1 and adherens junction protein VE‐cadherin in injured HLMVECs. Ang1 siRNA pretreatment of MSC MV prior to administration to injured HLMVECs eliminated the therapeutic effect of MV. In summary, MSC MVs restored protein permeability across HLMVEC in part by increasing Ang1 secretion by injured HLMVEC. Stem Cells Translational Medicine 2018;7:615–624

Current status of cell-based therapies for respiratory virus infections: applicability to COVID-19

“…[5] While lodged in the lungs, the MSCs are able to release a wide variety of soluble mediators including anti-inflammatory cytokines, [6] antimicrobial peptides, [7] angiogenic growth factors, and extracellular vesicles (EVs) (Figure 1). [8] Direct cell-cell transmission of mitochondria from MSCs to respiratory epithelial and immune cells [9] has also been described. [10] A growing literature demonstrates that the pattern of anti-inflammatory mediators released is specific for the inflammatory lung environment encountered and is mediated through differential activation of damage and pathogen-associated molecular pathogen receptors expressed on MSC cell surfaces.…”

“…Human-to-human transmission occurs through respiratory droplets or contaminated surfaces. [1] The average incubation period is 5 days, but ranges from [1][2][3][4][5][6][7][8][9][10][11][12][13][14] days. Most patients present with mild respiratory tract infection, mostly commonly characterized by fever (82%) and cough (81%).…”

The role of microvesicles and its active molecules in regulating cellular biology

“…This indicates that the active protein carried by MVs is consistent with the components expressed by parental cells. In addition, MVs have also been considered to the main carrier of functional mRNA horizontal metastasis between cells, including large number of parental cell mRNAs . The main reason is that MVs engulfs some cytoplasm during production, which contains the protein and mRNA from parental cells.…”

Effects of Mesenchymal Stem Cell Coculture on Human Lung Small Airway Epithelial Cells

“…The enhanced secretion of angiopoietin-1 and keratinocyte growth factor of MSCs from the bone marrow was also shown to lower inflammation and apoptosis in alveolar epithelial cells that had been stimulated with lipopolysaccharides [36]. EVs from bone marrow MSCs also increased angiopoietin-1 secretion of lung microvascular endothelial cells and thereby restored their protein permeability [37].…”