Abstract
BACKGROUND: Lung ischemia/reperfusion (IR) injury contributes to the development of severe complications in patients undergoing transplantation. Mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs) exert beneficial actions comparable to those of MSCs without the risks of the cell-based strategy. This research investigated EV effects during IR injury in isolated rat lungs. METHODS: An established model of 180-minutes ex vivo lung perfusion (EVLP) was used. At 60 minutes EVs (n = 5) or saline (n = 5) were administered. Parallel experiments used labeled EVs to determine EV biodistribution (n = 4). Perfusate samples were collected to perform gas analysis and to assess the concentration of nitric oxide (NO), hyaluronan (HA), inflammatory mediators, and leukocytes. Lung biopsies were taken at 180 minutes to evaluate HA, adenosine triphosphate (ATP), gene expression, and histology. RESULTS: Compared with untreated lungs, EV-treated organs showed decreased vascular resistance and a rise of perfusate NO metabolites. EVs prevented the reduction in pulmonary ATP caused by IR. Increased medium-high-molecular-weight HA was detected in the perfusate and in the lung tissue of the IR + EV group. Significant differences in cell count on perfusate and tissue samples, together with induction of transcription and synthesis of chemokines, suggested EV-dependent modulation of leukocyte recruitment. EVs upregulated genes involved in the resolution of inflammation and oxidative stress. Biodistribution analysis showed that EVs were retained in the lung tissue and internalized within pulmonary cells. CONCLUSIONS: This study shows multiple novel EV influences on pulmonary energetics, tissue integrity, and gene expression during IR. The use of cell-free therapies during EVLP could constitute a valuable strategy for reconditioning and repair of injured lungs before transplantation.
| Original language | English |
|---|---|
| Pages (from-to) | 1306-1316 |
| Journal | Journal of Heart and Lung Transplantation |
| Volume | 38 |
| Issue number | 12 |
| DOIs | |
| Publication status | Published - 2019 |
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Keywords
- ex vivo lung perfusion
- hyaluronan
- ischemia/reperfusion injury
- lung transplantation
- mesenchymal stem cell–derived extracellular vesicles
ASJC Scopus subject areas
- Surgery
- Pulmonary and Respiratory Medicine
- Cardiology and Cardiovascular Medicine
- Transplantation
Cite this
Mesenchymal stem cell–derived extracellular vesicles improve the molecular phenotype of isolated rat lungs during ischemia/reperfusion injury. / Lonati, Caterina; Bassani, Giulia Alessandra; Brambilla, Daniela; Leonardi, Patrizia; Carlin, Andrea; Maggioni, Marco; Zanella, Alberto; Dondossola, Daniele; Fonsato, Valentina; Grange, Cristina; Camussi, Giovanni; Gatti, Stefano.
In: Journal of Heart and Lung Transplantation, Vol. 38, No. 12, 2019, p. 1306-1316.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Mesenchymal stem cell–derived extracellular vesicles improve the molecular phenotype of isolated rat lungs during ischemia/reperfusion injury
AU - Lonati, Caterina
AU - Bassani, Giulia Alessandra
AU - Brambilla, Daniela
AU - Leonardi, Patrizia
AU - Carlin, Andrea
AU - Maggioni, Marco
AU - Zanella, Alberto
AU - Dondossola, Daniele
AU - Fonsato, Valentina
AU - Grange, Cristina
AU - Camussi, Giovanni
AU - Gatti, Stefano
PY - 2019
Y1 - 2019
N2 - BACKGROUND: Lung ischemia/reperfusion (IR) injury contributes to the development of severe complications in patients undergoing transplantation. Mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs) exert beneficial actions comparable to those of MSCs without the risks of the cell-based strategy. This research investigated EV effects during IR injury in isolated rat lungs. METHODS: An established model of 180-minutes ex vivo lung perfusion (EVLP) was used. At 60 minutes EVs (n = 5) or saline (n = 5) were administered. Parallel experiments used labeled EVs to determine EV biodistribution (n = 4). Perfusate samples were collected to perform gas analysis and to assess the concentration of nitric oxide (NO), hyaluronan (HA), inflammatory mediators, and leukocytes. Lung biopsies were taken at 180 minutes to evaluate HA, adenosine triphosphate (ATP), gene expression, and histology. RESULTS: Compared with untreated lungs, EV-treated organs showed decreased vascular resistance and a rise of perfusate NO metabolites. EVs prevented the reduction in pulmonary ATP caused by IR. Increased medium-high-molecular-weight HA was detected in the perfusate and in the lung tissue of the IR + EV group. Significant differences in cell count on perfusate and tissue samples, together with induction of transcription and synthesis of chemokines, suggested EV-dependent modulation of leukocyte recruitment. EVs upregulated genes involved in the resolution of inflammation and oxidative stress. Biodistribution analysis showed that EVs were retained in the lung tissue and internalized within pulmonary cells. CONCLUSIONS: This study shows multiple novel EV influences on pulmonary energetics, tissue integrity, and gene expression during IR. The use of cell-free therapies during EVLP could constitute a valuable strategy for reconditioning and repair of injured lungs before transplantation.
AB - BACKGROUND: Lung ischemia/reperfusion (IR) injury contributes to the development of severe complications in patients undergoing transplantation. Mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs) exert beneficial actions comparable to those of MSCs without the risks of the cell-based strategy. This research investigated EV effects during IR injury in isolated rat lungs. METHODS: An established model of 180-minutes ex vivo lung perfusion (EVLP) was used. At 60 minutes EVs (n = 5) or saline (n = 5) were administered. Parallel experiments used labeled EVs to determine EV biodistribution (n = 4). Perfusate samples were collected to perform gas analysis and to assess the concentration of nitric oxide (NO), hyaluronan (HA), inflammatory mediators, and leukocytes. Lung biopsies were taken at 180 minutes to evaluate HA, adenosine triphosphate (ATP), gene expression, and histology. RESULTS: Compared with untreated lungs, EV-treated organs showed decreased vascular resistance and a rise of perfusate NO metabolites. EVs prevented the reduction in pulmonary ATP caused by IR. Increased medium-high-molecular-weight HA was detected in the perfusate and in the lung tissue of the IR + EV group. Significant differences in cell count on perfusate and tissue samples, together with induction of transcription and synthesis of chemokines, suggested EV-dependent modulation of leukocyte recruitment. EVs upregulated genes involved in the resolution of inflammation and oxidative stress. Biodistribution analysis showed that EVs were retained in the lung tissue and internalized within pulmonary cells. CONCLUSIONS: This study shows multiple novel EV influences on pulmonary energetics, tissue integrity, and gene expression during IR. The use of cell-free therapies during EVLP could constitute a valuable strategy for reconditioning and repair of injured lungs before transplantation.
KW - ex vivo lung perfusion
KW - hyaluronan
KW - ischemia/reperfusion injury
KW - lung transplantation
KW - mesenchymal stem cell–derived extracellular vesicles
UR - http://www.scopus.com/inward/record.url?scp=85072184921&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85072184921&partnerID=8YFLogxK
U2 - 10.1016/j.healun.2019.08.016
DO - 10.1016/j.healun.2019.08.016
M3 - Article
AN - SCOPUS:85072184921
VL - 38
SP - 1306
EP - 1316
JO - Journal of Heart and Lung Transplantation
JF - Journal of Heart and Lung Transplantation
SN - 1053-2498
IS - 12
ER -