Mesenchymal stem cell–derived extracellular vesicles improve the molecular phenotype of isolated rat lungs during ischemia/reperfusion injury

Caterina Lonati, Giulia Alessandra Bassani, Daniela Brambilla, Patrizia Leonardi, Andrea Carlin, Marco Maggioni, Alberto Zanella, Daniele Dondossola, Valentina Fonsato, Cristina Grange, Giovanni Camussi, Stefano Gatti

Research output: Contribution to journalArticle

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 languageEnglish
Pages (from-to)1306-1316
JournalJournal of Heart and Lung Transplantation
Volume38
Issue number12
DOIs
Publication statusPublished - 2019

Fingerprint

Reperfusion Injury
Phenotype
Lung
Hyaluronic Acid
Reperfusion
Ischemia
Extracellular Vesicles
Nitric Oxide
Leukocytes
Perfusion
Adenosine Triphosphate
Gene Expression
Lung Transplantation
Cell- and Tissue-Based Therapy
Mesenchymal Stromal Cells
Chemokines
Vascular Resistance
Histology
Oxidative Stress
Cell Count

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 journalArticle

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. / Mesenchymal stem cell–derived extracellular vesicles improve the molecular phenotype of isolated rat lungs during ischemia/reperfusion injury. In: Journal of Heart and Lung Transplantation. 2019 ; Vol. 38, No. 12. pp. 1306-1316.
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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.",
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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.

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