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Article

Adipose Mesenchymal Extracellular Vesicles as Alpha-1-Antitrypsin Physiological Delivery Systems for Lung Regeneration

by
Elia Bari
1,
Ilaria Ferrarotti
2,
Dario Di Silvestre
3,
Pietro Grisoli
1,
Valentina Barzon
2,
Alice Balderacchi
2,
Maria Luisa Torre
1,4,*,
Rossana Rossi
3,
Pierluigi Mauri
3,
Angelo Guido Corsico
2,4 and
Sara Perteghella
1,4
1
Department of Drug Sciences, University of Pavia, Viale Taramelli 12, 27100 Pavia, Italy
2
Center for Diagnosis of Inherited Alpha1-antitrypsin Deficiency, Department of Internal Medicine and Therapeutics, Pneumology Unit, IRCCS San Matteo Hospital Foundation, University of Pavia, 27100 Pavia, Italy
3
Institute for Biomedical Technologies, F.lli Cervi 93, 20090 Segrate, Milan, Italy
4
PharmaExceed S.r.l., Piazza Castello, 19, 27100 Pavia, Italy
*
Author to whom correspondence should be addressed.
Cells 2019, 8(9), 965; https://doi.org/10.3390/cells8090965
Submission received: 8 July 2019 / Revised: 14 August 2019 / Accepted: 23 August 2019 / Published: 23 August 2019
(This article belongs to the Section Intracellular and Plasma Membranes)
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Abstract

Accumulating evidence shows that Mesenchymal Stem/Stromal Cells (MSCs) exert their therapeutic effects by the release of secretome, made of both soluble proteins and nano/microstructured extracellular vesicles (EVs). In this work, for the first time, we proved by a proteomic investigation that adipose-derived (AD)-MSC-secretome contains alpha-1-antitrypsin (AAT), the main elastase inhibitor in the lung, 72 other proteins involved in protease/antiprotease balance, and 46 proteins involved in the response to bacteria. By secretome fractionation, we proved that AAT is present both in the soluble fraction of secretome and aggregated and/or adsorbed on the surface of EVs, that can act as natural carriers promoting AAT in vivo stability and activity. To modulate secretome composition, AD-MSCs were cultured in different stimulating conditions, such as serum starvation or chemicals (IL-1β and/or dexamethasone) and the expression of the gene encoding for AAT was increased. By testing in vitro the anti-elastase activity of MSC-secretome, a dose-dependent effect was observed; chemical stimulation of AD-MSCs did not increase their secretome anti-elastase activity. Finally, MSC-secretome showed anti-bacterial activity on Gram-negative bacteria, especially for Klebsiella pneumoniae. These preliminary results, in addition to the already demonstrated immunomodulation, pave the way for the use of MSC-secretome in the treatment of AAT-deficiency lung diseases.
Keywords: mesenchymal secretome; mesenchymal extracellular vesicles; mesenchymal exosomes; mesenchymal microvesicles; alpha-1-antitrypsin; lung diseases; anti-elastase mesenchymal secretome; mesenchymal extracellular vesicles; mesenchymal exosomes; mesenchymal microvesicles; alpha-1-antitrypsin; lung diseases; anti-elastase

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MDPI and ACS Style

Bari, E.; Ferrarotti, I.; Di Silvestre, D.; Grisoli, P.; Barzon, V.; Balderacchi, A.; Torre, M.L.; Rossi, R.; Mauri, P.; Corsico, A.G.; et al. Adipose Mesenchymal Extracellular Vesicles as Alpha-1-Antitrypsin Physiological Delivery Systems for Lung Regeneration. Cells 2019, 8, 965. https://doi.org/10.3390/cells8090965

AMA Style

Bari E, Ferrarotti I, Di Silvestre D, Grisoli P, Barzon V, Balderacchi A, Torre ML, Rossi R, Mauri P, Corsico AG, et al. Adipose Mesenchymal Extracellular Vesicles as Alpha-1-Antitrypsin Physiological Delivery Systems for Lung Regeneration. Cells. 2019; 8(9):965. https://doi.org/10.3390/cells8090965

Chicago/Turabian Style

Bari, Elia, Ilaria Ferrarotti, Dario Di Silvestre, Pietro Grisoli, Valentina Barzon, Alice Balderacchi, Maria Luisa Torre, Rossana Rossi, Pierluigi Mauri, Angelo Guido Corsico, and et al. 2019. "Adipose Mesenchymal Extracellular Vesicles as Alpha-1-Antitrypsin Physiological Delivery Systems for Lung Regeneration" Cells 8, no. 9: 965. https://doi.org/10.3390/cells8090965

APA Style

Bari, E., Ferrarotti, I., Di Silvestre, D., Grisoli, P., Barzon, V., Balderacchi, A., Torre, M. L., Rossi, R., Mauri, P., Corsico, A. G., & Perteghella, S. (2019). Adipose Mesenchymal Extracellular Vesicles as Alpha-1-Antitrypsin Physiological Delivery Systems for Lung Regeneration. Cells, 8(9), 965. https://doi.org/10.3390/cells8090965

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