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Evaluation and manipulation of tissue and cellular distribution of cardiac progenitor cell-derived extracellular vesicles

Cardiac progenitor cell-derived extracellular vesicles (CPC-EVs) have been successfully applied via different delivery routes for treating post-myocardial infarction injury in several preclinical models. Hence, understanding the in vivo fate of CPC-EVs after systemic or local, i.e. myocardial, deliv...

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Autores principales: Roefs, Marieke T., Heusermann, Wolf, Brans, Maike A. D., Snijders Blok, Christian, Lei, Zhiyong, Vader, Pieter, Sluijter, Joost P. G.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9729535/
https://www.ncbi.nlm.nih.gov/pubmed/36506565
http://dx.doi.org/10.3389/fphar.2022.1052091
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author Roefs, Marieke T.
Heusermann, Wolf
Brans, Maike A. D.
Snijders Blok, Christian
Lei, Zhiyong
Vader, Pieter
Sluijter, Joost P. G.
author_facet Roefs, Marieke T.
Heusermann, Wolf
Brans, Maike A. D.
Snijders Blok, Christian
Lei, Zhiyong
Vader, Pieter
Sluijter, Joost P. G.
author_sort Roefs, Marieke T.
collection PubMed
description Cardiac progenitor cell-derived extracellular vesicles (CPC-EVs) have been successfully applied via different delivery routes for treating post-myocardial infarction injury in several preclinical models. Hence, understanding the in vivo fate of CPC-EVs after systemic or local, i.e. myocardial, delivery is of utmost importance for the further therapeutic application of CPC-EVs in cardiac repair. Here, we studied the tissue- and cell distribution and retention of CPC-EVs after intramyocardial and intravenous injection in mice by employing different EV labeling and imaging techniques. In contrast to progenitor cells, CPC-EVs demonstrated no immediate flush-out from the heart upon intramyocardial injection and displayed limited distribution to other organs over time, as determined by near-infrared imaging in living animals. By employing CUBIC tissue clearing and light-sheet fluorescent microscopy, we observed CPC-EV migration in the interstitial space of the myocardium shortly after EV injection. Moreover, we demonstrated co-localization with cTnI and CD31-positive cells, suggesting their interaction with various cell types present in the heart. On the contrary, after intravenous injection, most EVs accumulated in the liver. To potentiate such a potential systemic cardiac delivery route, targeting the cardiac endothelium could provide openings for directed CPC-EV therapy. We therefore evaluated whether decorating EVs with targeting peptides (TPs) RGD-4C or CRPPR connected to Lamp2b could enhance EV delivery to endothelial cells. Expression of both TPs enhanced CPC-EV uptake under in vitro continuous flow, but did not affect uptake under static cell culture conditions. Together, these data demonstrate that the route of administration influences CPC-EV biodistribution pattern and suggest that specific TPs could be used to target CPC-EVs to the cardiac endothelium. These insights might lead to a better application of CPC-EV therapeutics in the heart.
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spelling pubmed-97295352022-12-09 Evaluation and manipulation of tissue and cellular distribution of cardiac progenitor cell-derived extracellular vesicles Roefs, Marieke T. Heusermann, Wolf Brans, Maike A. D. Snijders Blok, Christian Lei, Zhiyong Vader, Pieter Sluijter, Joost P. G. Front Pharmacol Pharmacology Cardiac progenitor cell-derived extracellular vesicles (CPC-EVs) have been successfully applied via different delivery routes for treating post-myocardial infarction injury in several preclinical models. Hence, understanding the in vivo fate of CPC-EVs after systemic or local, i.e. myocardial, delivery is of utmost importance for the further therapeutic application of CPC-EVs in cardiac repair. Here, we studied the tissue- and cell distribution and retention of CPC-EVs after intramyocardial and intravenous injection in mice by employing different EV labeling and imaging techniques. In contrast to progenitor cells, CPC-EVs demonstrated no immediate flush-out from the heart upon intramyocardial injection and displayed limited distribution to other organs over time, as determined by near-infrared imaging in living animals. By employing CUBIC tissue clearing and light-sheet fluorescent microscopy, we observed CPC-EV migration in the interstitial space of the myocardium shortly after EV injection. Moreover, we demonstrated co-localization with cTnI and CD31-positive cells, suggesting their interaction with various cell types present in the heart. On the contrary, after intravenous injection, most EVs accumulated in the liver. To potentiate such a potential systemic cardiac delivery route, targeting the cardiac endothelium could provide openings for directed CPC-EV therapy. We therefore evaluated whether decorating EVs with targeting peptides (TPs) RGD-4C or CRPPR connected to Lamp2b could enhance EV delivery to endothelial cells. Expression of both TPs enhanced CPC-EV uptake under in vitro continuous flow, but did not affect uptake under static cell culture conditions. Together, these data demonstrate that the route of administration influences CPC-EV biodistribution pattern and suggest that specific TPs could be used to target CPC-EVs to the cardiac endothelium. These insights might lead to a better application of CPC-EV therapeutics in the heart. Frontiers Media S.A. 2022-11-24 /pmc/articles/PMC9729535/ /pubmed/36506565 http://dx.doi.org/10.3389/fphar.2022.1052091 Text en Copyright © 2022 Roefs, Heusermann, Brans, Snijders Blok, Lei, Vader and Sluijter. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Roefs, Marieke T.
Heusermann, Wolf
Brans, Maike A. D.
Snijders Blok, Christian
Lei, Zhiyong
Vader, Pieter
Sluijter, Joost P. G.
Evaluation and manipulation of tissue and cellular distribution of cardiac progenitor cell-derived extracellular vesicles
title Evaluation and manipulation of tissue and cellular distribution of cardiac progenitor cell-derived extracellular vesicles
title_full Evaluation and manipulation of tissue and cellular distribution of cardiac progenitor cell-derived extracellular vesicles
title_fullStr Evaluation and manipulation of tissue and cellular distribution of cardiac progenitor cell-derived extracellular vesicles
title_full_unstemmed Evaluation and manipulation of tissue and cellular distribution of cardiac progenitor cell-derived extracellular vesicles
title_short Evaluation and manipulation of tissue and cellular distribution of cardiac progenitor cell-derived extracellular vesicles
title_sort evaluation and manipulation of tissue and cellular distribution of cardiac progenitor cell-derived extracellular vesicles
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9729535/
https://www.ncbi.nlm.nih.gov/pubmed/36506565
http://dx.doi.org/10.3389/fphar.2022.1052091
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