Bio-distribution and longevity of mesenchymal stromal cell derived membrane particles

H. Tejeda-Mora; A. Merino; L. Wu; W. W. Woud; J. A.A. Demmers; W. F.J. van IJcken; M. E.J. Reinders; M. J. Hoogduijn

doi:10.1016/j.jconrel.2022.08.060

Bio-distribution and longevity of mesenchymal stromal cell derived membrane particles

H. Tejeda-Mora, A. Merino, L. Wu, W. W. Woud, J. A.A. Demmers, W. F.J. van IJcken, M. E.J. Reinders, M. J. Hoogduijn^*

^*Corresponding author for this work

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Abstract

Vesicle-based medicines hold great promise for therapy development but essential knowledge on the bio-distribution and longevity of vesicles after administration is lacking. We generated vesicles from the membranes of human mesenchymal stromal cells (MSC) and we demonstrated earlier that these so-called membrane particles (MP) mediate immunomodulatory and regenerative responses in target cells. In the present study we examined the bio-distribution and longevity of MP after intravenous administration in mice. While most vesicle tracking methods are based on imaging techniques, which require labeling of vesicles and can only detect dense accumulations of vesicles, we used proteomics analysis to detect the presence of MP-derived proteins in multiple organs and tissues. MP proteins were mainly present in plasma and leukocytes at 1 h after injection, indicating that MP - in contrast to whole MSC - do not accumulate in the lungs upon first passage but remain in circulation. After 24 h, MP proteins were still present in plasma but were most abundant in the liver. RNA sequencing of livers demonstrated that MP impact liver function and in particular induce metabolic pathways. These data provide a clear view of the bio-distribution and longevity of MP, which is likely extrapolatable to other types of vesicles, and demonstrate that MP circulate for up to 24 h and may be a tool for targeting the liver.

Original language	English
Pages (from-to)	642-651
Number of pages	10
Journal	Journal of Controlled Release
Volume	350
DOIs	https://doi.org/10.1016/j.jconrel.2022.08.060
Publication status	Published - Oct 2022

Bibliographical note

Funding Information:
This project is co-funded by the public-private partnerships Allowance made available by Health∼Holland, Top Sector Life Sciences & Health , to stimulate public-private partnerships (grant number LSHM18005 ). The funders had no role in study design, data collection and analysis, decision to publish, or manuscript preparation.

Publisher Copyright: © 2022 The Authors

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1-s2.0-S0168365922005831-mainFinal published version, 5.41 MBLicence: CC BY

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title = "Bio-distribution and longevity of mesenchymal stromal cell derived membrane particles",

abstract = "Vesicle-based medicines hold great promise for therapy development but essential knowledge on the bio-distribution and longevity of vesicles after administration is lacking. We generated vesicles from the membranes of human mesenchymal stromal cells (MSC) and we demonstrated earlier that these so-called membrane particles (MP) mediate immunomodulatory and regenerative responses in target cells. In the present study we examined the bio-distribution and longevity of MP after intravenous administration in mice. While most vesicle tracking methods are based on imaging techniques, which require labeling of vesicles and can only detect dense accumulations of vesicles, we used proteomics analysis to detect the presence of MP-derived proteins in multiple organs and tissues. MP proteins were mainly present in plasma and leukocytes at 1 h after injection, indicating that MP - in contrast to whole MSC - do not accumulate in the lungs upon first passage but remain in circulation. After 24 h, MP proteins were still present in plasma but were most abundant in the liver. RNA sequencing of livers demonstrated that MP impact liver function and in particular induce metabolic pathways. These data provide a clear view of the bio-distribution and longevity of MP, which is likely extrapolatable to other types of vesicles, and demonstrate that MP circulate for up to 24 h and may be a tool for targeting the liver.",

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note = "Funding Information: This project is co-funded by the public-private partnerships Allowance made available by Health∼Holland, Top Sector Life Sciences & Health , to stimulate public-private partnerships (grant number LSHM18005 ). The funders had no role in study design, data collection and analysis, decision to publish, or manuscript preparation. Publisher Copyright: {\textcopyright} 2022 The Authors",

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doi = "10.1016/j.jconrel.2022.08.060",

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AU - Wu, L.

AU - Woud, W. W.

AU - Demmers, J. A.A.

AU - van IJcken, W. F.J.

AU - Reinders, M. E.J.

AU - Hoogduijn, M. J.

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PY - 2022/10

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N2 - Vesicle-based medicines hold great promise for therapy development but essential knowledge on the bio-distribution and longevity of vesicles after administration is lacking. We generated vesicles from the membranes of human mesenchymal stromal cells (MSC) and we demonstrated earlier that these so-called membrane particles (MP) mediate immunomodulatory and regenerative responses in target cells. In the present study we examined the bio-distribution and longevity of MP after intravenous administration in mice. While most vesicle tracking methods are based on imaging techniques, which require labeling of vesicles and can only detect dense accumulations of vesicles, we used proteomics analysis to detect the presence of MP-derived proteins in multiple organs and tissues. MP proteins were mainly present in plasma and leukocytes at 1 h after injection, indicating that MP - in contrast to whole MSC - do not accumulate in the lungs upon first passage but remain in circulation. After 24 h, MP proteins were still present in plasma but were most abundant in the liver. RNA sequencing of livers demonstrated that MP impact liver function and in particular induce metabolic pathways. These data provide a clear view of the bio-distribution and longevity of MP, which is likely extrapolatable to other types of vesicles, and demonstrate that MP circulate for up to 24 h and may be a tool for targeting the liver.

AB - Vesicle-based medicines hold great promise for therapy development but essential knowledge on the bio-distribution and longevity of vesicles after administration is lacking. We generated vesicles from the membranes of human mesenchymal stromal cells (MSC) and we demonstrated earlier that these so-called membrane particles (MP) mediate immunomodulatory and regenerative responses in target cells. In the present study we examined the bio-distribution and longevity of MP after intravenous administration in mice. While most vesicle tracking methods are based on imaging techniques, which require labeling of vesicles and can only detect dense accumulations of vesicles, we used proteomics analysis to detect the presence of MP-derived proteins in multiple organs and tissues. MP proteins were mainly present in plasma and leukocytes at 1 h after injection, indicating that MP - in contrast to whole MSC - do not accumulate in the lungs upon first passage but remain in circulation. After 24 h, MP proteins were still present in plasma but were most abundant in the liver. RNA sequencing of livers demonstrated that MP impact liver function and in particular induce metabolic pathways. These data provide a clear view of the bio-distribution and longevity of MP, which is likely extrapolatable to other types of vesicles, and demonstrate that MP circulate for up to 24 h and may be a tool for targeting the liver.

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Bio-distribution and longevity of mesenchymal stromal cell derived membrane particles

Abstract

Bibliographical note

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