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Nanofiber-Based Delivery of Bioactive Lipids Promotes Pro-regenerative Inflammation and Enhances Muscle Fiber Growth After Volumetric Muscle Loss
Volumetric muscle loss (VML) injuries after extremity trauma results in an important clinical challenge often associated with impaired healing, significant fibrosis, and long-term pain and functional deficits. While acute muscle injuries typically display a remarkable capacity for regeneration, crit...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8017294/ https://www.ncbi.nlm.nih.gov/pubmed/33816455 http://dx.doi.org/10.3389/fbioe.2021.650289 |
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author | San Emeterio, Cheryl L. Hymel, Lauren A. Turner, Thomas C. Ogle, Molly E. Pendleton, Emily G. York, William Y. Olingy, Claire E. Liu, Alan Y. Lim, Hong Seo Sulchek, Todd A. Warren, Gordon L. Mortensen, Luke J. Qiu, Peng Jang, Young C. Willett, Nick J. Botchwey, Edward A. |
author_facet | San Emeterio, Cheryl L. Hymel, Lauren A. Turner, Thomas C. Ogle, Molly E. Pendleton, Emily G. York, William Y. Olingy, Claire E. Liu, Alan Y. Lim, Hong Seo Sulchek, Todd A. Warren, Gordon L. Mortensen, Luke J. Qiu, Peng Jang, Young C. Willett, Nick J. Botchwey, Edward A. |
author_sort | San Emeterio, Cheryl L. |
collection | PubMed |
description | Volumetric muscle loss (VML) injuries after extremity trauma results in an important clinical challenge often associated with impaired healing, significant fibrosis, and long-term pain and functional deficits. While acute muscle injuries typically display a remarkable capacity for regeneration, critically sized VML defects present a dysregulated immune microenvironment which overwhelms innate repair mechanisms leading to chronic inflammation and pro-fibrotic signaling. In this series of studies, we developed an immunomodulatory biomaterial therapy to locally modulate the sphingosine-1-phosphate (S1P) signaling axis and resolve the persistent pro-inflammatory injury niche plaguing a critically sized VML defect. Multiparameter pseudo-temporal 2D projections of single cell cytometry data revealed subtle distinctions in the altered dynamics of specific immune subpopulations infiltrating the defect that were critical to muscle regeneration. We show that S1P receptor modulation via nanofiber delivery of Fingolimod (FTY720) was characterized by increased numbers of pro-regenerative immune subsets and coincided with an enriched pool of muscle stem cells (MuSCs) within the injured tissue. This FTY720-induced priming of the local injury milieu resulted in increased myofiber diameter and alignment across the defect space followed by enhanced revascularization and reinnervation of the injured muscle. These findings indicate that localized modulation of S1P receptor signaling via nanofiber scaffolds, which resemble the native extracellular matrix ablated upon injury, provides great potential as an immunotherapy for bolstering endogenous mechanisms of regeneration following VML injury. |
format | Online Article Text |
id | pubmed-8017294 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-80172942021-04-03 Nanofiber-Based Delivery of Bioactive Lipids Promotes Pro-regenerative Inflammation and Enhances Muscle Fiber Growth After Volumetric Muscle Loss San Emeterio, Cheryl L. Hymel, Lauren A. Turner, Thomas C. Ogle, Molly E. Pendleton, Emily G. York, William Y. Olingy, Claire E. Liu, Alan Y. Lim, Hong Seo Sulchek, Todd A. Warren, Gordon L. Mortensen, Luke J. Qiu, Peng Jang, Young C. Willett, Nick J. Botchwey, Edward A. Front Bioeng Biotechnol Bioengineering and Biotechnology Volumetric muscle loss (VML) injuries after extremity trauma results in an important clinical challenge often associated with impaired healing, significant fibrosis, and long-term pain and functional deficits. While acute muscle injuries typically display a remarkable capacity for regeneration, critically sized VML defects present a dysregulated immune microenvironment which overwhelms innate repair mechanisms leading to chronic inflammation and pro-fibrotic signaling. In this series of studies, we developed an immunomodulatory biomaterial therapy to locally modulate the sphingosine-1-phosphate (S1P) signaling axis and resolve the persistent pro-inflammatory injury niche plaguing a critically sized VML defect. Multiparameter pseudo-temporal 2D projections of single cell cytometry data revealed subtle distinctions in the altered dynamics of specific immune subpopulations infiltrating the defect that were critical to muscle regeneration. We show that S1P receptor modulation via nanofiber delivery of Fingolimod (FTY720) was characterized by increased numbers of pro-regenerative immune subsets and coincided with an enriched pool of muscle stem cells (MuSCs) within the injured tissue. This FTY720-induced priming of the local injury milieu resulted in increased myofiber diameter and alignment across the defect space followed by enhanced revascularization and reinnervation of the injured muscle. These findings indicate that localized modulation of S1P receptor signaling via nanofiber scaffolds, which resemble the native extracellular matrix ablated upon injury, provides great potential as an immunotherapy for bolstering endogenous mechanisms of regeneration following VML injury. Frontiers Media S.A. 2021-03-19 /pmc/articles/PMC8017294/ /pubmed/33816455 http://dx.doi.org/10.3389/fbioe.2021.650289 Text en Copyright © 2021 San Emeterio, Hymel, Turner, Ogle, Pendleton, York, Olingy, Liu, Lim, Sulchek, Warren, Mortensen, Qiu, Jang, Willett and Botchwey. http://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 | Bioengineering and Biotechnology San Emeterio, Cheryl L. Hymel, Lauren A. Turner, Thomas C. Ogle, Molly E. Pendleton, Emily G. York, William Y. Olingy, Claire E. Liu, Alan Y. Lim, Hong Seo Sulchek, Todd A. Warren, Gordon L. Mortensen, Luke J. Qiu, Peng Jang, Young C. Willett, Nick J. Botchwey, Edward A. Nanofiber-Based Delivery of Bioactive Lipids Promotes Pro-regenerative Inflammation and Enhances Muscle Fiber Growth After Volumetric Muscle Loss |
title | Nanofiber-Based Delivery of Bioactive Lipids Promotes Pro-regenerative Inflammation and Enhances Muscle Fiber Growth After Volumetric Muscle Loss |
title_full | Nanofiber-Based Delivery of Bioactive Lipids Promotes Pro-regenerative Inflammation and Enhances Muscle Fiber Growth After Volumetric Muscle Loss |
title_fullStr | Nanofiber-Based Delivery of Bioactive Lipids Promotes Pro-regenerative Inflammation and Enhances Muscle Fiber Growth After Volumetric Muscle Loss |
title_full_unstemmed | Nanofiber-Based Delivery of Bioactive Lipids Promotes Pro-regenerative Inflammation and Enhances Muscle Fiber Growth After Volumetric Muscle Loss |
title_short | Nanofiber-Based Delivery of Bioactive Lipids Promotes Pro-regenerative Inflammation and Enhances Muscle Fiber Growth After Volumetric Muscle Loss |
title_sort | nanofiber-based delivery of bioactive lipids promotes pro-regenerative inflammation and enhances muscle fiber growth after volumetric muscle loss |
topic | Bioengineering and Biotechnology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8017294/ https://www.ncbi.nlm.nih.gov/pubmed/33816455 http://dx.doi.org/10.3389/fbioe.2021.650289 |
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