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Nanofiber-Based Delivery of Bioactive Lipids Promotes Pro-regenerative Inflammation and Enhances Muscle Fiber Growth After Volumetric Muscle Loss

Authors :
Cheryl L. San Emeterio
Lauren A. Hymel
Thomas C. Turner
Molly E. Ogle
Emily G. Pendleton
William Y. York
Claire E. Olingy
Alan Y. Liu
Hong Seo Lim
Todd A. Sulchek
Gordon L. Warren
Luke J. Mortensen
Peng Qiu
Young C. Jang
Nick J. Willett
Edward A. Botchwey
Source :
Frontiers in Bioengineering and Biotechnology, Vol 9 (2021)
Publication Year :
2021
Publisher :
Frontiers Media S.A., 2021.

Abstract

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.

Details

Language :
English
ISSN :
22964185
Volume :
9
Database :
Directory of Open Access Journals
Journal :
Frontiers in Bioengineering and Biotechnology
Publication Type :
Academic Journal
Accession number :
edsdoj.4154dda49c484927a8c096ea80518274
Document Type :
article
Full Text :
https://doi.org/10.3389/fbioe.2021.650289