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

Frontiers in Bioengineering and Biotechnology

卷:9

Nick J. Willett¹  Lauren A. Hymel²  Molly E. Ogle²  Claire E. Olingy²  Hong Seo Lim²  Thomas C. Turner²  Cheryl L. San Emeterio²  William Y. York²  Gordon L. Warren⁴  Edward A. Botchwey⁵  Peng Qiu⁵  Emily G. Pendleton⁶  Young C. Jang⁷  Todd A. Sulchek⁷  Luke J. Mortensen⁸  Alan Y. Liu⁹ 

[1] Atlanta Veterans Affairs Medical Center, Decatur, GA, United States;

[2] Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA, United States;

[3] Department of Orthopedics, Emory University, Atlanta, GA, United States;

[4] Department of Physical Therapy, Georgia State University, Atlanta, GA, United States;

[5] Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA, United States;

[6] Regenerative Bioscience Center, Rhodes Center for ADS, University of Georgia, Athens, GA, United States;

[7] School of Biological Sciences, Georgia Institute of Technology, Atlanta, GA, United States;

[8] School of Chemical, Materials, and Biomedical Engineering, University of Georgia, Athens, GA, United States;

[9] School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA, United States;

关键词: immunomodulation;    inflammation;    tissue engineering;    regeneration;    sphingolipid;   

DOI  :  10.3389/fbioe.2021.650289

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown