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Modulating local S1P receptor signaling as a regenerative immunotherapy after volumetric muscle loss injury
Author(s) -
Hymel Lauren A.,
Ogle Molly E.,
Anderson Shan E.,
San Emeterio Cheryl L.,
Turner Thomas C.,
York William Y.,
Liu Alan Y.,
Olingy Claire E.,
Sridhar Sraeyes,
Lim Hong Seo,
Sulchek Todd,
Qiu Peng,
Jang Young C.,
Willett Nick J.,
Botchwey Edward A.
Publication year - 2021
Publication title -
journal of biomedical materials research part a
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.849
H-Index - 150
eISSN - 1552-4965
pISSN - 1549-3296
DOI - 10.1002/jbm.a.37053
Subject(s) - inflammation , microbiology and biotechnology , immune system , receptor , regeneration (biology) , immunotherapy , cancer research , skeletal muscle , biology , immunology , anatomy , biochemistry
Regeneration of skeletal muscle after volumetric injury is thought to be impaired by a dysregulated immune microenvironment that hinders endogenous repair mechanisms. Such defects result in fatty infiltration, tissue scarring, chronic inflammation, and debilitating functional deficits. Here, we evaluated the key cellular processes driving dysregulation in the injury niche through localized modulation of sphingosine‐1‐phosphate (S1P) receptor signaling. We employ dimensionality reduction and pseudotime analysis on single cell cytometry data to reveal heterogeneous immune cell subsets infiltrating preclinical muscle defects due to S1P receptor inhibition. We show that global knockout of S1P receptor 3 (S1PR3) is marked by an increase of muscle stem cells within injured tissue, a reduction in classically activated relative to alternatively activated macrophages, and increased bridging of regenerating myofibers across the defect. We found that local S1PR3 antagonism via nanofiber delivery of VPC01091 replicated key features of pseudotime immune cell recruitment dynamics and enhanced regeneration characteristic of global S1PR3 knockout. Our results indicate that local S1P receptor modulation may provide an effective immunotherapy for promoting a proreparative environment leading to improved regeneration following muscle injury.