# Local modulation of S1P receptor signaling with nanofibrous hyaluronic acid scaffolds as a regenerative immunotherapy following critical volumetric muscle loss injury

> **NIH NIH F31** · GEORGIA INSTITUTE OF TECHNOLOGY · 2023 · $27,323

## Abstract

PROJECT SUMMARY
Extremity trauma is an increasingly significant clinical challenge among both civilian and military populations, particularly
in cases that result in volumetric muscle loss (VML). Current standards of treatment for VML fail to successfully restore
muscle function after injury and result in fibrosis rather than newly formed muscle fibers. Many approaches aimed to treat
VML fail to pay attention to the local endogenous immune response of the host which underlies the aberrant chronic
inflammation and fibrotic signaling characteristic of VML pathology. VML injury rapidly leads to degeneration and necrosis
of damaged myofibers and the invasion and activation of a broad range of immune cells, including monocytes and
macrophages. This creates an environment rich in both pro- and anti-inflammatory cues that most often leads to pathological
fibrosis. Designing anti-inflammatory strategies to reduce overall macrophage burden and promote their removal from sites
of injury is critical to restore function. The study's hypothesis is that sphingosine-1-phophate (S1P), a bioactive signaling
sphingolipid that is produced in tissue upon inflammation, plays a crucial role in the pro-longed immune cell retention
following VML, as S1P is a potent chemoattractant towards injury. S1P signals through 5 known G protein-coupled
receptors (S1PR1-5) and therefore S1P-dependent immune cell responses are dependent on their S1PR profile. S1P has
been implicated in propagating tissue fibrosis via the S1P/S1PR3 signaling axis and our previous studies reveal a crucial
role for S1PR3 in promoting immune cell niche occupancy or egress. In Aim 1, the role of S1P on aberrant immune cell
retention and macrophage-mediated fibrosis will be evaluated in a murine quadriceps VML model via lipidomic analysis of
injured muscle and single-cell time-of-flight mass cytometry (CyTOF) from injured muscle tissue and its draining lymph
node. Sphingosine kinase 1 knockout (SPHK1-/-) mice will be utilized to directly assess the role of S1P in impairing efficient
immune cell egress and mediating pro-fibrotic macrophage signaling on fibroadipogenic progenitors (FAPs) which drives
pathological fibrosis. In Aim 2, the effect of S1PR3 antagonism on promoting immune cell egress and abrogating
macrophage-induced fibrosis to enhance overall muscle recovery after VML injury will be assessed. This will be
accomplished by creating bone marrow chimeras between C57/BL6 mice and S1PR3-/- mice to determine the contribution
of S1PR3 signaling on immune cell recruitment vs egress in a microenvironment of chronic inflammatory stimuli.
Moreover, local, pharmacological antagonism of S1PR3 by delivery of VPC01091 (S1PR3 antagonist) from novel,
nanofibrous hyaluronic acid scaffolds to the injury milieu of critically sized VML defects will be evaluated. Lipidomic and
single-cell CyTOF analysis will be performed to analyze how S1PR3 antagonism affects local lipid metabolism and
inflammation following injury....

## Key facts

- **NIH application ID:** 10591401
- **Project number:** 5F31AR080563-02
- **Recipient organization:** GEORGIA INSTITUTE OF TECHNOLOGY
- **Principal Investigator:** Lauren Alexandra Hymel
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $27,323
- **Award type:** 5
- **Project period:** 2022-09-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10591401

## Citation

> US National Institutes of Health, RePORTER application 10591401, Local modulation of S1P receptor signaling with nanofibrous hyaluronic acid scaffolds as a regenerative immunotherapy following critical volumetric muscle loss injury (5F31AR080563-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10591401. Licensed CC0.

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