# Mechanisms of functional skeletal muscle repair: critical role of matrix associated IL-33

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $517,163

## Abstract

ABSTRACT
Skeletal muscle is inherently regenerative following acute injury. It is well established that the spatiotemporal
dynamics of the responding immune cell populations are critical determinants of the regenerative process.
Specifically, an appropriately timed switch from a type-I to a type-II immune response is required for skeletal
muscle regeneration following injury, and this self-regenerative capacity is lost after a critical size volumetric
muscle loss (VML) event such as trauma or tumor excision. We recently showed that an acellular biologic scaffold
composed entirely of extracellular matrix (ECM) can facilitate a macrophage phenotype transition that leads to
downstream site-appropriate functional tissue deposition and myogenesis as a treatment for volumetric muscle
loss in preclinical animal models and in 13 human patients. Our current objective is to gain translatable
mechanistic insights into the immunobiology behind both normal skeletal muscle regeneration following acute
injury and in the presence of an ECM bioscaffold with the broad aim of developing therapeutics that enable and
direct immune cells to facilitate constructive, functional remodeling after VML. The proposed studies will
investigate the ability and necessity of a newly identified component of the ECM, the interleukin-33 (IL-33), to
influence remodeling after skeletal muscle injury. Typically found in the nucleus of stromal cells, IL-33 has been
shown to be a potent mediator of skeletal muscle, cardiac muscle, lung epithelium, and dermal repair via poorly
defined mechanisms involving immune cells expressing the IL-33 receptor, ST2. The subject matter of the
present proposal is based upon our discovery that IL-33 is stably integrated into the ECM via encapsulation
within matrix bound nanovesicles (MBV) thereby protecting IL-33 from rapid oxidation. Following ECM
degradation, MBV are released from the matrix, taken up by immune cells wherein IL-33 activates macrophages
towards a pro-remodeling phenotype via a non-canonical ST2-indendent pathway. The discovery of IL-33 as an
integral component of ECM-MBV represents a distinct therapeutic target and marker of tissue
remodeling. Furthermore, our experimental design will allow for the first in-depth molecular characterization of
the genes and signaling pathways regulated by the ST2-independent IL-33 pathway and will greatly advance
our understanding of the molecular mechanisms by which ECM facilitates the functional remodeling response.
Separately, the use of ECM therapies (either as a hydrogel as is presently being tested in a Phase I clinical trial
by Ventrix for cardiac repair) or as a bioscaffold sheet (recently used as a treatment for VML in a 13 patient
cohort study) can now be studied from a new perspective, and will help guide the design of next generation
products, diagnostics and therapeutic applications.

## Key facts

- **NIH application ID:** 9852966
- **Project number:** 5R01AR073527-03
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Stephen F. Badylak
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $517,163
- **Award type:** 5
- **Project period:** 2018-04-01 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9852966

## Citation

> US National Institutes of Health, RePORTER application 9852966, Mechanisms of functional skeletal muscle repair: critical role of matrix associated IL-33 (5R01AR073527-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9852966. Licensed CC0.

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