Wound healing driven by unique population of muscle-specific Tregs
Researchers at Harvard have identified and isolated a unique population of FoxP3+ CD4+ Tregs from muscle which exhibit tissue-regenerative properties. These cells, as well as agents that enhance their proliferation/differentiation, and products derived from the cells may be used to promote tissue regeneration and wound healing. The cells/agents may be applied to muscle tissue or directly to a wound. In addition, they may be administered to patients with degenerative muscle conditions such are muscular dystrophy to promote muscle regeneration, and to the elderly to enhance wound healing.
Innovations and Advantages
Wound healing is a fundamental biological process that must operate efficiently, lifelong, to ensure survival of the organism. It proceeds in two major stages: 1) recruitment, activation and expansion of inflammatory cells at the wound sit; and 2) waning of the inflammation in concert with mobilization of tissue-repair processes.
Researchers at Harvard have identified a population of unique, tissue regenerative regulatory T-cells (Tregs) in muscle which play a critical role in regulating wound healing. In addition to their tissue-regenerative properties, these Treg cells have a unique phenotype, distinct from that of previously described regulatory T-cell populations. The numbers of these muscle-specific Tregs fluctuate in muscle diseases such as muscular dystrophy, and with aging. These cells, as well as agents that modulate their differentiation, and agents produced by the cells can be used to promote wound healing and muscle regeneration.
• Treg population expands at site of muscle injury. Researchers in the labs identified a unique population of FoxP3+ CD4+ Tregs that infiltrate injured muscle as the inflammatory stage of wound healing transitions to the regenerative stage.
• Ablating Tregs inhibits muscle regeneration. In the absence of Tregs, the initial inflammation following muscle injury is not resolved, and muscle regeneration is impaired, indicating that these Tregs are required for efficient muscle repair.
• Muscle-specific Tregs are a unique population. A comparative gene-expression analysis of Tregs from spleen and from injured skeletal muscle shows that more than 500 genes are differentially expressed between these two populations. The researchers identified a constellation of gene transcripts which, as an ensemble, represent a muscle-Treg-specific gene expression signature.
• Muscle-specific Tregs are enriched in muscular dystrophy. In addition to increasing following acute muscle injury, the researchers showed that muscle-specific Tregs are enriched in murine models of the degenerative muscle condition, muscular dystrophy.
• Muscle-specific Tregs are decreased in aged mice. The regenerative capacity of muscle is known to decrease with age. Accordingly, following muscle injury in aged mice, the researchers found a reduced population of muscle-specific Tregs.
Ongoing experiments are underway to look at the effects of several Treg-augmenting reagents on treating acute wound healing, muscular dystrophy and wound healing in aged animals.
Benoist, Christophe O.
Mathis, Diane J.
Wagers, Amy Jo
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Reference Harvard Case #4069