Deciphering the dynamic heterogeneity of regulatory T-cells in muscle injury using single-cell RNA sequencing

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Poor muscle regenerative ability due to genetic or age-related pathologies represents an increasing health challenge that mandates expanding research in that field. Immune cells have been increasingly appreciated for their role in regulating muscle repair and regeneration. Recently, researchers in the lab of Dr. Diane Mathis and Dr. Christophe Benoist have described a unique population of regulatory T-cells (Tregs) that accumulate in injured muscles and play a fundamental role in orchestrating tissue repair. Several lines of evidence from these studies suggested that muscle Tregs comprise phenotypically and functionally heterogeneous cell subsets. This drove the hypothesis that distinct Treg populations are dynamically recruited to injured muscle in order to contribute to different aspects of repair in a temporally punctual manner. However, the current conventional bulk analysis methods offer only a limited insight into the heterogeneity of such complex system and are rendered largely insufficient for studying rare cell populations. Therefore, the proposed project aims at using the novel single-cell RNA sequencing technology, inDrop, to decipher the dynamic changes in muscle Tregs after injury. Moreover, the identified transcriptomes will be linked to T-cell receptor sequences to infer the clonal relationship between different Treg clusters. Thereafter, key transcriptional regulators of the newly-identified Treg populations will be uncovered and validated for their functional relevance in models of muscle dystrophy and chronic injury. The expected findings of this project will have immediate impact on our understanding of Treg specialization in tissue injury. Furthermore, it will provide a methodological framework for subsequent studies aiming to uncover immune cell dynamic heterogeneity in various inflammatory processes. Ultimately, translation of these findings to the human context would have clinical potential for both muscular dystrophy patients and geriatric individuals.