Epitenon-derived progenitor cells in tendon healing and adaptation

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Project Summary Pain associated with tendon injuries is an difficult clinical problem that significantly affects the overall quality of life of affected patients. Current treatments for tendon pain are anti-inflammatory drugs (non-steroidal anti- inflammatory drugs (NSAIDS) and corticosteroids) or opioids; however, anti-inflammatory drugs can negatively affect the tendon healing process and long-term opioid use can lead to dependency and contributes to the national opioid public health crisis. Thus, the need for novel, more targeted mechanisms to alleviate pain in tendon injuries is high. The parent award seeks to define the overall role that epitenon cells play in tendon healing using a novel driver (GLASTCreERT) to track and manipulate epitenon cells (GLASTLin) through a combination of genetic lineage tracing, single-cell RNA-sequencing, and depletion/inhibitions studies. This administrative supplement builds on preliminary data gathered during completion of Aim 1 of the parent award wherein we discovered that a GLASTLin epitenon cells are the sole expressors of the peptidase inhibitor 16 (Pi16) gene, a key non-neuronal regulator of persistent pain. This suggests that Pi16 expression by epitenon cells may be a therapeutic target to mitigate the pain associated with tendon injury. Therefore, in parallel with the parent award, the proposed administrative supplement will test the central hypothesis that epitenon-derived cells are primary drivers of the tendon pain response. In supplemental experiments to Aim 2A of the parent award, we will first identify pain-related behavioral metrics that can be used to longitudinally evaluate tendon pain in mouse models. We will then assess how loss of Pi16 via GLASTLin epitenon cell depletion affects the pain response during healing by a combination of histological and pain-related behavioral analyses. Successful completion of these experiments will identify epitenon cell-derived Pi16 as a potential target by which tendon-related pain can be alleviated and establish methods to measure tendon pain in future studies.