Project description:Here, we performed time-series analysis of transcriptomic and proteomic changes associated with VML in a mouse model, focusing on the dynamics of gene and protein expression patterns at up to three weeks after muscle injury. We identified signaling pathways associated with temporal expression patterns that fail to restore within 3 weeks after VML, including those with sustained upregulation or downregulation. Using temporal expression analysis, we identified Sp1 as a novel molecular mediator of dysregulated muscle recovery after VML as well as elucidated pro-inflammatory and extracellular matrix (ECM) remodeling pathways mediating the remodeling process. These insights pave the way for the development of new targets that promote muscle regeneration and functional recovery of traumatically injured muscle.
Project description:Volumetric muscle loss (VML) is an acute loss of a critical volume of skeletal muscle that results in inflammation, fibrotic scarring in muscle tissue, and permanent muscle defects. The cellular and molecular processes that underlie fibrosis induced from VML injury need to be evaluated in larger animal models. Therefore, we used a canine model of VML alongisde treatment with an extracellular matrix (ECM) hydrogel. Treatment with the ECM hydrogel improved muscle regenerative responses and decreased proportions and spatial signatures of fibrotic and inflammatory cell populations.
Project description:The acute traumatic or surgical loss of skeletal muscle, known as volumetric muscle loss (VML), is a devastating type of injury that results in exacerbated and persistent inflammation followed by fibrosis. The mechanisms that mediate the magnitude and duration of the inflammatory response and ensuing fibrosis after VML remain understudied, and as such, the development of regenerative therapies has been limited. To address this need, we profiled how lipid mediators, which are potent regulators of the immune response after injury, varied with VML injuries that heal or result in fibrosis. We observed that non-healing VML injuries displayed increased pro-inflammatory eicosanoids and a lack of pro-resolving lipid mediators. Treatment of VML with a pro-resolving lipid mediator synthesized from docosahexaenoic acid, called Maresin 1, ameliorated fibrosis through reduction of neutrophils and macrophages and enhanced recovery of muscle strength. These results expand our knowledge of the dysregulated immune response that develops after VML and identify a novel immuno-regenerative therapeutic modality in Maresin 1.
Project description:Volumetric muscle loss (VML) resulting from extremity trauma presents chronic and persistent functional deficits which ultimately manifest disability. Acellular biological scaffolds, or decellularized extracellular matrices (ECMs), embody an ideal treatment platform due to their current clinical use for soft tissue repair, off-the-shelf availability, and zero autogenous donor tissue burden. ECMs have been reported to promote functional skeletal muscle tissue remodeling in small and large animal models of VML injury, and this conclusion was reached in a recent clinical trial that enrolled 13 patients. However, numerous other pre-clinical reports have not observed ECM-mediated skeletal muscle regeneration. The current study was designed to reconcile these discrepancies. The capacity of ECMs to orchestrate functional muscle tissue remodeling was interrogated in a porcine VML injury model using unbiased assessments of muscle tissue regeneration and functional recovery. Here, we show that VML injury incites an overwhelming inflammatory and fibrotic response that leads to expansive fibrous tissue deposition and chronic functional deficits, which ECM repair does not augment.