Abstract
Skeletal muscle possesses a remarkable capacity for repair and regeneration following a variety of injuries. When successful, this highly orchestrated regenerative process requires the contribution of several muscle resident cell populations including satellite stem cells (SSCs), fibroblasts, macrophages and vascular cells. However, volumetric muscle loss injuries (VML) involve simultaneous destruction of multiple tissue components (e.g., as a result of battlefield injuries or vehicular accidents) and are so extensive that they exceed the intrinsic capability for scarless wound healing and result in permanent cosmetic and functional deficits. In this scenario, the regenerative process fails and is dominated by an unproductive inflammatory response and accompanying fibrosis. The failure of current regenerative therapeutics to completely restore functional muscle tissue is not surprising considering the incomplete understanding of the cellular mechanisms that drive the regeneration response in the setting of VML injury. To begin to address this profound knowledge gap, we developed an agent-based model to predict the tissue remodeling response following surgical creation of a VML injury. Once the model was able to recapitulate key aspects of the tissue remodeling response in the absence of repair, we validated the model by simulating the tissue remodeling response to VML injury following implantation of either a decellularized extracellular matrix scaffold or a minced muscle graft. The model suggested that the SSC microenvironment and absence of pro-differentiation SSC signals were the most important aspects of failed muscle regeneration in VML injuries. The major implication of this work is that agent-based models may provide a much-needed predictive tool to optimize the design of new therapies, and thereby, accelerate the clinical translation of regenerative therapeutics for VML injuries.
Highlights
In response to common injuries, such as lacerations or strains, skeletal muscle repair occurs through a well described process governed by temporally-regulated, highly orchestrated, multicellular interactions [1,2]
There are no therapies that adequately repair muscle tissue for volumetric muscle loss (VML) injuries, and a contributing factor is that the cellular mechanisms driving the response to these injuries are poorly understood
To aid in addressing this knowledge gap, we have developed an agent-based model to capture the cellular remodeling processes following the creation of a VML injury
Summary
In response to common injuries, such as lacerations or strains, skeletal muscle repair occurs through a well described process governed by temporally-regulated, highly orchestrated, multicellular interactions [1,2]. VML typically results from trauma, such as battlefield injuries to wounded warriors, or civilian vehicular accidents and there are no current treatment options for complete restoration of form and function. In this scenario, the lack of insight into the mechanisms responsible for the failure of functional regeneration, in the context of VML injury, represents a major barrier to development of novel therapeutics for improved functional outcomes. SSCs fail to differentiate, and fibroblasts and myofibroblasts do not undergo apoptosis like in other muscle injuries but instead fill the defect space with fibrotic tissue, which includes densely packed collagen (Fig 1) [3,9,10,11]
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