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Single cell deconstruction of murine volumetric muscle loss reveals inflammatory imbalances preventing muscle stem cell mediated regeneration

ABSTRACT: Single cell deconstruction of murine volumetric muscle loss reveals inflammatory imbalances preventing muscle stem cell mediated regeneration

PROVIDER: PRJNA685848 | ENA |

REPOSITORIES: ENA

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Single cell deconstruction of murine volumetric muscle loss reveals inflammatory imbalances preventing muscle stem cell mediated regeneration

Project description:Volumetric muscle loss (VML) overwhelms the innate regenerative capacity of mammalian skeletal muscle (SkM), leading to numerous disabilities and reduced quality of life. Immune cells are critical responders to muscle injury and guide tissue resident stem cell and progenitor mediated myogenic repair. However, how immune cell infiltration and inter-cellular communication networks are altered following VML and drive pathological outcomes remains under-explored. Herein, we characterize the cellular and molecular mechanisms of VML injuries that result in fibrotic degeneration or regeneration of SkM. Following degenerative VML injuries, we observe heightened infiltration of a previously uncharacterized population of Natural Killer (NK) cells as well as persistence of neutrophils beyond two weeks post injury. Functional validation of NK cells revealed an antagonistic role on neutrophil accumulation in part via CCR1 mediated chemotaxis. The persistent infiltration of neutrophils in degenerative VML injuries was found to contribute to impairments in muscle stem cell regenerative function, which was also attenuated by transforming growth factor beta 1 (TGFb1). Blocking TGFb signaling antagonized neutrophil accumulation, reduced fibrosis, and improved muscle specific force. Collectively, these results enhance our understanding of immune cell-stem cell crosstalk that drives regenerative dysfunction and provide further insight into possible avenues for fibrotic therapy exploration.

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Maresin 1 Repletion Improves Muscle Regeneration After Volumetric Muscle Loss

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Project description:Unwavering Pathobiology of Volumetric Muscle Loss Injury

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Unwavering Pathobiology of Volumetric Muscle Loss Injury

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.

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Deconstruction of cellular dynamics after treatment of volumetric muscle loss injury with extracellular matrix

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Project description:Skeletal muscle possesses a remarkable capacity to regenerate when injured, but when confronted with major traumatic injury resulting in volumetric muscle loss (VML), the regenerative process consistently fails. The loss of muscle tissue and function from VML injury has prompted development of a suite of therapeutic approaches but these strategies have proceeded without a comprehensive understanding of the molecular landscape that drives the injury response. Herein, we administered a VML injury in an established rodent model and monitored the evolution of the healing phenomenology over multiple time points using muscle function testing, histology, and expression profiling by RNA sequencing. The injury response was then compared to a regenerative medicine treatment using orthotopic transplantation of autologous minced muscle grafts (~1 mm3 tissue fragments). A chronic inflammatory and fibrotic response was observed at all time points following VML. These results suggest that the pathological response to VML injury during the acute stage of the healing response overwhelms endogenous and therapeutic regenerative processes. Overall, the data presented delineate key molecular characteristics of the pathobiological response to VML injury that are critical effectors of effective regenerative treatment paradigms.

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