title: In Silico and In Vivo Experiments Reveal M-CSF Injections Accelerate Regeneration Following Muscle Laceration.
abstract: Numerous studies have pharmacologically modulated the muscle milieu in the hopes of promoting muscle regeneration; however, the timing and duration of these interventions are difficult to determine. This study utilized a combination of in silico and in vivo experiments to investigate how inflammation manipulation improves muscle recovery following injury. First, we measured macrophage populations following laceration injury in the rat tibialis anterior (TA). Then we calibrated an agent-based model (ABM) of muscle injury to mimic the observed inflammation profiles. The calibrated ABM was used to simulate macrophage and satellite stem cell (SC) dynamics, and suggested that delivering macrophage colony stimulating factor (M-CSF) prior to injury would promote SC-mediated injury recovery. Next, we performed an experiment wherein 1 day prior to injury, we injected M-CSF into the rat TA muscle. M-CSF increased the number of macrophages during the first 4 days post-injury. Furthermore, treated muscles experienced a swifter increase in the appearance of PAX7+SCs and regenerating muscle fibers. Our study suggests that computational models of muscle injury provide novel insights into cellular dynamics during regeneration, and further, that pharmacologically altering inflammation dynamics prior to injury can accelerate the muscle regeneration process.
authors.affiliation: Department of Biomedical Engineering, The University of Virginia, Health System, PO Box 800759, Charlottesville, VA 22908, USA.
authors.forename: Kyle S
authors.initials: KS
authors.lastname: Martin
authors.affiliation: Department of Biomedical Engineering, The University of Virginia, Health System, PO Box 800759, Charlottesville, VA 22908, USA.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Kegelman
authors.affiliation: Department of Biomedical Engineering, The University of Virginia, Health System, PO Box 800759, Charlottesville, VA 22908, USA.
authors.forename: Kelley M
authors.initials: KM
authors.lastname: Virgilio
authors.affiliation: Department of Biomedical Engineering, The University of Virginia, Health System, PO Box 800759, Charlottesville, VA 22908, USA.
authors.forename: Julianna A
authors.initials: JA
authors.lastname: Passipieri
authors.affiliation: Department of Biomedical Engineering, The University of Virginia, Health System, PO Box 800759, Charlottesville, VA 22908, USA.|Department of Orthopaedic Surgery, The University of Virginia, Charlottesville, VA, USA.
authors.forename: George J
authors.initials: GJ
authors.lastname: Christ
authors.affiliation: Department of Biomedical Engineering, The University of Virginia, Health System, PO Box 800759, Charlottesville, VA 22908, USA. ssblemker@virginia.edu.|Department of Mechanical and Aerospace Engineering, The University of Virginia, Charlottesville, VA, USA. ssblemker@virginia.edu.
authors.forename: Silvia S
authors.initials: SS
authors.lastname: Blemker
authors.affiliation: Department of Biomedical Engineering, The University of Virginia, Health System, PO Box 800759, Charlottesville, VA 22908, USA.|Department of Ophthalmology, The University of Virginia, Charlottesville, VA, USA.
authors.forename: Shayn M
authors.initials: SM
authors.lastname: Peirce
mesh_terms: D000818:Animals; D003198:Computer Simulation; D022125:Lacerations / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008954:Models, Biological; D018482:Muscle, Skeletal / Q000293:injuries / Q000502:physiology; D051381:Rats; D012038:Regeneration / Q000187:drug effects*; D032496:Satellite Cells, Skeletal Muscle / Q000378:metabolism / Q000473:pathology
chemical_list: D016173:Macrophage Colony-Stimulating Factor
keywords: Agent-based model; Computational model; Inflammation; Macrophages; Muscle regeneration; Regenerative pharmacology; Satellite stem cells