Regulation of skeletal muscle regeneration by macrophages and the urokinase-type plasminogen activator

• Main Author: Bryer, Scott C
• Format: Dissertation
• Language: English
• Published: ProQuest Dissertations & Theses 01-01-2007
• Subjects: Anatomy & physiology; Cellular biology; Physiology
• ISBN: 9780549052128; 0549052127

Although macrophages are thought to promote tissue repair, the molecular mechanisms involved remain to be elucidated. The hypothesis of this dissertation was that skeletal muscle regeneration requires macrophage accumulation and their expression of components of the plasminogen activator system. Results suggest uPA can act independently of its specific receptor, uPAR, since macrophage accumulation and subsequent muscle regeneration was not impaired following injury in uPAR null mice in vivo. Additional in vitro experiments demonstrated that uPA was required for macrophage chemotaxis independent of uPAR. Adhesion, phagocytosis and expression of selected growth factors and cytokines were not different between macrophages from wild-type (WT) and uPA null mice. uPA null mice demonstrated impaired macrophage accumulation and muscle regeneration. Intramuscular injection of exogenous uPA to injured muscle in uPA null mice restored macrophage accumulation and muscle regeneration. Specific depletion of macrophages using clodronate-liposomes resulted in impaired muscle regeneration, mimicking the healing response in uPA null mice. The transfer of WT bone marrow cells to uPA null mice rescued macrophage accumulation and muscle regeneration following injury in uPA null mice. Interestingly, transfer of uPA null bone marrow to WT mice also resulted in muscle regeneration. These results suggest expression of uPA is critical for macrophage accumulation and muscle regeneration, and as such, may represent a therapeutic target for enhancing macrophage chemotaxis and muscle regeneration.