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  • Although our data show that agrin accelerates the innervatio

    2023-01-31

    Although our data show that agrin accelerates the innervation of engineered muscle tissue following implantation, there are still several issues that need to be considered. First, the use of primary muscle stem or progenitor PFK-015 (satellite cells) instead of an immortalized muscle cell line (C2C12) should be considered in further investigations, as satellite cells are more appropriate for clinical applications. Second, well-designed scaffold systems are required to enhance myogenic maturation of engineered muscle tissue. In fact, the gel system used in these studies may not be ideal, because it does not provide aligned structures that can guide the formation of parallel myotubes that make up normal skeletal muscle. In this study we observed that the implanted C2C12 cells did not develop into well-oriented myofibers in vivo. The use of a scaffold system that can provide newly formed myofibers with the proper cues for unidirectional alignment, along with the accelerated innervations provided by agrin treatment, may result in improved functional characteristics in vivo. This type of scaffold has been created in our laboratory using electrospinning techniques [11] and these electrospun scaffolds may be a better alternative for muscle tissue engineering. Other parameters, such as topography, mechanical stimulation, chemical stimulation, and electrical stimulation should be considered in future experiments as well.
    Conclusions
    Acknowledgments We thank John Scott for DRG isolation, Dr. Venu Kesireddy for calcium imaging, Ken Grant for TEM study, Ken Gyabaah, Dr. Hyunhee Ahn, and Dr. Qingguo Zhao for assistance with molecular analysis, and Dr. John D. Jackson and Dr. Jennifer Olson for editorial assistance. This study was supported, in part, by a grant from the Department of Defense [Orthopaedic Trauma Research Program (W81XWH-08-1-0333)].
    Introduction Current treatment of Myasthenia Gravis (MG) with a series of immune therapies has changed the prognosis of the disease and eliminates or minimizes the clinical symptoms in the majority of cases. However, some patients do not respond to conventional immunotherapy. MG patients are treated with the same therapies regardless of whether they are seropositive for antibodies to Acetylcholine Receptor (AChR+MG) or seronegative (seronegative-MG) (Conti-Fine et al., 2006, Deymeer et al., 2007, Keesey, 2004, Newsom-Davis, 2003, Richman and Agius, 2003, Saperstein and Barohn, 2004, Skeie et al., 2006). Until recently, the seronegative-MG group included the subgroup of patients with anti-muscle-specific tyrosine kinase (MuSK) antibodies (MuSK+MG) (Hoch et al., 2001, McConville et al., 2004, Scuderi et al., 2002). Several studies suggest that MuSK+MG patients have a more severe form of the disease and may be more refractory to established treatments than AChR+MG patients (Evoli et al., 2003, Illa et al., 2005, Sanders et al., 2003, Stickler et al., 2005, Vincent et al., 2003, Vincent and Leite, 2005, Zhou et al., 2004). We have recently reported the presence of both antibodies in a single patient and we observed that while AChR antibodies decreased with first line immunosuppressants, MuSK antibodies did not, supporting the view that MuSK+MG may be more resistant to conventional treatments. Furthermore, when the patient was treated with Rituximab, she improved clinically and MuSK antibodies decreased more dramatically than the AChR antibodies (Diaz-Manera et al., 2007). Rituximab is a genetically engineered anti-CD20 monoclonal antibody that binds with high affinity to cells expressing CD20 and induces B-lymphocytes depletion (Pescovitz, 2006). Originally used as a therapy for B cell malignancies, Rituximab has recently been considered a therapeutic option for autoimmune diseases where B cells are thought to play a prominent role (Chambers and Isenberg, 2005, Taylor and Lindorfer, 2007). Although anti-CD20 monoclonal antibodies are generally safe, the appearance of progressive multifocal leukoencephalopathy has been reported in some patients treated with Rituximab (Berger, 2007).