Immunomodulation and immunoevasion strategies to enhance allogeneic mesenchymal stem cell/muscle satellite cell transplantation strategies to treat muscular dystrophy

Muscular dystrophy is a group of genetic diseases characterized by progressive skeletal muscle weakness and wasting. Among the ~30 types of muscular dystrophy, Duchenne muscular dystrophy (DMD) in pediatric patients (primarily 3–6-year-old boys) is the most severe. Stem cell and gene therapy are potential treatments for DMD. Regarding stem cells, there are two options – (i) Reimplantation of genetically altered patient autologous stem cells with restored dystrophin expression to prevent muscle degeneration; and (ii) Transplantation of allogeneic stem cells/ muscle satellite cells with functional dystrophin from suitable donors to DMD patients. In the latter context, most transplanted donor stem cells die via immune rejection and lack of a beneficial niche to mature. Against this backdrop, the current project will explore strategies for promoting the immunomodulation of allogeneic stem cells and immunoevasion by encapsulation of stem cells in specially designed soft, injectable nanofibrillar hydrogels. These hydrogels will be designed to both support and protect the stem cells. Different core-shell geometries and immune stealth coatings will be tested to minimize immune recognition and maximize stem/ satellite cell survival. Furthermore, hydrogel stiffness of 8-17 kPa and mechanical conditioning of the hydrogel encapsulated cells in custom-designed bioreactors will be used to promote myogenic expression, and specifically, dystrophin (mechano-responsive protein not expressed in muscular dystrophy) in stem cells/ muscle satellite cells. Lastly, the survival, integration and therapeutic potential of the hydrogel-encapsulated mechanically conditioned allogeneic stem cells/ satellite cells via intramuscular implantation in DMD mice will be evaluated.