Gene and cell therapy via alginate microgels for muscle injuries

Abstract

Injuries and diseases of the musculoskeletal system are extremely common and account for over 6 million visits to emergency departments each year. After injury, muscle tissue needs to be repaired and allowed to regenerate. During this process, the formation of fibrous tissue makes adequate muscle contraction extremely difficult, and can lead to muscle contractures and chronic pain. Gene (GT) and cellular therapies associated with biomaterials such as alginate hydrogels emerge as innovative forms of treatment to reduce fibrosis. However, they are unable to act only when tissue regeneration is necessary. In this sense, it is suggested that modulation of the main cytokine involved during the fibrosis process, TGFb1, via GT and cell therapy may confer great clinical relevance in cases of tissue regeneration. Therefore, this project has two major parts. The first part investigates a GT procedure for muscle regeneration based on the modulation of TGFb1 level. For this, a lentivector (Lv) will be constructed that will express the soluble TGFb1 type II receptor (sTbRII) under the control of the NF-kB-inducible promoter. The Lv will be encapsulated in alginate microgels, which will serve as carriers to obtain a controlled release of the vectors in target tissue. The second part of the project will involve cell therapy with muscle-derived stem cell-like cells (MDSCs) and injury induced muscle-derived stem cell-like cells (iMDSCs), which have a high capacity for differentiation, including the formation of blood vessels. MDSCs and iMDSCs will be encapsulated in alginate microgels to create a therapeutic flap, containing stem cells and endothelial cells for the treatment of muscle damage in a murine model in vivo. These results are expected to reduce muscle fibrosis, increase tissue regeneration, and promote functional recovery of skeletal muscle. (AU)