Cell-free therapy: biomaterial-based delivery of engineered mesenchymal stem cells extracellular vesicles (MSCs-EVs) to enhance skeletal muscle repair and reduce fibrosis.

• Grant number: 23/17660-5
• Support Opportunities: Scholarships abroad - Research Internship - Master's degree
• Start date: April 01, 2024
• End date: September 30, 2024
• Field of knowledge: Biological Sciences - Biology
• Principal Investigator: Roberta Sessa Stilhano Yamaguchi
• Grantee: Luana de Mambro
• Supervisor: Jonathan Kent Leach
• Host Institution: Faculdade de Ciências Médicas da Santa Casa de São Paulo (FCMSCSP). Fundação Arnaldo Vieira de Carvalho. São Paulo , SP, Brazil
• Institution abroad: University of California, Davis (UC Davis), United States
• Associated to the scholarship: 22/07471-8 - In vivo gene therapy in a murine model of injury, from a lentiviral vector carrying the soluble TGF²-1 receptor, aiming at reducing skeletal muscle fibrosis during muscle repair., BP.MS

Abstract

Muscle injuries, ranging from mild strains to severe trauma, undergo a well-defined repair process involving degeneration, inflammation, regeneration, and remodeling phases. However, extensive injuries can overwhelm this process, leading to volumetric muscle loss (VML) characterized by dysfunctional muscle and fibrotic tissue. Notably, even a 10-20% loss in muscle mass can result in a substantial strength reduction. This research project focuses on innovative therapeutic strategies addressing VML, specifically exploring the roles of Stromal-derived factor 1 (SDF-1), Transforming Growth Factor-beta 1 (TGFB-1), Mesenchymal Stem Cells (MSCs), and their Extracellular Vesicles (EVs). SDF-1, known for its impact on cellular processes, emerges as a promising candidate for promoting migration, proliferation, and survival of progenitor stem cells crucial for effective muscle repair. Conversely, TGFB-1, a fibrosis trigger, motivates the critical need for the investigation of engineered constructs to counteract its effects. This study proposes utilizing EVs derived from engineered MSCs overexpressing SDF-1 or sTBRII (a construct inhibiting TGFB-1 effects), encapsulated in PLGA biomaterials nanospheres with different degradation rates, to enable controlled release and assess their impact on myoblasts and fibroblasts. Methodologically, the project involves lentivector production, cell culture, EV preconditioning, isolation, and characterization, as well as the creation of biomaterials with different degradation times. The study's objectives align with the urgent need for effective therapies for VML, a global concern linked to trauma. Rigorous statistical analysis, including tests for normal distribution and significance considerations, will ensure a comprehensive evaluation of the proposed interventions. In conclusion, this research project offers a comprehensive plan to explore the therapeutic potential of two engineered MSC-derived approaches to enhance muscle injury repair and reduce fibrosis.