Effect of S100A8 knockdown in the regeneration of human iPSC-derived myogenic progenitor in dystrophic skeletal muscle.

• Grant number: 25/05922-0
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor
• Start date: August 31, 2025
• End date: August 30, 2026
• Field of knowledge: Biological Sciences - Morphology - Anatomy
• Principal Investigator: Elen Haruka Miyabara
• Grantee: Audrei dos Reis Santos
• Supervisor: Rita Perlingeiro Kyba
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Institution abroad: University of Minnesota (U of M), United States
• Associated to the scholarship: 23/10309-0 - Strategy to improve the function of satellite cells and fibro-adipogenic progenitors (FAPs) of regenerating skeletal muscle during aging: implications of the modulation of S100A8 expression, BP.PD

Abstract

Skeletal muscle has a great capacity to regenerate after injuries, due to the activity of muscle stem cells called satellite cells. Furthermore, after muscle damage, fibroadipogenic progenitor cells (FAPs) resident in skeletal muscle are activated, proliferate and provide a favorable environment for the occurrence of muscle regeneration mediated by satellite cells. On the other hand, elderly individuals have impaired function of satellite cells and FAPs, with the latter being accumulated and contributing to the aberrant production of profibrotic factors in skeletal muscle. Consequently, there is impairment in the activation and differentiation niche of satellite cells during muscle regeneration in elderly individuals. Promising preliminary results from our current FAPESP post-doctoral project (23/10309-0) demonstrated that the in vivo knockdown of the calcium binding protein S100A8 significantly reduces muscle fibrosis and collagen I expression in regenerating muscle of aged mice. Considering these preliminary results, the scientific premise underlying this application is that reducing S100A8 expression in regenerating skeletal muscle of aged animals is a strategy capable of modulating the function of FAPs, in order to reduce the fibrogenic process and, consequently, enhance the skeletal muscle regenerative process and satellite cell function during aging. This can be best addressed in vivo, in transplantation assays. Therefore, our proposal is to learn transplantation assays of human (induced pluripotent stem cell) iPSC-derived myogenic progenitors in muscles from the dystrophin-deficient immunodeficient mouse (NSG-mdx4Cv), and evaluate the effect of the S100A8 knockdown (through shRNAS100A8 transfection) in these muscles. The mdx mouse is a model of Duchenne muscular dystrophy characterized by a reduction of muscle regenerative capacity and fibrosis. Training of these transplantation assays during one-year BEPE-FAPESP internship at the University of Minnesota, USA, under the supervision of Dr. Rita Perlingeiro will allow us to perform similar experiments in aging immunodeficient NSG mouse, when back to Brazil, to test if the S100A8 knockdown can improve the function of human iPSC-derived myogenic progenitors in regenerating skeletal muscles during aging (see details in the project). (AU)