Interleukin-4 improved adipose-derived stem cells engraftment via interacting with fibro/adipogenic progenitors in dystrophic mice

Abstract Adipose-derived stem cells (ADSC) therapy is a promising therapy for dystrophinopathy. Fibro/adipogenic progenitors (FAP) are important in regulating the myogenesis of muscle satellite cells and contribute to muscle fibrosis and adipocyte infiltration. The interleukin-4 (IL4) pathway is found to be a switcher regulating the functions of FAP. The interaction between FAP and engrafted cells has not yet been studied. We used a co-culture system to investigate the possible crosstalk between FAP of dystrophic mice and IL4-overexpressed ADSC (IL4-ADSC) and control ADSC. The systemic transplantation of IL4-ADSC and control ADSC was conducted in dystrophic mice for 16 weeks and motor function and molecular improvements of mice were evaluated. Overexpression of IL4 in ADSC significantly promoted terminal myogenesis in vitro with significant increased expression of Myogenin and MyHC. Through co-culture, we discovered that myoblasts derived from control ADSC promoted adipogenic and fibrogenic differentiation of FAP, but FAP did not significantly affect their myogenesis, while overexpression of IL4 in ADSC inhibited their myotube-dependent promotion of FAP differentiation but promoted FAP to support myogenesis. Dystrophic mice delivered with IL4-ADSC-derived myoblasts had a significant better motor ability, more engrafted cells with dystrophin expression, less muscle fibrosis, and intramuscular adipocytes and macrophage infiltration than mice delivered with control-ADSC-derived myoblasts. Our results revealed the importance of focusing on the crosstalk between engrafted cells and resident FAP in cell therapy and the positive therapeutic effect of IL4 administration combined with ADSC therapy in dystrophic mice.