Bifunctional adECM bioscaffold with STIM1-ASCs and IGF-2 promotes functional masseter VML repair via myogenesis and fibrosis suppression

Abstract

Craniofacial muscles are essential for a variety of functions, including fine facial expressions. Severe injuries to these muscles often lead to more devastating consequences than limb muscle injuries, resulting in the loss of critical functions such as mastication and eyelid closure, as well as facial aesthetic impairment. Therefore, the development of targeted repair strategies for craniofacial muscle injuries is crucial. In this study, we engineered an adipose-derived decellularized extracellular matrix (adECM) bioscaffold co-loaded with seed cells and bioactive factors. The seed cells were STIM1-overexpressing adipose-derived stem cells (STIM1-ASCs), which exhibit directed and highly efficient myogenic differentiation, addressing the low differentiation efficiency of conventional ASCs that limits muscle regeneration. The bioactive factor used was insulin-like growth factor-2 (IGF-2), which modulates the immune microenvironment by reprogramming mitochondrial energy metabolism to promote M2 macrophage polarization. These M2 macrophages further suppress fibroblast collagen deposition, alleviating muscle fibrosis, while simultaneously enhancing the myogenic differentiation of STIM1-ASCs and myotube formation. Together, the recellularized adECM bioscaffold harnesses these dual mechanisms (promoting functional muscle regeneration and anti-fibrotic repair) to significantly improve the recovery of volumetric muscle loss (VML) in the masseter. The development of this bifunctional bioscaffold offers a novel therapeutic strategy and theoretical foundation for treating severe craniofacial muscle injuries.