Mesenchymal stem cells and extracellular matrix scaffold promote muscle regeneration by synergistically regulating macrophage polarization toward the M2 phenotype

Xinyu Qiu, Shiyu Liu, Hao Zhang, Bin Zhu, Yuting Su, Chenxi Zheng, Rong Tian, Miao Wang, Huijuan Kuang, Xinyi Zhao, Yan Jin

Skeletal muscle plays an important role in the body's physiology but there are still no effective treatments for volumetric muscle loss (VML) resulting from severe traumatic injury or tumor excision. Recent studies show that a tissue engineering strategy using a compound containing mesenchymal stem cells (MSCs) and decellularized extracellular matrix (ECM) scaffold generates significant regenerative effects on VML injury, but the underlying mechanisms are not fully understood. The characteristics of human umbilical cord MSCs, including multiplication capacity and multidifferentiation ability, were determined. We constructed a compound containing MSCs and decellularized ECM scaffold which was used for tissue regeneration in a VML model. We found that MSCs and decellularized ECM scaffold generated synergistic effects on promoting skeletal muscle tissue regeneration. Interestingly, both MSCs and decellularized ECM scaffold could promote macrophage polarization toward the M2 phenotype and suppress macrophage polarization toward the M1 phenotype, which is widely regarded as an important promoting factor in tissue regeneration. More importantly, MSCs and decellularized ECM scaffold generate synergistic promoting effects on macrophage polarization toward the M2 phenotype, not just an additive effect. Our findings uncover a previously unknown mechanism that MSCs and decellularized ECM scaffold promote tissue regeneration via collaboratively regulating macrophage polarization.