Muscle stem cells (MuSCs) fuse to form multinucleated cells to repair skeletal muscle after injury. While adult MuSCs express a cell autonomous myogenesis program, in vivo investigations demonstrated that the MuSC environment is required for efficient adult myogenesis and muscle regeneration. Particularly, anti-inflammatory/restorative macrophages stimulate MuSC differentiation and fusion, although the molecular mechanisms involved are still largely unknown. Here, we show that restorative macrophages secrete ribonuclease T2 (RNAseT2) which specifically stimulates MuSC fusion. Co-immuprecipitation coupled to mass spectrometry-based proteomics identified Ste20-like kinase (SLK) as binding partner of RNAseT2. SLK triggered the phosphorylation-mediated activation of N-WASP, allowing actin remodeling at the time of MuSC fusion.