Noggin Combined With Dental Pulp Stem Cells Repair Muscle Injury Through Smad/Pax7 Signaling Pathway

Abstract Background: A proper stem cell source is key to muscle injury repair. Dental pulp stem cells (DPSCs) are an available source for the treatment of muscle injury due to their high reproductive and differential activities. However, the application of DPSCs in muscle regeneration is incompletely understood. Noggin, a secreted BMP antagonist promoted by Wnt-1, is required for embryonic myogenesis. Our research is to study whether Noggin can promote myogenic differentiation of DPSCs, and then to investigate the repair effect of Noggin combined with DPSCs in muscle injury.Methods: DPSCs were treated with Noggin to induce myogenic differentiation in vitro. The levels of myogenic markers (MyoD, Desmin, MRF4 and MyHC), and satellite cell markers (Pax3, Pax7, Six1 and Eya2) were detected during this process. Next, we blocked the effect of Noggin by adding BMP, and Samd phosphorylation level was tested. Then, we implanted Noggin-pretreated DPSC combined Matrigel into the mouse tibialis anterior muscle with volumetric muscle loss (VML). After 30-day recovery, morphometric analysis of the tibialis anterior muscle was performed.Results: Noggin effectively increased myotube formation in DPSCs. We also found Noggin accelerated the skeletal myogenic differentiation of DPSCs and promote Pax7+ satellite-like cell generation. These satellite-like cells had the capacity to generate myofibers and could self-renew. Pax7 and Pax3 levels were repressed when blocked the effect of Noggin by adding BMP, and Noggin eliminated the level of BMP/Smad phosphorylation. This suggested that Noggin facilitated the skeletal myogenic differentiation of DPSCs via Smad/Pax7 pathway. Morphometric analysis of muscle cross-sections revealed that DPSCs therapy could increase repair size and decrease scar tissue in tibialis anterior muscle of VML. Moreover, Noggin-treated DPSCs can benefit to Pax7+ satellite cell pool and promote muscle regeneration. Conclusions: This work reveals that Noggin can promote the generation of satellite-like cells for the myogenic process in DPSCs through Smad/Pax7 signaling pathway, and these satellite-like cells bioconstructs might possess a relatively fast capacity to regenerate for muscle injury.