Wnt7a-releasing synthetic hydrogel enhances local skeletal muscle regeneration and muscle stem cell engraftment

Abstract

Skeletal muscle possesses efficient ability to regenerate upon minor injuries, but its capacity to regenerate is severely compromised with traumatic injuries and muscle-associated diseases. Recent evidence suggests that skeletal muscle regeneration can be accelerated by transplantation of muscle satellite cells (MuSCs) or treatment with promyogenic factors, such as Wingless-type MMTV Integrated 7a (Wnt7a) protein. Although direct intramuscular injection is the simplest method to deliver MuSCs and Wnt7a for regenerative therapy, direct injection is not viable in many clinical cases where the structural integrity is severely compromised. To address this challenge, we engineered a synthetic poly(ethylene glycol) (PEG)-based hydrogel to facilitate the co-delivery of pro-myogenic factors, such as Wnt7a, and MuSCs to skeletal muscles affected by severe trauma or muscular dystrophies. Wnt7a release rate can be controlled by modulating the polymer density of the hydrogel, and this release rate can be further accelerated through the proteolytic degradation of the hydrogel. Treating cryo-injured tibialis anterior (TA) muscles with Wnt7a-loaded hydrogels resulted in an accelerated regenerative response, measured by increased muscle fiber cross-sectional area, bulk TA mass, and number of Pax7+ MuSCs at the injury site, compared to the TA muscles treated with Wnt7a-free hydrogels. Co-delivery of Wnt7a and primary MuSCs using the synthetic hydrogel to the cryo-injured TA muscles significantly increased cellular migration during the engraftment process. This work provides a synthetic biomaterial platform for advancing treatment strategies of skeletal muscle trauma and diseases, specifically in conditions where direct intramuscular injection may be challenging.