Bioengineered constructs combined with exercise enhance stem cell-mediated treatment of volumetric muscle loss

Marco Quarta,Melinda Cromie,Thomas A Rando,Mark Hamer,Merel Stok,Victor Garcia,Patrick Paine,Joseph B Shrager,Justin Blonigan,Igor Akimenko,Robert Chacon

doi:10.1038/ncomms15613

Abstract

Volumetric muscle loss (VML) is associated with loss of skeletal muscle function, and current treatments show limited efficacy. Here we show that bioconstructs suffused with genetically-labelled muscle stem cells (MuSCs) and other muscle resident cells (MRCs) are effective to treat VML injuries in mice. Imaging of bioconstructs implanted in damaged muscles indicates MuSCs survival and growth, and ex vivo analyses show force restoration of treated muscles. Histological analysis highlights myofibre formation, neovascularisation, but insufficient innervation. Both innervation and in vivo force production are enhanced when implantation of bioconstructs is followed by an exercise regimen. Significant improvements are also observed when bioconstructs are used to treat chronic VML injury models. Finally, we demonstrate that bioconstructs made with human MuSCs and MRCs can generate functional muscle tissue in our VML model. These data suggest that stem cell-based therapies aimed to engineer tissue in vivo may be effective to treat acute and chronic VML.

Highlights

Volumetric muscle loss (VML) is associated with loss of skeletal muscle function, and current treatments show limited efficacy
These results suggest that our defined surgical ablation resulted in consistent and permanent loss of tibialis anterior (TA) mass and function, characteristic of VML injuries
These results suggest that endothelial cells (ECs) are required for the enhancing effect of the total muscle resident cells (MRCs) population to sustain muscle stem cells (MuSCs) viability, expansion and engraftment within bioconstructs transplanted in VML injuries, and that ECs alone are sufficient to produce nearly the full effect of the total MRC population

Summary

Introduction

Volumetric muscle loss (VML) is associated with loss of skeletal muscle function, and current treatments show limited efficacy. We demonstrate that bioconstructs made with human MuSCs and MRCs can generate functional muscle tissue in our VML model. These data suggest that stem cell-based therapies aimed to engineer tissue in vivo may be effective to treat acute and chronic VML. We find that bioconstructs generated with MuSCs and muscle resident cells (MRCs) are capable of restoring structure and function of muscles with acute and chronic VML injuries. Bioconstructs generated with human MuSCs and MRCs result in functional muscle tissue in our VML model These advances in stem cell-based methods may offer new tools to design treatments for VML in the clinical setting

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Conclusion