Mechanoregulation of Vascularization in Aligned Tissue-Engineered Muscle: A Role for Vascular Endothelial Growth Factor

TLDR

Skeletal muscle tissue engineering holds promise for treating muscle loss but faces significant challenges to clinical translation. The study aimed to generate an aligned, prevascularized 3D muscle construct by applying uniaxial stress alone. Uniaxial stress caused both cell types to align and led endothelial cells to form vascular structures without added growth factors, with stress‑induced VEGF from muscle cells driving vessel organization.

Abstract

Skeletal muscle tissue engineering has major promise for regenerative treatment of patients suffering from muscle loss due to, for example, traumatic injury, but faces considerable challenges to progress toward clinical application. In the present study the creation of an aligned prevascularized muscle tissue was addressed. We hypothesized that an aligned vascularized three-dimensional (3D) muscle tissue can be induced in vitro by merely using uniaxial stress. The present study showed that not only do endothelial cells and muscle cells independently align in the direction of uniaxial stress in a hydrogel-based 3D culture system, but also, more importantly, the endothelial cells in the co-cultured 3D constructs organized into vascular structures. Strikingly, in these cultures no additional growth factors were needed to induce vascular formation of the endothelial cells. Vascular endothelial growth factor (VEGF) production by the muscle cells was stimulated by the uniaxial stress that develops in the tissue when constrained in one direction. This stress accompanied by VEGF production appeared to play a key role in the organization of the endothelial cells into vessel-like structures.