Functional muscle regeneration with combined delivery of angiogenesis and myogenesis factors

TLDR

Regenerative strategies often use single factors, but combining agents that target distinct aspects such as vascularization and stem cell activation may enhance functional tissue repair, particularly in ischemic muscle injury that causes necrosis and loss of function. The study investigated whether sustained delivery of VEGF and IGF1 via an injectable hydrogel could restore muscle function in ischemic rodent hindlimbs. The authors used an injectable hydrogel to provide sustained release of VEGF and IGF1 to ischemic hindlimbs. Combined sustained delivery of VEGF and IGF1 produced angiogenesis, reinnervation, and myogenesis, leading to highly functional muscle, whereas each factor alone or bolus delivery was less effective, supporting simultaneous targeting of distinct regenerative pathways.

Abstract

Regenerative efforts typically focus on the delivery of single factors, but it is likely that multiple factors regulating distinct aspects of the regenerative process (e.g., vascularization and stem cell activation) can be used in parallel to affect regeneration of functional tissues. This possibility was addressed in the context of ischemic muscle injury, which typically leads to necrosis and loss of tissue and function. The role of sustained delivery, via injectable gel, of a combination of VEGF to promote angiogenesis and insulin-like growth factor-1 (IGF1) to directly promote muscle regeneration and the return of muscle function in ischemic rodent hindlimbs was investigated. Sustained VEGF delivery alone led to neoangiogenesis in ischemic limbs, with complete return of tissue perfusion to normal levels by 3 weeks, as well as protection from hypoxia and tissue necrosis, leading to an improvement in muscle contractility. Sustained IGF1 delivery alone was found to enhance muscle fiber regeneration and protected cells from apoptosis. However, the combined delivery of VEGF and IGF1 led to parallel angiogenesis, reinnervation, and myogenesis; as satellite cell activation and proliferation was stimulated, cells were protected from apoptosis, the inflammatory response was muted, and highly functional muscle tissue was formed. In contrast, bolus delivery of factors did not have any benefit in terms of neoangiogenesis and perfusion and had minimal effect on muscle regeneration. These results support the utility of simultaneously targeting distinct aspects of the regenerative process.