Functional muscle regeneration with combined delivery of angiogenesis and myogenesis factors

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.

VEGF Improves Skeletal Muscle Regeneration After Acute Trauma and Reconstruction of the Limb in a Rabbit Model

“…Another study showed that intramuscular administration of a plasmid engineered to induce VEGF expression enhanced preserved grip strength in a rat model of amyotrophic lateral sclerosis which suggests that VEGF administration might be neuroprotective and a practical approach for treating motor disorders [16]. Although data on muscle force restoration after musculoskeletal injury for this type of model were not available at the time we conducted our study, recently published studies [2,4] confirm the restoration of muscle force we observed.…”

“…We also suspect VEGF might have had more a direct effect on stimulating myogenesis, as we saw better muscle regeneration rather than contributing to repair by aiding neovascularization as the number of vessels did not increase. In addition, this might be explained by the mechanism that VEGF stimulates satellite cell activation and proliferation, cells are protected from apoptosis, the inflammatory response is muted, and highly functional muscle tissue is formed [4]. Furthermore, muscle regeneration appears to be mediated by MDSCs [7] which are superior to myoblasts in terms of proliferating ability, multipotent differentiation, and strong self-renewal [27].…”

Immunomodulatory effect of a decellularized skeletal muscle scaffold in a discordant xenotransplantation model

“…The field continues to expand and tissue bioengineering has provided, or is close to delivering, functional human organ replacements elsewhere (6,7,(13)(14)(15)(16)(17). The ability to produce innervated and revascularized muscles would hugely extend the possible applications of regenerative medicine (18)(19)(20)(21)(22)(23)(24)(25)(26).…”

Hydrogels for cardiac tissue engineering

“…In other studies, IGF and VEGF delivery was shown to prevent cellular damage by apoptosis or necrosis. 97,99 In addition to cell survival, small molecule/growth factor delivery can also be utilized to promote vascularization processes and improve functionality of tissue constructs. 51,55,100,101 For example, in one study angiopoietin-1 and VEGF were incorporated into hyaluronan gels with and without heparin.…”