Functional muscle regeneration with combined delivery of angiogenesis and myogenesis

[wildwilly]

Proc Natl Acad Sci U S A. 2009 Dec 4.

Functional muscle regeneration with combined delivery of angiogenesis and myogenesis factors.

Borselli C, Storrie H, Benesch-Lee F, Shvartsman D, Cezar C, Lichtman JW, Vandenburgh HH, Mooney DJ.

School of Engineering and Applied Sciences and Wyss Institute, Harvard University, Cambridge, MA 02138 Department of Material Engineering and Production, University of Naples Federico II, Naples 80138, Italy Myomics Inc., Providence, RI 02906 Department of Pathology, Brown Medical School/Miriam Hospital, Providence, RI 02912 Department of Molecular and Cellular Biology, Center for Brain Science, Harvard University, Cambridge, MA 02138.

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.

http://www.ncbi.nlm.nih.gov/pubmed/1...m&ordinalpos=3