Skeletal Muscle Engineering for Degenerative Muscle Disorders

A collaborative effort between researchers in Italy, Israel and the United Kingdom has resulted in the development of a new therapeutic technique to repair and rebuild muscle in those who suffer from degenerative muscle disorders. This therapeutic strategy brings together two existing techniques for muscle repair: 1) cell transplantation; and 2) tissue engineering.

Several different conditions can lead to muscle degeneration or loss of skeletal muscle. Skeletal muscle only has a limited capacity to repair itself. Therefore, strategies for muscle reconstitution and regeneration are often necessary.

There are presently two different ways to rebuild muscle. The first utilizes stem cells that are injected directly into the muscle or injected into the arteries that feed blood into large muscles. Stem cell transplantation often shows limited success because the transplanted cells show poor survival rates. The second method is tissue engineering in which cells are embedded into the muscle on a biodegradable biomaterial scaffold that reconstructs the muscle. In this present study, the authors hoped to increase the rates of stem cell survival by implanting them in hydrogel material.

For this experiment, the research team went with a tried and true method for tissue engineering: polyethylene glycol and fibrinogen (PF) hydrogel scaffolds. PF scaffolds have been successfully employed in several experiments and when stem cells are embedded into these scaffolds, the stem cells survive at very high rates.

The stem cell chosen for this experiment is a “mesoangioblast” (Mab). Mabs are stem cells found in the walls of large blood vessels that have the ability to differentiate into blood vessel cells and, under some conditions, muscle.  Why use Mabs for muscle regeneration rather than stem cells that give rise to muscle (myoblasts)? Several experiments have shown that Mabs overcome some of the problems associated with injecting myoblasts into muscle. When injected into muscle, myoblasts tend to not migrate very well, then many of them die and few of them get incorporated into muscle. Mabs, on the other hand, survive better and get incorporated into muscle at a much higher rate. Mabs have the ability to cross the endothelium and to migrate extensively in the space between blood vessels and muscles, where they are recruited by regenerating muscle to reconstitute new functional muscle fibers (See M. Sampaolesi, et al., Science 2003, 301(5632):487–492; M. Guttinger Exp Cell Res 2006, 312:3872–3879; & M. Sampaolesi, et al., Nature 2006, 444(7119):574–579).  These experiments show that mesoangioblasts can also form skeletal muscle.  A phase I/II clinical trial based on intraarterial delivery of donor-derived mesoangioblasts is currently ongoing in children affected by Duchene Muscular Dystrophy at the San Raffaele Hospital in Milan (EudraCT no. 2011-



When this team implanted PF scaffolds with embedded Mabs directly into the inflamed and sclerotic regions typical of the advanced states of muscular dystrophy, they observed high levels of Mab survival and engraftment. Five weeks after treatments, the mice treated with Mabs embedded into PF scaffolds showed much higher rates of integration into the muscle fibers than Mabs that were injected directly into the muscle. Also, Mabs that had been delivered into the muscle on PF scaffolds resulted in muscle that showed much better organization that muscle treated with direct injections of Mabs.

This study demonstrated that a novel tissue engineering approach can produce enriched donor cell engraftment into skeletal muscle after an acute injury or in those more difficult to treat cases of advanced muscular dystrophy.