In vivo generation of a mature and functional artificial skeletal muscle

Abstract

Extensive loss of skeletal muscle tissue results in mutilations and severe loss of function. In vitro-generated artificial muscles undergo necrosis when transplanted in vivo before host angiogenesis may provide oxygen for fibre survival. Here, we report a novel strategy based upon the use of mouse or human mesoangioblasts encapsulated inside PEG-fibrinogen hydrogel. Once engineered to express placental-derived growth factor, mesoangioblasts attract host vessels and nerves, contributing to in vivo survival and maturation of newly formed myofibres. When the graft was implanted underneath the skin on the surface of the tibialis anterior, mature and aligned myofibres formed within several weeks as a complete and functional extra muscle. Moreover, replacing the ablated tibialis anterior with PEG-fibrinogen-embedded mesoangioblasts also resulted in an artificial muscle very similar to a normal tibialis anterior. This strategy opens the possibility for patient-specific muscle creation for a large number of pathological conditions involving muscle tissue wasting.

Biomaterials for skeletal muscle tissue engineering

“…In vivo , these systems have been shown to enhance the contractile function of severely injured muscle tissue when myoblasts were co-delivered with IGF-1 to promote myogenesis and VEGF to promote angiogenesis [33,34]. The importance of concurrently promoting angiogenesis with cell delivery was also shown using delivery of mesoangioblasts expressing placental-derived growth factor (PIGF) inside a PEG-fibrinogen hydrogel; the expression of PIGF led to the formation of new blood vessels and nerves within the newly formed myofibers that were used to replace ablated muscle tissue [35]. In the absence of cues to actively promote angiogenesis, it has been demonstrated that cells delivered progressively in thin fibrin gel layers to a site of volumetric muscle loss allows for host angiogenesis in each new layer, enhancing the survival of the new tissue [36].…”

Hydrogel biomaterials and their therapeutic potential for muscle injuries and muscular dystrophies

“…However, other applications that can potentially be applied more readily have been found, including tissue analogues that can be used for predicting the effect of new experimental drugs in models displaying muscular disorders. Furthermore, some studies employing biomaterial-based strategies have shed light upon the integration and function of regenerating muscle associated with the support of accelerated angiogenic and neurogenic responses [68,73].…”

“…One such hydrogel is the PEGfibrinogen (PF), a photopolymerizable hydrogel, which enables the controlled and localized gelation when seeded with a cell suspension [118], both in vitro and also in vivo, particularly within a damaged muscle [65]. This semi-synthetic hydrogel has shown to support skeletal muscle survival, growth and maturation [68]. These materials are capable of supporting cell growth and undergoing proteolytic degradation via their biological domains while still providing robust mechanical properties emanating from their synthetic components [106].…”

The mesmiRizing complexity of microRNAs for striated muscle tissue engineering

“…The implant was able to mature into artificial, functional skeletal muscle fibers in mice. Importantly, the cells were engineered to overexpress placental-derived growth factor, and the implant was successful with both murine and human mesoangioblasts [52]. With regard to the heart, myogenic mesoangioblasts [53] or pericytes [54] have been recently isolated also from the cardiac muscle, although their bench-to-bedside progression appears slower as compared to aforementioned cell systems.…”