The Effects of Adipose-Derived Stem Cells on Denervated Rat Skeletal Muscle Atrophy

Denervation is a physiological or pathological response to nerve damage due to congenital anomalies, peripheral nerve injuries, disuse, or iatrogenic procedures. Botulinum toxin A (BoNT-A) has been widely used as an adjunct to managing spasticity in patients with upper motor neuron syndrome and aesthetic purposes. BoNT-A denervates muscle by temporarily and reversibly inhibiting the release of acetylcholine at the neuromuscular junction (NMJ) for a period of less than 6 months. Stem cells (adipose-derived stem cells (ADSCs) or satellite cells) simultaneously execute self-renewal and multipotent differentiation. Our previous researches have not only developed a novel surgical techniques for calf hypertrophy, but also clarified the following facts: (1) There are some irreversible changes on the BoNT-A injection muscle, including muscle surface complexities and integrin alpha-7 expressions; (2) Apoptosis-inducing factor (AIF) makes a major difference from the neurectomy in the view of the biochemical signaling pathways; (3) The molecular expression pattern shows a biphasic and coherent pattern: initial increase with a peak at post-injection 4 weeks, then declines; (4) The integrin alpha-7 expression is highly correlated with the surface complexities of muscle. (5) Repeated liposuction (injury) diminishes the stemness of ADSCs, not the fibrosis. Thus, this injury area is not suitable for donor site selection of ADSCs. In this project, we hope to provide a practical cell therapy of denervation muscle atrophy, which can further strengthen the importance of above two issues. In-vitro cell co-cultures will be introduced to establish the relations between muscle and stem cells, especially molecular expressions (e.g., AIF). Subsequently, in-vivo animal studies verify the effects of two stem cells via different routes (direct muscle injection or tail veins). To our knowledge, there are rare studies focused on this issue. The project will have a great potential for the clinical application in the field of denervation injury and stem cells.