Trends in Mesenchymal Stem Cells' Applications for Skeletal Muscle Repair and Regeneration

Abstract

Skeletal muscle injuries are quite frequent in traumatic scenarios, such as war injuries or road- or work-related accidents. The skeletal muscle has good regenerative ability, but the extent or recurrence of muscle injury might impair complete structural and functional recovery. Severe tissue loss overwhelms skeletal muscleŽs intrinsic regenerative capabilities and culminates in the development of noncontractile fibrous tissue scar. Conservative RICE -based and surgical treatments show limited efficacy in terms of improving these severe cases outcomes, pressing the need for new approaches on skeletal muscles therapy. Since the first suggestions of the potential of mesenchymal stem cells for regenerative medicine and tissue engineering, many applications have been explored for a variety of tissues and diseases, including the skeletal muscle, which is the focus of this literature review. Current research has focused on the influence of nonmuscular MSCs on promoting tissue healing and limiting fibrotic scar formation, as well as on the modulation of the inflammatory response to injury. The most popular source of MSCs is, without a doubt, the bone marrow. However, MSC populations are present in virtually all body tissues, and alternative sources have been proposed, such as the adipose tissue, synovial membrane, dental pulp, and even umbilical cord tissue. MSCs from various sources have been demonstrated as capable of in vitro differen tiation into myogenic lineages, through adequate stimuli, displaying phenotypical markers of native skeletal muscle cells. In addition, in vivo applications suggest they are capable of integrating host muscular tissues, even when delivered systemically.MSCs are capable of secreting a wide range of active molecules to their surrounding media, including growth factors, chemokines, and cytokines. Most of these growth factors have been associated to the skeletal muscles regenerative process, and their efficiency has been demonstrated to increase when applied in spatial and temporal coordination. Hence, the combination of molecules secreted by MSCs gained interest as modulator of inflammatory, fibrotic, and regenerating events. This has been proposed as possibly the primary mode of action of undifferentiated MSCs into a lesion site, providing controlled release of such components. Concurrently to the implantation of undifferentiated cells, it has also been hypothesized that the applica tion of secretion products alone (termed as Conditioned Medium) display similar if not improved effects on skeletal tissue regeneration, as it does in other damaged tissues.