Mononucleated Cells to Regenerate Skeletal Muscle Syncytial Tissues

Abstract

Skeletal muscle is one of the most plastic tissues of vertebrates since it may able upon exercises to double in size due to a physiological hypertrophy. Despite the fact that it is mainly a syncytial tissue, it contains a relevant number of mononucleated cells that can be involved in its homeostasis and repair. Although the mononuclear cell types with the highest myogenic potential are the satellite cells located underneath the basal lamina of muscle fibres, other interstitial cells have been shown to contribute to muscle regeneration.Adding complexity to this scenario is the fact that several authors revealed myogenic potential in pluripotent stem cells, which can be generated from patient somatic cells and eventually manipulated to correct the genetic defect.Notwithstanding the copiousness of myogenic cell types, their use in ex vivo cell therapies for muscular degenerative diseases is still questionable. However, new discovers on their biological properties have advanced our comprehension in handling myogenic stem cells significantly.In this review, we will focus on the myogenic potential of multi-and pluri-potent stem cells and their use in preclinical and clinical studies. New insights from direct reprogramming and epigenetic signalling to generate myogenic stem cells are also considered. Keywords: Stem cells; Skeletal muscle; Regenerative medicine Mimicking Human Muscle PathologyMuscular dystrophies (MDs) are a group of muscle diseases that affect the musculoskeletal system and locomotion [1][2][3][4][5]. MDs are characterized by defects in muscle proteins, determining progressive death of muscle cells and tissue [2,3]. There are several forms of MDs, including the Duchenne muscular dystrophy (DMD), the Becker muscular dystrophy (BMD) and some forms of limb-girdle muscular dystrophy (LGMD).DMD is the most severe syndrome and it is caused by mutations in the dystrophin gene located on the human X chromosome, with an inheritance pattern of 3 cases per 10000 live male births [5][6][7]. Satellite cells are localized underneath the basal lamina of terminally differentiated muscle fibres and in response to injury, they proliferate, fuse and give rise to regenerated muscle. Unfortunately, genetic mutations responsible for DMD are also present in satellite cells. Hence, the ability to restore normal muscle function remains obstructed. In DMD patients a small number of muscle fibres are able to produce functional dystrophin, mostly due to secondary mutations in myogenic precursor cells, which restore the reading frame [8,9]. However, these so-called revertant fibres are in a too small minority to alleviate the pathology of the dystrophin-deficiency. Exhaustion of the satellite cell pool due to degeneration and regeneration cycles is thought to critically contribute to the disease [10,11].BMD is also caused by mutations in the dystrophin gene, but myofibrils retain a truncated and low-active form of the dystrophin protein, consequently the symptoms appear with a later, and much slower rate of progression [12...