Human Muscle Stem Cells and the Effect of Aging

The skeletal muscle tissue is able of maintaining its mass during adulthood thanks to the role played by myogenic precursors, activated under certain stimuli. In the adult skeletal muscle, the primary role to perform this process is due to Satellite Cells (SCs), a population of quiescent and undifferentiated cells that start the mitotic process in the form of myoblasts, fuse with each other or with pre-existing fibers and differentiate as myotubes in response to specific stimuli such as fiber damage or muscle tension increase or in conditions of chronic inflammation [1]. Blau defined the Muscle Stem Cells (MuSCs) as the satellite cells that reside in anatomically defined niches within muscle tissues [2]. In particular, it has been observed that the stimuli that alter the quiescent niche and contribute to SC activation include degenerative diseases (such as muscular dystrophy), denervation, injury to myofibers and exercise [3]. Also during aging changes occur in the key niche elements, the myofibers and the basal lamina that are in intimate contact with satellite cells. These elements are influenced by factors secreted by interstitial cells, immune system cells, and cells associated with the vasculature, all of which change with age [4]. Senescence goes along with a less effective regeneration of skeletal muscle tissue mainly due to the decreased myogenic capability of satellite cells, in part because of the niche aging and partly due to the intrinsic aging of the satellite cell. This occurrence impedes proper maintenance and contributes to the age-associated decline in muscle mass, known as sarcopenia. The myogenic potential impairment depends mainly on the difficulty of SCs to complete a differentiation program [5]. The activated SCs can lose the expression of myogenic markers or eventually leave the cell cycle showing that they are a heterogeneous mixture of stem cells and committed progenitors. The muscle has a different composition of myogenic cell pool due to individual variety but above all of the stimuli, environmental conditions and age. Apart from SCs, other stem/progenitor cells such as Mesenchymal Stem Cells (MSCs), interstitial stem cells called PICs (PW1+/PAX7-interstitial cells), together with fibro/adipogenic progenitors/ mesenchymal stem cells, muscle side population cells (Sca-1+ and CD45+) and pericytes, actively participate in the muscle regeneration process, if properly addressed [6,7]. As among MSCs Muscle Derived Stem Cells (MDSCs) have been included, expressing CD13 and to a lesser extent CD10 and CD56 as well as the lack of hematopoietic marker expression, including CD45 [8]. These cells were considered mesenchymal stem cells for their ability to differentiate into the mesodermal phenotypes. In a recent paper the authors indentify the muscle-derived stem cells, termining MuStem cells. These cells reside in human skeletal muscle and display a long-term ability to proliferate, allowing generation of a clinically relevant amount of cells. Cultured Human MuStem (hMuStem) cells do not express hematopoietic, endothelial or myo-endothelial cell markers and reproducibly correspond to a population of early myogenic-committed progenitors with a perivascular/ mesenchymal phenotypic signature, revealing a blood vessel wall origin. Importantly, they exhibit both myogenesis in vitro and skeletal muscle regeneration after intramuscular delivery into immunodeficient host mice [9]. These populations act as myogenic precursors but are able to generate also other tissue types [10]. The characterization and/or identification of myogenic stem cells utilizing specific surface markers may also depend on the method of isolation, as reported in a review Burdzinska et al. [11]. It is also noteworthy that there is considerable plasticity of myogenic stem cells. Whereas cell precursors of muscle tissue can give rise to adipogenic or osteogenic cells, various types of stem cells [such as those deriving from bone marrow, blood vessels (mesoangioblasts) or circulating blood (AC133+)] may give rise to skeletal muscle through two different mechanisms: via the direct fusion of newly formed fibers (if this is an active or passive process) and/or occupying the niche of resident stem cells (like satellite cells) [12]. The SC are difficult to isolate, and it is improbable to identify a single marker discriminating quiescent satellite cells from proliferating myogenic precursor cells, because several markers may only identify specific subpopulations of satellite cells or stage of satellite cell activation [13,14]. Together more markers help to understand what stage the cells stay. Some markers characterize specific subpopulations of SCs, but in literature there are controversial results. CD34 is considered one of muscle markers most represented, but Stefania Fulle*