Skeletal muscle stem cells in comfort and stress

Abstract

Investigations on developmental and regenerative myogenesis have led to major advances in decrypting stem cell properties and potential, as well as their interactions within the evolving niche. As a consequence, regenerative myogenesis has provided a forum to investigate intrinsic regulators of stem cell properties as well as extrinsic factors, including stromal cells, during normal growth and following injury and disease. Here we review some of the latest advances in the field that have exposed fundamental processes including regulation of stress following trauma and ageing, senescence, DNA damage control and modes of symmetric and asymmetric cell divisions. Recent studies have begun to explore the nature of the niche that is distinct in different muscle groups, and that is altered from prenatal to postnatal stages, and during ageing. We also discuss heterogeneities among muscle stem cells and how distinct properties within the quiescent and proliferating cell states might impact on homoeostasis and regeneration. Interestingly, cellular quiescence, which was thought to be a passive cell state, is regulated by multiple mechanisms, many of which are deregulated in various contexts including ageing. These and other factors including metabolic activity and genetic background can impact on the efficiency of muscle regeneration.

Fig. 1

The satellite cell and stromal cell niche. Satellite cells states are regulated through their interactions with their microenvironment. While direct interactions (M-cadherin, Notch pathway)^, and communication (FGF2-FGFR1 pathway) between muscle fibres and satellite cells have been identified, muscle stem cells also interact with a variety of components of the extracellular matrix (e.g. Collagens VI and V, Laminin, Fibronectin, SDC3/4)^, and diffusable cytokines and growth factors (e.g. Angiopoietin-Tie2 receptor). In addition to satellite cells, several cell types contribute to muscle growth, homoeostasis and regeneration, including pericytes, mesenchymal stromal cells (e.g. Pw1+ Interstitial Cells, FibroAdipogenic Progenitors, Twist2+ cells)^,,, immune cells (e.g. resident or infiltrating macrophages) as well as connective tissue cells. These interactions are remodelled during ageing, notably with increased FGF2 production from muscle fibres and decreased expression of FGFR1 in satellite cells, driving satellite cells to break quiescence, and decreased levels of fibronectin, which weakens satellite cell adhesion capacity and increases their susceptibility to apoptosis by anoikis

Fig. 2

Developmental, adult, ageing and diseased skeletal muscle niches. During development and regeneration, stromal and myogenics cells can be in direct contact, and myogenic cells can be exposed to stromal-derived extracellular matrix proteins, whereas in the late foetal to postnatal stages, muscles stem cells are separated from stromal cells by a basement membrane (from mid-foetal stages)^,. Stromal cells have distinct embryonic origins depending on their anatomical location—those in the head are of neural crest and mesoderm origin, whereas those in the limbs are mostly of mesodermal origin. In addition to this spatial character, niche cells evolve during development and postnatal life thereby introducing a temporal dimension to the regulation of muscle stem cells as they give rise to quiescent satellite cells and age. The postnatal niche is disrupted following chronic (e.g. myopathies) and acute (chemical, physical) injury. In the former, there is an asynchronous response of infiltrate and in the latter, more phasic appearance and disappearance of neutrophils and macrophages is noted

Fig. 3

Quiescence to proliferation transition in satellite cells. a During homoeostasis, adult satellite cells are maintained in a reversible non-proliferating quiescent G0 state by regulators including Calcitonin receptor, Collagen V, Notch pathway, FGF signalling and effectors of the RNAi machinery^,,,,. However, specific quiescence markers are still lacking. Satellite cells within a healthy tissue respond to a distant injury by transiting from deep quiescence to a quiescent G0/G1 or ‘G(alert)’ state, with increased proliferative capacity and regenerative potential. This transition is under the control of mammalian target of rapamycin (mTOR) signalling, which in turns controls mitochondrial metabolism (see text). Following an acute tissue injury or chronic mild degeneration of muscle fibres, satellite cells exit from their quiescent state and proliferate. This transition is accompanied by a metabolic shift from fatty acid oxidation to glycolysis. Some cells irreversibly exit the cell cycle to differentiate into mononuclear myocytes that eventually fuse to regenerate muscle fibres, while others self-renew and return to quiescence. Entry into quiescence is poorly characterised, and an activation marker is MYOD. b Isolation of adult quiescent satellite cells involves repeated mechanical and enzymatic dissociation of the tissue. These procedures invariably lead to satellite cell activation, as shown by the rapid upregulation of FOS and JUN, and phosphorylation of p38

Fig. 4

Cellular senescence in different contexts. Although senescence has been extensively reported in pathological contexts^–, recent studies have reported that cellular senescence is associated with developmental and regenerative processes, suggesting a beneficial role^,–. Senescence observed during muscle regeneration was not altered on a p53-null background, however, Numb:Numblike mutants that exhibit a higher level, and persistent cell senescence during regeneration, are rescued on a p53-null background and with antioxidants suggesting that senescence can be modulated differentially in this mutant compared to wild-type mice

Fig. 5

Models for regulation of satellite cells during regeneration. a Deterministic model (top), where PAX7^Hi cells retain this state through proliferation and return to the quiescent state. Here PAX7^Lo cells would derive from PAX7^Hi quiescent and proliferating cells and would be poised for commitment. This hierarchical model suggests intrinsic mechanisms as driving forces for maintenance of these relative states and would result in vulnerability if only a subset of the cells in the population have long-term stem-like properties. In the stochastic model (bottom), PAX7^Hi and PAX7^Lo cells are interchangeable states, presumably due to fluctuations in gene expression, and obedience to extrinsic signals. This model proposes that all satellite cells have the potential to assume a stem-like or committed state. b Satellite cells undergo rounds of exit and entry into the niche to assume a quiescent state, and during ageing, exit from the niche is suggested to occur more frequently without replenishment, thereby resulting in declining numbers of muscle stem cells. We entertain the possibility that re-entry into the niche could reset or rejuvenate the stem cell and endow it with properties for long-term persistence