Satellite cells and the muscle stem cell niche

Abstract

Adult skeletal muscle in mammals is a stable tissue under normal circumstances but has remarkable ability to repair after injury. Skeletal muscle regeneration is a highly orchestrated process involving the activation of various cellular and molecular responses. As skeletal muscle stem cells, satellite cells play an indispensible role in this process. The self-renewing proliferation of satellite cells not only maintains the stem cell population but also provides numerous myogenic cells, which proliferate, differentiate, fuse, and lead to new myofiber formation and reconstitution of a functional contractile apparatus. The complex behavior of satellite cells during skeletal muscle regeneration is tightly regulated through the dynamic interplay between intrinsic factors within satellite cells and extrinsic factors constituting the muscle stem cell niche/microenvironment. For the last half century, the advance of molecular biology, cell biology, and genetics has greatly improved our understanding of skeletal muscle biology. Here, we review some recent advances, with focuses on functions of satellite cells and their niche during the process of skeletal muscle regeneration.

Figure 1.

Characteristics of the satellite cell. A: numerous proteins are expressed in satellite cells and have been used as markers to distinguish between surrounding cell types within skeletal muscle. Due to heterogeneity in satellite cell populations, it is unlikely that all of these markers are expressed in a given satellite cell at a specific time. Nevertheless, this panel summarizes the cellular location of markers used to identify satellite cells. B: the satellite cell population is heterogeneous and can be classified in a hierarchical manner based on function and gene expression. Evidence from lineage tracing experiments identified a subpopulation of satellite cells having never expressed the myogenic transcription factor Myf5 (satellite stem cells) are placed hierarchically above satellite cells that have expressed Myf5 at some point during development (satellite myogenic cells). Satellite stem cells, upon asymmetric division (typically in a apical-basal orientation), will give rise to two daughter cells, only one of which has activated Myf5. Functional differences in regenerative potential exist between satellite stem cells and satellite myogenic cells. Following transplantation, satellite stem cells preferentially repopulate the satellite cell niche and contribute to long-term muscle regeneration. In contrast, satellite myogenic cells preferentially differentiate upon transplantation in vivo.

Figure 2.

Satellite cell activation, differentiation, and fusion. The myogenic program is orchestrated by key transcription factors that dictate the progression from quiescence, activation, proliferation, and differentiation/self-renewal of satellite cells. This results in the transformation of individual satellite cells into a syncytial contractile myofiber. Initially satellite cells are mitotically quiescent (G₀ phase) and reside in a sublaminar niche. Quiescent satellite cells are characterized by their expression of Pax7 and Myf5 but not MyoD or Myogenin. Damage to the environment surrounding satellite cells results in the deterioration of the basal lamina and their exit from the quiescent state (satellite cell activation). Proliferating satellite cells and their progeny are often referred to as myogenic precursor cells (MPC) or adult myoblasts. Adult myoblasts express the myogenic transcription factors MyoD and Myf5. Following proliferation, adult myoblasts begin differentiation by downregulating Pax7. The initiation of terminal differentiation and fusion begins with the expression of Myogenin, which in concert with MyoD will activate muscle specific structural and contractile genes. During regeneration, activated satellite cells have the capability to return to quiescence to maintain the satellite cell pool. This ability is critical for long-term muscle integrity.

Figure 3.

The satellite cell niche. A: satellite cells reside between the basal lamina and the sarcolemma of adult skeletal myofibers and as such are influenced by structural and biochemical cues emanating from this microenvironment. A complex set of diffusible molecules (e.g., Wnt, IGF, and FGF) are exchanged between the satellite cell and the myofiber to maintain quiescence or promote activation. In addition, numerous extracellular matrix components and cellular receptors are present either on the surface of the sarcolemma, satellite cell, or contained within the basal lamina. These components comprise the immediate niche of the satellite cell and dictate rapid changes in the satellite cell state. B: the muscle fascicle defines the extremities of the local milieu an environment that is more diverse compared with the immediate niche due to the heterogeneity of cell types and signaling factors. The local milieu surrounding the satellite cell is made up of other myofibers in addition to interstitial cells, capillaries, and neuromuscular junctions. Each of these cell types influences the surrounding environment and thereby affects the state of the satellite cell. C: the systemic milieu contains the greatest diversity with which the satellite cell is influenced. Exposure of satellite cells to the host's immune system, and circulating hormones along with the skeleton and surrounding skeletal muscles present the broadest environment for the satellite cell. Changes that occur in the systemic milieu affect the satellite cell gradually. Prolonged exposure of signals from the systemic milieu plays an important role in the ability of satellite cells to participate in multiple rounds of regeneration.