Intrinsic ability of adult stem cell in skeletal muscle: an effective and replenishable resource to the establishment of pluripotent stem cells

Abstract

Adult stem cells play an essential role in mammalian organ maintenance and repair throughout adulthood since they ensure that organs retain their ability to regenerate. The choice of cell fate by adult stem cells for cellular proliferation, self-renewal, and differentiation into multiple lineages is critically important for the homeostasis and biological function of individual organs. Responses of stem cells to stress, injury, or environmental change are precisely regulated by intercellular and intracellular signaling networks, and these molecular events cooperatively define the ability of stem cell throughout life. Skeletal muscle tissue represents an abundant, accessible, and replenishable source of adult stem cells. Skeletal muscle contains myogenic satellite cells and muscle-derived stem cells that retain multipotent differentiation abilities. These stem cell populations have the capacity for long-term proliferation and high self-renewal. The molecular mechanisms associated with deficits in skeletal muscle and stem cell function have been extensively studied. Muscle-derived stem cells are an obvious, readily available cell resource that offers promise for cell-based therapy and various applications in the field of tissue engineering. This review describes the strategies commonly used to identify and functionally characterize adult stem cells, focusing especially on satellite cells, and discusses their potential applications.

Figure 1

The self-renewal, activation, and differentiation of satellite cells in adult skeletal muscle. Satellite cells reside adjacent to the plasma membrane under the basal lamina on the surface of the myofiber. The nuclei of myofiber (myonuclei) are positioned at the periphery of the cell. Satellite cells are activated upon receiving various external stimuli and differentiate together with the upregulation of MyoD. Quiescent and activated satellite cells express a characteristic marker, Pax7. Immunohistochemical detection of Pax7 (red), dystrophin (green) and DAPI (blue) of adult rat skeletal muscle is shown (left bottom).

Figure 2

Regulatory switch between quiescent and activated states of satellite cells. Notch and Wnt signaling antagonize each other to define the state of satellite cells. Upon binding of DSL ligands (Delta) to Notch receptor, released Notch intracellular domain (NICD) translocates to the nucleus. After associating with RBP-Jκ, the complex activates the transcription of target genes, such as Hes, Hey, and Pax7 to maintain satellite cells in quiescent state (left). When the “molecular switch” turns from the quiescent state to the activation state by Wnt proteins (right), the Wnt signal transduction activates β-catenin/TCF/LEF transcriptional complexes. The transcription complex triggers the expression of target MyoD gene and positively regulates myogenic differentiation.

Figure 3

Satellite cell-mediated muscle regeneration upon injury. Damaged muscle fiber induces activation of quiescent satellite cells that reside between the plasma membrane and basal lamina. Macrophages digest myofiber debris at the damaged site (phagocytosis). Satellite cells migrate and proliferate through symmetric and asymmetric divisions. During the process, various external signals promote the differentiation of satellite cells and their fusions to myotube.

Figure 4

Trans-differentiation of muscle-derived stem cells. Possible trans-differentiation pathways of muscle-derived stem cells. Satellite cells retain a high intrinsic ability for trans-differentiation into multiple lineages (cardiac muscle, skeletal muscle, hematopoietic cells, adipocytes, neurons, chondrocytes, and osteocytes).