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Muscle Stem Cells at a Glance ß 2014. Published by The Company of Biologists Ltd | Journal of Cell Science (2014) 127, 4543–4548 doi:10.1242/jcs.151209 CELL SCIENCE AT A GLANCE ARTICLE SERIES: STEM CELLS Muscle stem cells at a glance Yu Xin Wang1,2, Nicolas A. Dumont1,2 and Michael A. Rudnicki1,2,* ABSTRACT regulation of muscle stem cells has significant implications towards Muscle stem cells facilitate the long-term regenerative capacity of the development of pharmacological or cell-based therapies for skeletal muscle. This self-renewing population of satellite cells has muscle disorders. This Cell Science at a Glance article and only recently been defined through genetic and transplantation accompanying poster will review satellite cell characteristics and experiments. Although muscle stem cells remain in a dormant therapeutic potential, and provide an overview of the muscle stem quiescent state in uninjured muscle, they are poised to activate and cell hallmarks: quiescence, self-renewal and commitment. produce committed progeny. Unlike committed myogenic progenitor KEY WORDS: Regeneration, Satellite cells, Skeletal muscle, Stem cells, the self-renewal capacity gives muscle stem cells the ability to cells, Therapy engraft as satellite cells and capitulate long-term regeneration. Similar to other adult stem cells, understanding the molecular Introduction Skeletal muscle has the remarkable ability to regenerate from severe injuries. This regenerative capacity requires the activation 1Sprott Centre for Stem Cell Research, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada. 2Faculty of Medicine, Department of Cellular and and expansion of myogenic satellite cells (Wang and Rudnicki, Molecular Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada. 2012). Named for their relative anatomical position, satellite cells reside juxtaposed between a myofibre and its surrounding *Author for correspondence ([email protected]) extracellular matrix (Mauro, 1961). Various degenerative or This is an Open Access article distributed under the terms of the Creative Commons Attribution disease states affect the functional capacity of satellite cells and, License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed. consequently, impede muscle regeneration. Hence, research to Journal of Cell Science 4543 CELL SCIENCE AT A GLANCE Journal of Cell Science (2014) 127, 4543–4548 doi:10.1242/jcs.151209 understand satellite cell behaviour has gained significant interest (Pasut et al., 2012). Other groups have raised antibodies against in recent years. satellite-cell-specific antigens that are useful in isolating Since their discovery, satellite cells have been thought of as a quiescent or activated satellite cells (Fukada et al., 2004). strategic therapeutic target in treating acute muscle injuries and Interestingly, variable expression of different markers, such chronic diseases such as muscular dystrophies. Indeed, the ability as MYF5 and CD34, suggests the existence of different of satellite cells and their progeny to fuse into the myofibre subpopulations of satellite cells (Beauchamp et al., 2000). syncytium make them favourable vectors for delivering Indeed, it has been demonstrated that, in quiescent muscles, corrective gene therapy (Partridge et al., 1989). Unfortunately, ,10% of satellite cells have never expressed MYF5, and that these cell-based therapies for muscle disorders are currently hindered cells possess self-renewal potential and long-term engraftment by a lack of long-term engraftment. This has prompted the capacity (Kuang et al., 2007). These MYF52 satellite cells identification of specific sub-populations of satellite cells that are represent a stem cell subpopulation that can give rise to MYF5+- capable of self-renewal and engraftment as satellite cells in committed satellite cells through asymmetric division. transplantation, coining the terms muscle stem cells or satellite Accordingly, dye-dilution studies that examine cell cycle stem cells. Here, we discuss satellite cell characteristics by kinetics by using labelling with PKH26 or BrdU showed that, in providing an overview of the hallmarks of muscle stem cells, i.e. the activated state, satellite cells exhibit heterogeneous behaviour their quiescence, self-renewal capacity and lineage commitment. 2 with the majority of satellite cells undergoing fast division and We also highlight their therapeutic potential. the minority of cells undergoing slow division (Ono et al., 2012; Schultz, 1996). These slow-dividing satellite cells have long-term Finding muscle stem cells self-renewal ability and can divide asymmetrically 2 two The first engraftment assays were done by transplanting minced hallmarks of stem cell behaviour. Label retention experiments muscles 2 using H3-thymidine labelling or isoenzymes as by using BrdU confirmed that this subpopulation of satellite stem markers 2 into wild-type muscles (Partridge and Sloper, 1977; cells can maintain its original template DNA strands during cell Snow, 1978). These studies showed the formation of labelled division (Shinin et al., 2006). Consistently, a transgenic mouse regenerating myotubes in the host muscle, indicating that model showed that, during regeneration, satellite cells that myogenic cells can efficiently fuse to allogenic fibres (Partridge express higher levels of PAX7 (Pax7Hi) possess a lower et al., 1978). In vitro purification of satellite-cell-derived metabolic rate and higher self-renewal ability (Rocheteau et al., myoblasts followed by transplantation demonstrated that these 2012). The same authors demonstrated that, during division, cells are the sole contributors in the fusion with host myofibres Pax7Hi cells can segregate their chromosomes asymmetrically in (Lipton and Schultz, 1979). However, in vitro cultured myoblasts order to generate a distinct daughter cell, whereas cells with low have low engraftment efficiency and exclusively differentiate into PAX7 expression (Pax7Lo) segregate their DNA randomly. myofibres in transplants (Huard et al., 1992). Consequently, these Altogether, these results indicate that satellite cells are a engrafted myofibres are subject to tissue turnover and can only heterogeneous population that can be divided into two establish short-term engraftment. subpopulations: committed progenitor cells and muscle stem With better purification methods and labelling for stem-cell- cells. The latter can divide asymmetrically in order to give rise to specific markers, recent transplantation studies have revealed myogenic progenitors or can self-renew in order to maintain the sub-populations of freshly isolated satellite cells that can pool of satellite cells. However, intrinsic differences between recapitulate the satellite cell compartment of recipient muscles these subpopulations are still unclear and a practical marker to (Collins et al., 2005; Kuang et al., 2007; Rocheteau et al., 2012; distinguish the subpopulations of satellite stem cells is still Sacco et al., 2008). These engrafted satellite stem cells give rise missing. to committed myogenic cells while maintaining their stem cell identity through mechanisms of self-renewal. Importantly, The quiescent muscle stem cell transplanted bona fide muscle stem cells were preserved As other tissue-resident stem cells in the adult body, muscle stem through multiple rounds of injuries, which is a prerequisite for cells remain quiescent during healthy resting periods (Cheung a useful and long-term therapeutic approach (Sacco et al., 2008). and Rando, 2013). In this G0 state, quiescent stem cells have a low metabolism and are more resistant to DNA damage. The Muscle stem cell markers quiescent state is required for the long-term maintenance of Satellite cells can be identified by the specific expression of muscle stem cells. Loss of the capacity to remain quiescent certain proteins. Some markers are intracellular, such as the generally leads to the precocious differentiation and loss of transcription factors PAX7 and the nuclear membrane proteins satellite cells over time. Indeed, long-term labelling experiments lamin A/C (LMNA) and emerin (EMD). Other markers are using transgenic doxycyclin-inducible H2B-GFP mice revealed located at the cell membrane surface, such as syndecans 3 and 4 that, under normal conditions, a proportion of PAX7+-satellite (SDC3 and SDC4), muscle (M)-cadherin, calcitonin receptor cells can remain quiescent for most of the lifetime of the animal (CALCR), C-X-C chemokine receptor type 4 (CXCR4), calveolin and retain their full stem cell function despite changes in the 1 (CAV1), a7- and b1-integrins, neural cell adhesion molecule 1 muscle stem cell niche (Chakkalakal et al., 2012). (NCAM1), vascular cell adhesion molecule 1 (VCAM1) and Quiescence of muscle stem cells is maintained by the CD34 (Fukada et al., 2007; Gnocchi et al., 2009) (see poster). combination of transcriptional repression of key cell cycle Several laboratories have developed cell-sorting techniques to genes and high expression of cell cycle inhibitors. Notably, low prospectively isolate satellite cells from muscle tissue. Most expression levels of cyclins, cyclin-dependent kinases (CDKs) groups use a combination of positive selection for satellite cell and checkpoint kinases (CHKs) in quiescent satellite cells prevent surface markers, such as a7-integrin and CD34, and a negative cell cycle progression (Fukada et al., 2007). Additionally, the selection
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