An Overview About the Biology of Skeletal Muscle Satellite Cells

Author(s): Laura Forcina, Carmen Miano, Laura Pelosi, Antonio Musarò*.

Journal Name: Current Genomics

Volume 20 , Issue 1 , 2019

Become EABM
Become Reviewer

Graphical Abstract:


Abstract:

The peculiar ability of skeletal muscle tissue to operate adaptive changes during post-natal development and adulthood has been associated with the existence of adult somatic stem cells. Satellite cells, occupying an exclusive niche within the adult muscle tissue, are considered bona fide stem cells with both stem-like properties and myogenic activities. Indeed, satellite cells retain the capability to both maintain the quiescence in uninjured muscles and to be promptly activated in response to growth or regenerative signals, re-engaging the cell cycle. Activated cells can undergo myogenic differentiation or self-renewal moving back to the quiescent state. Satellite cells behavior and their fate decision are finely controlled by mechanisms involving both cell-autonomous and external stimuli. Alterations in these regulatory networks profoundly affect muscle homeostasis and the dynamic response to tissue damage, contributing to the decline of skeletal muscle that occurs under physio-pathologic conditions. Although the clear myogenic activity of satellite cells has been described and their pivotal role in muscle growth and regeneration has been reported, a comprehensive picture of inter-related mechanisms guiding muscle stem cell activity has still to be defined. Here, we reviewed the main regulatory networks determining satellite cell behavior. In particular, we focused on genetic and epigenetic mechanisms underlining satellite cell maintenance and commitment. Besides intrinsic regulations, we reported current evidences about the influence of environmental stimuli, derived from other cell populations within muscle tissue, on satellite cell biology.

Keywords: Skeletal muscle, Satellite cells, Regeneration, Muscle growth, Quiescence, Activation, Myogenic differentiation, Tissue niche.

[1]
Tajbakhsh, S.; Cossu, G. Establishing myogenic identity during somitogenesis. Curr. Opin. Genet. Dev., 1997, 7(5), 634-641.
[2]
Buckingham, M.; Bajard, L.; Chang, T.; Daubas, P.; Hadchouel, J.; Meilhac, S.; Montarras, D.; Rocancourt, D.; Relaix, F. The formation of skeletal muscle: from somite to limb. J. Anat., 2003, 202(1), 59-68.
[3]
Musumeci, G.; Castrogiovanni, P.; Coleman, R.; Szychlinska, M.A.; Salvatorelli, L.; Parenti, R.; Magro, G.; Imbesi, R. Somitogenesis: From somite to skeletal muscle. Acta Histochem., 2015, 117(4-5), 313-328.
[4]
Chargè, S.B.P.; Rudnicki, M.A. Cellular and molecular regulation of muscle regeneration. Physiol. Rev., 2004, 84(1), 209-238.
[5]
Kuang, S.; Kuroda, K.; Le Grand, F.; Rudnicki, M.A. Asymmetric self-renewal and commitment of satellite stem cells in muscle. Cell, 2007, 129(5), 999-1010.
[6]
Dumont, N.A.; Bentzinger, C.F.; Sincennes, M-C.; Rudnicki, M.A. Satellite cells and skeletal muscle regeneration. Compr. Physiol., 2015, 5(3), 1027-1059.
[7]
Feige, P.; Brun, C.E.; Ritso, M.; Rudnicki, M.A. Orienting muscle stem cells for regeneration in homeostasis, aging, and disease. Cell Stem Cell, 2018, 23(5), 653-664.
[8]
Mauro, A. Satellite cell of skeletal muscle fibers. J. Biophys. Biochem. Cytol., 1961, 9(2), 493-495.
[9]
Katz, B. The terminations of the afferent nerve fibre in the muscle spindle of the frog. Philos. Trans. R. Soc. London . B Biol. Sci., 1961, 243(703), 221-240.
[10]
Seale, P.; Sabourin, L.A.; Girgis-Gabardo, A.; Mansouri, A.; Gruss, P.; Rudnicki, M.A. Pax7 is required for the specification of myogenic satellite cells. Cell, 2000, 102(6), 777-786.
[11]
Relaix, F.; Montarras, D.; Zaffran, S.; Gayraud-Morel, B.; Rocancourt, D.; Tajbakhsh, S.; Mansouri, A.; Cumano, A.; Buckingham, M. Pax3 and Pax7 have distinct and overlapping functions in adult muscle progenitor cells. J. Cell Biol., 2006, 172(1), 91-102.
[12]
Mechtersheimer, G.; Staudter, M.; Möller, P. Expression of the natural killer cell-associated antigens CD56 and CD57 in human neural and striated muscle cells and in their tumors. Cancer Res., 1991, 51(4), 1300-1307.
[13]
Irintchev, A.; Zeschnigk, M.; Starzinski-Powitz, A.; Wernig, A. Expression pattern of M-cadherin in normal, denervated, and regenerating mouse muscles. Dev. Dyn., 1994, 199(4), 326-337.
[14]
Garry, D.J.; Yang, Q.; Bassel-Duby, R.; Williams, R.S. Persistent expression of MNF identifies myogenic stem cells in postnatal muscles. Dev. Biol., 1997, 188(2), 280-294.
[15]
Tatsumi, R.; Anderson, J.E.; Nevoret, C.J.; Halevy, O.; Allen, R.E. HGF/SF is present in normal adult skeletal muscle and is capable of activating satellite cells. Dev. Biol., 1998, 194(1), 114-128.
[16]
Jesse, T.L.; LaChance, R.; Iademarco, M.F.; Dean, D.C. Interferon regulatory factor-2 is a transcriptional activator in muscle where It regulates expression of vascular cell adhesion molecule-1. J. Cell Biol., 1998, 140(5), 1265-1276.
[17]
Beauchamp, J.R.; Heslop, L.; Yu, D.S.; Tajbakhsh, S.; Kelly, R.G.; Wernig, A.; Buckingham, M.E.; Partridge, T.A.; Zammit, P.S. Expression of CD34 and Myf5 defines the majority of quiescent adult skeletal muscle satellite cells. J. Cell Biol., 2000, 151(6), 1221-1234.
[18]
Cornelison, D.D.W.; Filla, M.S.; Stanley, H.M.; Rapraeger, A.C.; Olwin, B.B. Syndecan-3 and syndecan-4 specifically mark skeletal muscle satellite cells and are implicated in satellite cell maintenance and muscle regeneration. Dev. Biol., 2001, 239(1), 79-94.
[19]
Schmidt, K.; Glaser, G.; Wernig, A.; Wegner, M.; Rosorius, O. Sox8 is a specific marker for muscle satellite cells and inhibits myogenesis. J. Biol. Chem., 2003, 278(32), 29769-29775.
[20]
Lee, H-J.; Göring, W.; Ochs, M.; Mühlfeld, C.; Steding, G.; Paprotta, I.; Engel, W.; Adham, I.M. Sox15 is required for skeletal muscle regeneration. Mol. Cell. Biol., 2004, 24(19), 8428-8436.
[21]
Sherwood, R.I.; Christensen, J.L.; Conboy, I.M.; Conboy, M.J.; Rando, T.A.; Weissman, I.L.; Wagers, A.J. Isolation of adult mouse myogenic progenitors. Cell, 2004, 119(4), 543-554.
[22]
Volonte, D.; Liu, Y.; Galbiati, F. The modulation of caveolin-1 expression controls satellite cell activation during muscle repair. FASEB J., 2005, 19(2), 237-239.
[23]
Fukada, S.; Uezumi, A.; Ikemoto, M.; Masuda, S.; Segawa, M.; Tanimura, N.; Yamamoto, H.; Miyagoe-Suzuki, Y.; Takeda, S. Molecular signature of quiescent satellite cells in adult skeletal muscle. Stem Cells, 2007, 25(10), 2448-2459.
[24]
Gnocchi, V.F.; White, R.B.; Ono, Y.; Ellis, J.A.; Zammit, P.S. Further characterisation of the molecular signature of quiescent and activated mouse muscle satellite cells. PLoS One, 2009, 4(4), e5205.
[25]
Fukada, S-i.; Yamaguchi, M.; Kokubo, H.; Ogawa, R.; Uezumi, A.; Yoneda, T.; Matev, M.M.; Motohashi, N.; Ito, T.; Zolkiewska, A.; Johnson, R.L.; Saga, Y.; Miyagoe-Suzuki, Y.; Tsujikawa, K.; Takeda, S.; Yamamoto, H. Hesr1 and Hesr3 are essential to generate undifferentiated quiescent satellite cells and to maintain satellite cell numbers. Development, 2011, 138(21), 4609-4619.
[26]
Dumont, N.A.; Wang, Y.X.; von Maltzahn, J.; Pasut, A.; Bentzinger, C.F.; Brun, C.E.; Rudnicki, M.A. Dystrophin expression in muscle stem cells regulates their polarity and asymmetric division. Nat. Med., 2015, 21(12), 1455-1463.
[27]
Bischoff, R.; Heintz, C. Enhancement of skeletal muscle regeneration. Dev. Dyn., 1994, 201(1), 41-54.
[28]
Blaauw, B.; Reggiani, C. The role of satellite cells in muscle hypertrophy. J. Muscle Res. Cell Motil., 2014, 35(1), 3-10.
[29]
Murach, K.A.; Englund, D.A.; Dupont-Versteegden, E.E.; McCarthy, J.J.; Peterson, C.A. Myonuclear domain flexibility challenges rigid assumptions on satellite cell contribution to skeletal muscle fiber hypertrophy. Front. Physiol., 2018, 9, 635.
[30]
Fry, C.S.; Lee, J.D.; Jackson, J.R.; Kirby, T.J.; Stasko, S.A.; Liu, H.; Dupont-Versteegden, E.E.; McCarthy, J.J.; Peterson, C.A. Regulation of the muscle fiber microenvironment by activated satellite cells during hypertrophy. FASEB J., 2014, 28(4), 1654-1665.
[31]
McCarthy, J.J.; Mula, J.; Miyazaki, M.; Erfani, R.; Garrison, K.; Farooqui, A.B.; Srikuea, R.; Lawson, B.A.; Grimes, B.; Keller, C.; Van Zant, G.; Campbell, K.S.; Esser, K.A.; Dupont-Versteegden, E.E.; Peterson, C.A. Effective fiber hypertrophy in satellite cell-depleted skeletal muscle. Development, 2011, 138(17), 3657-3666.
[32]
Murach, K.A.; White, S.H.; Wen, Y.; Ho, A.; Dupont-Versteegden, E.E.; McCarthy, J.J.; Peterson, C.A. Differential requirement for satellite cells during overload-induced muscle hypertrophy in growing versus mature mice. Skelet. Muscle, 2017, 7(1), 14.
[33]
Lee, J.D.; Fry, C.S.; Mula, J.; Kirby, T.J.; Jackson, J.R.; Liu, F.; Yang, L.; Dupont-Versteegden, E.E.; McCarthy, J.J.; Peterson, C.A. Aged muscle demonstrates fiber-type adaptations in response to mechanical overload, in the absence of myofiber hypertrophy, independent of satellite cell abundance. J. Gerontol.Ser A Biol. Sci. Med. Sci., 2016, 71(4), 461-467.
[34]
Shefer, G.; Van de Mark, D.P.; Richardson, J.B.; Yablonka-Reuveni, Z. Satellite-cell pool size does matter: Defining the myogenic potency of aging skeletal muscle. Dev. Biol., 2006, 294(1), 50-66.
[35]
Scicchitano, B.M.; Sica, G.; Musarò, A. Stem Cells and Tissue Niche: Two Faces of the Same Coin of Muscle Regeneration. Eur. J. Transl. Myol., 2016, 26(4), 6125.
[36]
Barberi, L.; Scicchitano, B.M.; De Rossi, M.; Bigot, A.; Duguez, S.; Wielgosik, A.; Stewart, C.; McPhee, J.; Conte, M.; Narici, M.; Franceschi, C.; Mouly, V.; Butler-Browne, G.; Musarò, A. Age-dependent alteration in muscle regeneration: the critical role of tissue niche. Biogerontology, 2013, 14(3), 273-292.
[37]
Bischoff, R. Interaction between satellite cells and skeletal muscle fibers. Development, 1990, 109(4), 943-952.
[38]
Xu, X.; Wilschut, K.J.; Kouklis, G.; Tian, H.; Hesse, R.; Garland, C.; Sbitany, H.; Hansen, S.; Seth, R.; Knott, P.D.; Hoffman, W.Y.; Pomerantz, J.H. Human satellite cell transplantation and regeneration from diverse skeletal muscles. Stem Cell Rep, 2015, 5(3), 419-434.
[39]
Murphy, M.M.; Lawson, J.A.; Mathew, S.J.; Hutcheson, D.A.; Kardon, G. Satellite cells, connective tissue fibroblasts and their interactions are crucial for muscle regeneration. Development, 2011, 138(17), 3625-3637.
[40]
Boonsanay, V.; Zhang, T.; Georgieva, A.; Kostin, S.; Qi, H.; Yuan, X.; Zhou, Y.; Braun, T. Regulation of skeletal muscle stem cell quiescence by Suv4-20h1-dependent facultative heterochromatin formation. Cell Stem Cell, 2016, 18(2), 229-242.
[41]
Yamaguchi, M.; Watanabe, Y.; Ohtani, T.; Uezumi, A.; Mikami, N.; Nakamura, M.; Sato, T.; Ikawa, M.; Hoshino, M.; Tsuchida, K.; Miyagoe-Suzuki, Y.; Tsujikawa, K.; Takeda, S.; Yamamoto, H.; Fukada, S. Calcitonin receptor signaling inhibits muscle stem cells from escaping the quiescent state and the niche. Cell Rep, 2015, 13(2), 302-314.
[42]
Quarta, M.; Brett, J.O.; DiMarco, R.; De Morree, A.; Boutet, S.C.; Chacon, R.; Gibbons, M.C.; Garcia, V.A.; Su, J.; Shrager, J.B.; Heilshorn, S.; Rando, T.A. An artificial niche preserves the quiescence of muscle stem cells and enhances their therapeutic efficacy. Nat. Biotechnol., 2016, 34(7), 752-759.
[43]
Sato, T.; Yamamoto, T.; Sehara-Fujisawa, A. miR-195/497 induce postnatal quiescence of skeletal muscle stem cells. Nat. Commun., 2014, 5(1), 4597.
[44]
Cheung, T.H.; Quach, N.L.; Charville, G.W.; Liu, L.; Park, L.; Edalati, A.; Yoo, B.; Hoang, P.; Rando, T.A. Maintenance of muscle stem-cell quiescence by microRNA-489. Nature, 2012, 482(7386), 524-528.
[45]
Westholm, J.O.; Lai, E.C. Mirtrons: microRNA biogenesis via splicing. Biochimie, 2011, 93(11), 1897-1904.
[46]
Baghdadi, M.B.; Firmino, J.; Soni, K.; Evano, B.; Di Girolamo, D.; Mourikis, P.; Castel, D.; Tajbakhsh, S. Notch-Induced miR-708 Antagonizes satellite cell migration and maintains quiescence. Cell Stem Cell, 2018, 23, 1-10.
[47]
Scharner, J.; Zammit, P.S. The muscle satellite cell at 50: the formative years. Skelet. Muscle, 2011, 1(1), 28.
[48]
Creuzet, S.; Lescaudron, L.; Li, Z.; Fontaine-Pérus, J.; Myo, D. Myogenin, and Desmin-nls-lacZ Transgene emphasize the distinct patterns of satellite cell activation in growth and regeneration. Exp. Cell Res., 1998, 243(2), 241-253.
[49]
Yablonka-Reuveni, Z.; Rivera, A.J. Temporal expression of regulatory and structural muscle proteins during myogenesis of satellite cells on isolated adult rat fibers. Dev. Biol., 1994, 164(2), 588-603.
[50]
van Velthoven, C.T.J.; de Morree, A.; Egner, I.M.; Brett, J.O.; Rando, T.A. Transcriptional profiling of quiescent muscle stem cells in vivo. Cell Rep, 2017, 21(7), 1994-2004.
[51]
Fu, X.; Wang, H.; Hu, P. Stem cell activation in skeletal muscle regeneration. Cell. Mol. Life Sci., 2015, 72(9), 1663-1677.
[52]
Zhang, K.; Sha, J.; Harter, M.L. Activation of Cdc6 by MyoD is associated with the expansion of quiescent myogenic satellite cells. J. Cell Biol., 2010, 188(1), 39-48.
[53]
Relaix, F.; Zammit, P.S. Satellite cells are essential for skeletal muscle regeneration: the cell on the edge returns centre stage. Development, 2012, 139(16), 2845-2856.
[54]
Chang, N.C.; Sincennes, M-C.; Chevalier, F.P.; Brun, C.E.; Lacaria, M.; Segalés, J.; Muñoz-Cánoves, P.; Ming, H.; Rudnicki, M.A. The dystrophin glycoprotein complex regulates the epigenetic activation of muscle stem cell commitment. Cell Stem Cell, 2018, 22(5), 755-768.
[55]
Palacios, D.; Mozzetta, C.; Consalvi, S.; Caretti, G.; Saccone, V.; Proserpio, V.; Marquez, V.E.; Valente, S.; Mai, A.; Forcales, S.V.; Sartorelli, V.; Puri, P.L. TNF/p38α/polycomb signaling to Pax7 locus in satellite cells links inflammation to the epigenetic control of muscle regeneration. Cell Stem Cell, 2010, 7(4), 455-469.
[56]
Mozzetta, C.; Consalvi, S.; Saccone, V.; Forcales, S.V.; Puri, P.L.; Palacios, D. Selective control of Pax7 expression by TNF-activated p38α/polycomb repressive complex 2 (PRC2) signaling during muscle satellite cell differentiation. Cell Cycle, 2011, 10(2), 191-198.
[57]
Ding, S.; Swennen, G.N.M.; Messmer, T.; Gagliardi, M.; Molin, D.G.M.; Li, C.; Zhou, G.; Post, M.J. Maintaining bovine satellite cells stemness through p38 pathway. Sci. Rep., 2018, 8(1), 10808.
[58]
Chen, J-F.; Mandel, E.M.; Thomson, J.M.; Wu, Q.; Callis, T.E.; Hammond, S.M.; Conlon, F.L.; Wang, D-Z. The role of microRNA-1 and microRNA-133 in skeletal muscle proliferation and differentiation. Nat. Genet., 2006, 38(2), 228-233.
[59]
Kim, H.K.; Lee, Y.S.; Sivaprasad, U.; Malhotra, A.; Dutta, A. Muscle-specific microRNA miR-206 promotes muscle differentiation. J. Cell Biol., 2006, 174(5), 677-687.
[60]
Baghdadi, M.B.; Castel, D.; Machado, L.; Fukada, S.; Birk, D.E.; Relaix, F.; Tajbakhsh, S.; Mourikis, P. Reciprocal signalling by Notch-Collagen V-CALCR retains muscle stem cells in their niche. Nature, 2018, 557(7707), 714-718.
[61]
Fujimaki, S.; Seko, D.; Kitajima, Y.; Yoshioka, K.; Tsuchiya, Y.; Masuda, S.; Ono, Y. Notch1 and Notch2 coordinately regulate stem cell function in the quiescent and activated states of muscle satellite cells. Stem Cells, 2018, 36(2), 278-285.
[62]
Chen, Z.; Bu, N.; Qiao, X.; Zuo, Z.; Shu, Y.; Liu, Z.; Qian, Z.; Chen, J.; Hou, Y. Forkhead box M1 transcriptionally regulates the expression of long noncoding RNAs Snhg8 and Gm26917 to promote proliferation and survival of muscle satellite cells. Stem Cells, 2018, 36(7), 1097-1108.
[63]
Yan, Z.; Choi, S.; Liu, X.; Zhang, M.; Schageman, J.J.; Lee, S.Y.; Hart, R.; Lin, L.; Thurmond, F.A.; Williams, R.S. Highly coordinated gene regulation in mouse skeletal muscle regeneration. J. Biol. Chem., 2003, 278(10), 8826-8836.
[64]
Musarò, A. The basis of muscle regeneration. Adv. Biol., 2014, 1-16.
[65]
Halevy, O.; Novitch, B.G.; Spicer, D.B.; Skapek, S.X.; Rhee, J.; Hannon, G.J.; Beach, D.; Lassar, A.B. Correlation of terminal cell cycle arrest of skeletal muscle with induction of p21 by MyoD. Science, 1995, 267(5200), 1018-1021.
[66]
Dey, B.K.; Gagan, J.; Dutta, A. miR-206 and -486 induce myoblast differentiation by downregulating Pax7. Mol. Cell. Biol., 2011, 31(1), 203-214.
[67]
Yu, X.; Zhang, Y.; Li, T.; Ma, Z.; Jia, H.; Chen, Q.; Zhao, Y.; Zhai, L.; Zhong, R.; Li, C.; Zou, X.; Meng, J.; Chen, A.K.; Puri, P.L.; Chen, M.; Zhu, D. Long non-coding RNA Linc-RAM enhances myogenic differentiation by interacting with MyoD. Nat. Commun., 2017, 8, 14016.
[68]
Hernández-Hernández, J.M.; García-González, E.G.; Brun, C.E.; Rudnicki, M.A. The myogenic regulatory factors, determinants of muscle development, cell identity and regeneration. Semin. Cell Dev. Biol., 2017, 72, 10-18.
[69]
Teixeira, C.F.P.; Chaves, F.; Zamunér, S.R.; Fernandes, C.M.; Zuliani, J.P.; Cruz-Hofling, M.A.; Fernandes, I.; Gutiérrez, J.M. Effects of neutrophil depletion in the local pathological alterations and muscle regeneration in mice injected with Bothrops jararaca snake venom. Int. J. Exp. Pathol., 2005, 86(2), 107-115.
[70]
Huang, W-C.; Sala-Newby, G.B.; Susana, A.; Johnson, J.L.; Newby, A.C. Classical macrophage activation up-regulates several matrix metalloproteinases through mitogen activated protein kinases and nuclear factor-κB. PLoS One, 2012, 7(8), e42507.
[71]
Chen, S-E.; Jin, B.; Li, Y-P. TNF-alpha regulates myogenesis and muscle regeneration by activating p38 MAPK. Am. J. Physiol. Cell Physiol., 2007, 292(5), C1660-C1671.
[72]
Peterson, J.M.; Bakkar, N.; Guttridge, D.C. NF-κB signaling in skeletal muscle health and disease. Curr. Top. Dev. Biol., 2011, 96, 85-119.
[73]
Muñoz-Cánoves, P.; Scheele, C.; Pedersen, B.K.; Serrano, A.L. Interleukin-6 myokine signaling in skeletal muscle: a double-edged sword? FEBS J., 2013, 280(17), 4131-4148.
[74]
Deng, B.; Wehling-Henricks, M.; Villalta, S.A.; Wang, Y.; Tidball, J.G. IL-10 triggers changes in macrophage phenotype that promote muscle growth and regeneration. J. Immunol., 2012, 189(7), 3669-3680.
[75]
Arnold, L.; Henry, A.; Poron, F.; Baba-Amer, Y.; van Rooijen, N.; Plonquet, A.; Gherardi, R.K.; Chazaud, B. Inflammatory monocytes recruited after skeletal muscle injury switch into antiinflammatory macrophages to support myogenesis. J. Exp. Med., 2007, 204(5), 1057-1069.
[76]
Ruffell, D.; Mourkioti, F.; Gambardella, A.; Kirstetter, P.; Lopez, R.G.; Rosenthal, N.; Nerlov, C.A. CREB-C/EBPbeta cascade induces M2 macrophage-specific gene expression and promotes muscle injury repair. Proc. Natl. Acad. Sci. USA, 2009, 106(41), 17475-17480.
[77]
Liu, X.; Liu, Y.; Zhao, L.; Zeng, Z.; Xiao, W.; Chen, P. Macrophage depletion impairs skeletal muscle regeneration: The roles of regulatory factors for muscle regeneration. Cell Biol. Int., 2017, 41(3), 228-238.
[78]
Engert, J.C.; Berglund, E.B.; Rosenthal, N. Proliferation precedes differentiation in IGF-I-stimulated myogenesis. J. Cell Biol., 1996, 135(2), 431-440.
[79]
Musarò, A.; Rosenthal, N. Maturation of the myogenic program is induced by postmitotic expression of insulin-like growth factor I. Mol. Cell. Biol., 1999, 19(4), 3115-3124.
[80]
Tonkin, J.; Temmerman, L.; Sampson, R.D.; Gallego-Colon, E.; Barberi, L.; Bilbao, D.; Schneider, M.D.; Musarò, A.; Rosenthal, N. Monocyte/Macrophage-derived IGF-1 Orchestrates murine skeletal muscle regeneration and modulates autocrine polarization. Mol. Ther., 2015, 23(7), 1189-1200.
[81]
Zhang, C.; Li, Y.; Wu, Y.; Wang, L.; Wang, X.; Du, J. Interleukin-6/STAT3 pathway is essential for macrophage infiltration and myoblast proliferation during muscle regeneration. J. Biol. Chem., 2013, 288(3), 1489-1499.
[82]
Forcina, L.; Miano, C.; Musarò, A. The physiopathologic interplay between stem cells and tissue niche in muscle regeneration and the role of IL-6 on muscle homeostasis and diseases. Cytokine Growth Factor Rev., 2018, 41, 1-9.
[83]
Serrano, A.L.; Baeza-Raja, B.; Perdiguero, E.; Jardí, M.; Muñoz-Cánoves, P. Interleukin-6 Is an essential regulator of satellite cell-mediated skeletal muscle hypertrophy. Cell Metab., 2008, 7(1), 33-44.
[84]
Joe, A.W.B.; Yi, L.; Natarajan, A.; Le Grand, F.; So, L.; Wang, J.; Rudnicki, M.A.; Rossi, F.M.V. Muscle injury activates resident fibro/adipogenic progenitors that facilitate myogenesis. Nat. Cell Biol., 2010, 12(2), 153-163.
[85]
Formicola, L.; Marazzi, G.; Sassoon, D.A. The extraocular muscle stem cell niche is resistant to ageing and disease. Front. Aging Neurosci., 2014, 6, 328.
[86]
Uezumi, A.; Fukada, S.; Yamamoto, N.; Takeda, S.; Tsuchida, K. Mesenchymal progenitors distinct from satellite cells contribute to ectopic fat cell formation in skeletal muscle. Nat. Cell Biol., 2010, 12(2), 143-152.
[87]
Lemos, D.R.; Babaeijandaghi, F.; Low, M.; Chang, C-K.; Lee, S.T.; Fiore, D.; Zhang, R-H.; Natarajan, A.; Nedospasov, S.A.; Rossi, F.M.V. Nilotinib reduces muscle fibrosis in chronic muscle injury by promoting TNF-mediated apoptosis of fibro/adipogenic progenitors. Nat. Med., 2015, 21(7), 786-794.
[88]
Shin, J.; McFarland, D.C.; Velleman, S.G. Heparan sulfate proteoglycans, syndecan-4 and glypican-1, differentially regulate myogenic regulatory transcription factors and paired box 7 expression during turkey satellite cell myogenesis: Implications for muscle growth. Poult. Sci., 2012, 91(1), 201-207.
[89]
Harthan, L.B.; McFarland, D.C.; Velleman, S.G. The effect of syndecan-4 and glypican-1 expression on age-related changes in myogenic satellite cell proliferation, differentiation, and fibroblast growth factor 2 responsiveness. Comp. Biochem. Physiol.Part A Mol. Integr. Physiol., 2013, 166(4), 590-602.
[90]
Yin, H.; Price, F.; Rudnicki, M.A. Satellite cells and the muscle stem cell niche. Physiol. Rev., 2013, 93(1), 23-67.
[91]
Fiore, D.; Judson, R.N.; Low, M.; Lee, S.; Zhang, E.; Hopkins, C.; Xu, P.; Lenzi, A.; Rossi, F.M.V.; Lemos, D.R. Pharmacological blockage of fibro/adipogenic progenitor expansion and suppression of regenerative fibrogenesis is associated with impaired skeletal muscle regeneration. Stem Cell Res. , 2016, 17(1), 161-169.
[92]
Urciuolo, A.; Quarta, M.; Morbidoni, V.; Gattazzo, F.; Molon, S.; Grumati, P.; Montemurro, F.; Tedesco, F.S.; Blaauw, B.; Cossu, G.; Vozzi, G.; Rando, T.A.; Bonaldo, P. Collagen VI regulates satellite cell self-renewal and muscle regeneration. Nat. Commun., 2013, 4(1), 1964.
[93]
Hardy, D.; Besnard, A.; Latil, M.; Jouvion, G.; Briand, D.; Thépenier, C.; Pascal, Q.; Guguin, A.; Gayraud-Morel, B.; Cavaillon, J-M.; Tajbakhsh, S.; Rocheteau, P.; Chrétien, F. Comparative study of injury models for studying muscle regeneration in mice. PLoS One, 2016, 11(1), e0147198.
[94]
Latroche, C.; Weiss-Gayet, M.; Muller, L.; Gitiaux, C.; Leblanc, P.; Liot, S.; Ben-Larbi, S.; Abou-Khalil, R.; Verger, N.; Bardot, P.; Magnan, M.; Chrétien, F.; Mounier, R.; Germain, S.; Chazaud, B. Coupling between myogenesis and angiogenesis during skeletal muscle regeneration is stimulated by restorative macrophages. Stem Cell Rep, 2017, 9(6), 2018-2033.
[95]
Qahar, M.; Takuma, Y.; Mizunoya, W.; Tatsumi, R.; Ikeuchi, Y.; Nakamura, M. Semaphorin 3A promotes activation of Pax7, Myf5, and MyoD through inhibition of emerin expression in activated satellite cells. FEBS Open Bio, 2016, 6(6), 529-539.
[96]
Tatsumi, R.; Sankoda, Y.; Anderson, J.E.; Sato, Y.; Mizunoya, W.; Shimizu, N.; Suzuki, T.; Yamada, M.; Rhoads, R.P.; Ikeuchi, Y.; Allen, R.E.; Furuse, M.; Ikcuchi, Y.; Nishimura, T.; Yagi, T. Possible implication of satellite cells in regenerative motoneuritogenesis: HGF upregulates neural chemorepellent Sema3A during myogenic differentiation. Am. J. Physiol., 2009, 297(2), C238-C252.
[97]
Tatsumi, R.; Suzuki, T.; Do, M.Q.; Ohya, Y.; Anderson, J.E.; Shibata, A.; Kawaguchi, M.; Ohya, S.; Ohtsubo, H.; Mizunoya, W.; Sawano, S.; Komiya, Y.; Ichitsubo, R.; Ojima, K.; Nishimatsu, S.I.; Nohno, T.; Ohsawa, Y.; Sunada, Y.; Nakamura, M.; Furuse, M.; Ikeuchi, Y.; Nishimura, T.; Yagi, T.; Allen, R.E. Slow-myofiber commitment by semaphorin 3A secreted from myogenic stem cells. Stem Cells, 2017, 35(7), 1815-1834.
[98]
De Angelis, L.; Berghella, L.; Coletta, M.; Lattanzi, L.; Zanchi, M.; Cusella-De Angelis, M.G.; Ponzetto, C.; Cossu, G. Skeletal myogenic progenitors originating from embryonic dorsal aorta coexpress endothelial and myogenic markers and contribute to postnatal muscle growth and regeneration. J. Cell Biol., 1999, 147(4), 869-878.
[99]
Tamaki, T.; Akatsuka, A.; Ando, K.; Nakamura, Y.; Matsuzawa, H.; Hotta, T.; Roy, R.R.; Edgerton, V.R. Identification of myogenic-endothelial progenitor cells in the interstitial spaces of skeletal muscle. J. Cell Biol., 2002, 157(4), 571-577.
[100]
Polesskaya, A.; Seale, P.; Rudnicki, M.A. Wnt signaling induces the myogenic specification of resident CD45+ adult stem cells during muscle regeneration. Cell, 2003, 113(7), 841-852.
[101]
Kuang, S.; Chargé, S.B.; Seale, P.; Huh, M.; Rudnicki, M.A. Distinct roles for Pax7 and Pax3 in adult regenerative myogenesis. J. Cell Biol., 2006, 172(1), 103-113.
[102]
Minasi, M.G.; Riminucci, M.; De Angelis, L.; Borello, U.; Berarducci, B.; Innocenzi, A.; Caprioli, A.; Sirabella, D.; Baiocchi, M.; De Maria, R.; Boratto, R.; Jaffredo, T.; Broccoli, V.; Bianco, P.; Cossu, G. The meso-angioblast: a multipotent, self-renewing cell that originates from the dorsal aorta and differentiates into most mesodermal tissues. Development, 2002, 129(11), 2773-2783.
[103]
Tonlorenzi, R.; Dellavalle, A.; Schnapp, E.; Cossu, G.; Sampaolesi, M. Isolation and characterization of mesoangioblasts from mouse, dog, and human tissues. Curr. Protoc. Stem Cell Biol., 2007, 2, 2B.1..
[104]
Gussoni, E.; Soneoka, Y.; Strickland, C.D.; Buzney, E.A.; Khan, M.K.; Flint, A.F.; Kunkel, L.M.; Mulligan, R.C. Dystrophin expression in the mdx mouse restored by stem cell transplantation. Nature, 1999, 401(6751), 390-394.
[105]
Asakura, A.; Rudnicki, M.A. Side population cells from diverse adult tissues are capable of in vitro hematopoietic differentiation. Exp. Hematol., 2002, 30(11), 1339-1345.
[106]
Torrente, Y.; Belicchi, M.; Sampaolesi, M.; Pisati, F.; Meregalli, M.; D’Antona, G.; Tonlorenzi, R.; Porretti, L.; Gavina, M.; Mamchaoui, K.; Pellegrino, M.A.; Furling, D.; Mouly, V.; Butler-Browne, G.S.; Bottinelli, R.; Cossu, G.; Bresolin, N. Human circulating AC133+ stem cells restore dystrophin expression and ameliorate function in dystrophic skeletal muscle. J. Clin. Invest., 2004, 114(2), 182-195.
[107]
Meeson, A.P.; Hawke, T.J.; Graham, S.; Jiang, N.; Elterman, J.; Hutcheson, K.; DiMaio, J.M.; Gallardo, T.D.; Garry, D.J. Cellular and molecular regulation of skeletal muscle side population cells. Stem Cells, 2004, 22(7), 1305-1320.
[108]
Montanaro, F.; Liadaki, K.; Schienda, J.; Flint, A.; Gussoni, E.; Kunkel, L.M. Demystifying SP cell purification: viability, yield, and phenotype are defined by isolation parameters. Exp. Cell Res., 2004, 298(1), 144-154.
[109]
Rivier, F.; Alkan, O.; Flint, A.F.; Muskiewicz, K.; Allen, P.D.; Leboulch, P.; Gussoni, E. Role of bone marrow cell trafficking in replenishing skeletal muscle SP and MP cell populations. J. Cell Sci., 2004, 117(10), 1979-1988.
[110]
Tanaka, K.K.; Hall, J.K.; Troy, A.A.; Cornelison, D.D.W.; Majka, S.M.; Olwin, B.B. Syndecan-4-expressing muscle progenitor cells in the SP engraft as satellite cells during muscle regeneration. Cell Stem Cell, 2009, 4(3), 217-225.
[111]
Sancricca, C.; Mirabella, M.; Gliubizzi, C.; Broccolini, A.; Gidaro, T.; Morosetti, R. Vessel-associated stem cells from skeletal muscle: From biology to future uses in cell therapy. World J. Stem Cells, 2010, 2(3), 39.
[112]
Quattrocelli, M.; Palazzolo, G.; Perini, I.; Crippa, S.; Cassano, M.; Sampaolesi, M. Mouse and human mesoangioblasts: Isolation and characterization from adult skeletal muscles. Methods Mol. Biol., 2012, 798, 65-76.
[113]
Sampaolesi, M.; Torrente, Y.; Innocenzi, A.; Tonlorenzi, R.; D’Antona, G.; Pellegrino, M.A.; Barresi, R.; Bresolin, N.; De Angelis, M.G.C.; Campbell, K.P.; Bottinelli, R.; Cossu, G. Cell therapy of -sarcoglycan null dystrophic mice through intra-arterial delivery of mesoangioblasts. Science, 2003, 301(5632), 487-492.
[114]
Sampaolesi, M.; Blot, S.; D’Antona, G.; Granger, N.; Tonlorenzi, R.; Innocenzi, A.; Mognol, P.; Thibaud, J-L.; Galvez, B.G.; Barthélémy, I.; Perani, L.; Mantero, S.; Guttinger, M.; Pansarasa, O.; Rinaldi, C.; Cusella De Angelis, M.G.; Torrente, Y.; Bordignon, C.; Bottinelli, R.; Cossu, G. Mesoangioblast stem cells ameliorate muscle function in dystrophic dogs. Nature, 2006, 444(7119), 574-579.
[115]
Cossu, G.; Previtali, S.C.; Napolitano, S.; Cicalese, M.P.; Tedesco, F.S.; Nicastro, F.; Noviello, M.; Roostalu, U.; Natali Sora, M.G.; Scarlato, M.; De Pellegrin, M.; Godi, C.; Giuliani, S.; Ciotti, F.; Tonlorenzi, R.; Lorenzetti, I.; Rivellini, C.; Benedetti, S.; Gatti, R.; Marktel, S.; Mazzi, B.; Tettamanti, A.; Ragazzi, M.; Imro, M.A.; Marano, G.; Ambrosi, A.; Fiori, R.; Sormani, M.P.; Bonini, C.; Venturini, M.; Politi, L.S.; Torrente, Y.; Ciceri, F. Intra-arterial transplantation of HLA-matched donor mesoangioblasts in Duchenne muscular dystrophy. EMBO Mol. Med., 2015, 7(12), 1513-1528.
[116]
Dellavalle, A.; Sampaolesi, M.; Tonlorenzi, R.; Tagliafico, E.; Sacchetti, B.; Perani, L.; Innocenzi, A.; Galvez, B.G.; Messina, G.; Morosetti, R.; Li, S.; Belicchi, M.; Peretti, G.; Chamberlain, J.S.; Wright, W.E.; Torrente, Y.; Ferrari, S.; Bianco, P.; Cossu, G. Pericytes of human skeletal muscle are myogenic precursors distinct from satellite cells. Nat. Cell Biol., 2007, 9(3), 255-267.
[117]
Dellavalle, A.; Maroli, G.; Covarello, D.; Azzoni, E.; Innocenzi, A.; Perani, L.; Antonini, S.; Sambasivan, R.; Brunelli, S.; Tajbakhsh, S.; Cossu, G. Pericytes resident in postnatal skeletal muscle differentiate into muscle fibres and generate satellite cells. Nat. Commun., 2011, 2(1), 499.
[118]
Crisan, M.; Yap, S.; Casteilla, L.; Chen, C-W.; Corselli, M.; Park, T.S.; Andriolo, G.; Sun, B.; Zheng, B.; Zhang, L.; Norotte, C.; Teng, P-N.; Traas, J.; Schugar, R.; Deasy, B.M.; Badylak, S.; Bűhring, H-J.; Giacobino, J-P.; Lazzari, L.; Huard, J.; Péault, B. A perivascular origin for mesenchymal stem cells in multiple human organs. Cell Stem Cell, 2008, 3(3), 301-313.
[119]
Birbrair, A.; Zhang, T.; Wang, Z-M.; Messi, M.L.; Enikolopov, G.N.; Mintz, A.; Delbono, O. Role of pericytes in skeletal muscle regeneration and fat accumulation. Stem Cells Dev., 2013, 22(16), 2298-2314.
[120]
Scicchitano, B.M.; Dobrowolny, G.; Sica, G.; Musaro, A. Molecular insights into muscle homeostasis, atrophy and wasting. Curr. Genomics, 2018, 19(5), 356-369.
[121]
Scicchitano, B.M.; Pelosi, L.; Sica, G.; Musarò, A. The physiopathologic role of oxidative stress in skeletal muscle. Mech. Ageing Dev., 2018, 170, 37-44.
[122]
Franco, I.; Johansson, A.; Olsson, K.; Vrtačnik, P.; Lundin, P.; Helgadottir, H.T.; Larsson, M.; Revêchon, G.; Bosia, C.; Pagnani, A.; Provero, P.; Gustafsson, T.; Fischer, H.; Eriksson, M. Somatic mutagenesis in satellite cells associates with human skeletal muscle aging. Nat. Commun., 2018, 9(1), 800.
[123]
Hayflick, L. The limited in vitro lifetime of human diploid cell strains. Exp. Cell Res., 1965, 37(3), 614-636.
[124]
George, T.; Velloso, C.P.; Alsharidah, M.; Lazarus, N.R.; Harridge, S.D.R. Sera from young and older humans equally sustain proliferation and differentiation of human myoblasts. Exp. Gerontol., 2010, 45(11), 875-881.
[125]
Hikida, R.S. Aging changes in satellite cells and their functions. Curr. Aging Sci., 2011, 4(3), 279-297.
[126]
Tichy, E.D.; Sidibe, D.K.; Tierney, M.T.; Stec, M.J.; Sharifi-Sanjani, M.; Hosalkar, H.; Mubarak, S.; Johnson, F.B.; Sacco, A.; Mourkioti, F. Single stem cell imaging and analysis reveals telomere length differences in diseased human and mouse skeletal muscles. Stem Cell Reports, 2017, 9(4), 1328-1341.
[127]
Decary, S.; Hamida, C.B.; Mouly, V.; Barbet, J.P.; Hentati, F.; Butler-Browne, G.S. Shorter telomeres in dystrophic muscle consistent with extensive regeneration in young children. Neuromuscul. Disord., 2000, 10(2), 113-120.
[128]
Pelosi, L.; Berardinelli, M.G.; Forcina, L.; Spelta, E.; Rizzuto, E.; Nicoletti, C.; Camilli, C.; Testa, E.; Catizone, A.; De Benedetti, F.; Musarò, A. Increased levels of interleukin-6 exacerbate the dystrophic phenotype in mdx mice. Hum. Mol. Genet., 2015, 24(21), 6041-6053.
[129]
Bernet, J.D.; Doles, J.D.; Hall, J.K.; Kelly Tanaka, K.; Carter, T.A.; Olwin, B.B. p38 MAPK signaling underlies a cell-autonomous loss of stem cell self-renewal in skeletal muscle of aged mice. Nat. Med., 2014, 20(3), 265-271.
[130]
Price, F.D.; von Maltzahn, J.; Bentzinger, C.F.; Dumont, N.A.; Yin, H.; Chang, N.C.; Wilson, D.H.; Frenette, J.; Rudnicki, M.A. Inhibition of JAK-STAT signaling stimulates adult satellite cell function. Nat. Med., 2014, 20(10), 1174-1181.
[131]
Sousa-Victor, P.; Gutarra, S.; García-Prat, L.; Rodriguez-Ubreva, J.; Ortet, L.; Ruiz-Bonilla, V.; Jardí, M.; Ballestar, E.; González, S.; Serrano, A.L.; Perdiguero, E.; Muñoz-Cánoves, P. Geriatric muscle stem cells switch reversible quiescence into senescence. Nature, 2014, 506(7488), 316-321.
[132]
Carlson, B.M.; Faulkner, J.A. Muscle transplantation between young and old rats: age of host determines recovery. Am. J. Physiol., 1989, 256(6 Pt 1), C1262-C1266.
[133]
Carlson, B.M.; Dedkov, E.I.; Borisov, A.B.; Faulkner, J.A. Skeletal muscle regeneration in very old rats. J. Gerontol. A Biol. Sci. Med. Sci., 2001, 56(5), B224-B233.
[134]
Conboy, I.M.; Conboy, M.J.; Wagers, A.J.; Girma, E.R.; Weissman, I.L.; Rando, T.A. Rejuvenation of aged progenitor cells by exposure to a young systemic environment. Nature, 2005, 433(7027), 760-764.
[135]
Daynes, R.A.; Araneo, B.A.; Ershler, W.B.; Maloney, C.; Li, G.Z.; Ryu, S.Y. Altered regulation of IL-6 production with normal aging. Possible linkage to the age-associated decline in dehydroepiandrosterone and its sulfated derivative. J. Immunol., 1993, 150(12), 5219-5230.
[136]
Paliwal, P.; Pishesha, N.; Wijaya, D.; Conboy, I.M. Age dependent increase in the levels of osteopontin inhibits skeletal muscle regeneration. Aging (Albany N.Y.), 2012, 4(8), 553-566.
[137]
McKay, B.R.; Ogborn, D.I.; Baker, J.M.; Toth, K.G.; Tarnopolsky, M.A.; Parise, G. Elevated SOCS3 and altered IL-6 signaling is associated with age-related human muscle stem cell dysfunction. Am. J. Physiol. Cell Physiol., 2013, 304(8), C717-C728.
[138]
Barbieri, M.; Ferrucci, L.; Ragno, E.; Corsi, A.; Bandinelli, S.; Bonafè, M.; Olivieri, F.; Giovagnetti, S.; Franceschi, C.; Guralnik, J.M.; Paolisso, G. Chronic inflammation and the effect of IGF-I on muscle strength and power in older persons. Am. J. Physiol. Endocrinol. Metab., 2003, 284(3), E481-E487.
[139]
Hirata, A.; Masuda, S.; Tamura, T.; Kai, K.; Ojima, K.; Fukase, A.; Motoyoshi, K.; Kamakura, K.; Miyagoe-Suzuki, Y.; Takeda, S. Expression profiling of cytokines and related genes in regenerating skeletal muscle after cardiotoxin injection. Am. J. Pathol., 2003, 163(1), 203-215.
[140]
Uaesoontrachoon, K.; Yoo, H-J.; Tudor, E.M.; Pike, R.N.; Mackie, E.J.; Pagel, C.N. Osteopontin and skeletal muscle myoblasts: Association with muscle regeneration and regulation of myoblast function in vitro. Int. J. Biochem. Cell Biol., 2008, 40(10), 2303-2314.
[141]
Vetrone, S.A.; Montecino-Rodriguez, E.; Kudryashova, E.; Kramerova, I.; Hoffman, E.P.; Liu, S.D.; Miceli, M.C.; Spencer, M.J. Osteopontin promotes fibrosis in dystrophic mouse muscle by modulating immune cell subsets and intramuscular TGF-beta. J. Clin. Invest., 2009, 119(6), 1583-1594.
[142]
Kuswanto, W.; Burzyn, D.; Panduro, M.; Wang, K.K.; Jang, Y.C.; Wagers, A.J.; Benoist, C.; Mathis, D. Poor repair of skeletal muscle in aging mice reflects a defect in local, interleukin-33-dependent accumulation of regulatory T cells. Immunity, 2016, 44(2), 355-367.
[143]
Uezumi, A.; Fukada, S.; Yamamoto, N.; Takeda, S.; Tsuchida, K. Mesenchymal progenitors distinct from satellite cells contribute to ectopic fat cell formation in skeletal muscle. Nat. Cell Biol., 2010, 12(2), 143-152.
[144]
Uezumi, A.; Ito, T.; Morikawa, D.; Shimizu, N.; Yoneda, T.; Segawa, M.; Yamaguchi, M.; Ogawa, R.; Matev, M.M.; Miyagoe-Suzuki, Y.; Takeda, S.; Tsujikawa, K.; Tsuchida, K.; Yamamoto, H.; Fukada, S-i. Fibrosis and adipogenesis originate from a common mesenchymal progenitor in skeletal muscle. J. Cell Sci., 2011, 124(21), 3654-3664.
[145]
Pelosi, L.; Coggi, A.; Forcina, L.; Musarò, A. MicroRNAs modulated by local mIGF-1 expression in mdx dystrophic mice. Front. Aging Neurosci., 2015, 7, 69.
[146]
Barton, E.R.; Morris, L.; Musaro, A.; Rosenthal, N.; Sweeney, H.L. Muscle-specific expression of insulin-like growth factor I counters muscle decline in mdx mice. J. Cell Biol., 2002, 157(1), 137-148.
[147]
Petrillo, S.; Pelosi, L.; Piemonte, F.; Travaglini, L.; Forcina, L.; Catteruccia, M.; Petrini, S.; Verardo, M.; D’Amico, A.; Musarò, A.; Bertini, E. Oxidative stress in Duchenne muscular dystrophy: focus on the NRF2 redox pathway. Hum. Mol. Genet., 2017, 26(14), 2781-2790.
[148]
Pelosi, L.; Forcina, L.; Nicoletti, C.; Scicchitano, B.M.; Musarò, A. Increased circulating levels of interleukin-6 induce perturbation in redox-regulated signaling cascades in muscle of dystrophic mice. Oxid. Med. Cell. Longev., 2017, 2017, 1-10.
[149]
Forcina, L.; Pelosi, L.; Miano, C.; Musarò, A.; Forcina, L.; Pelosi, L.; Miano, C.; Musarò, A. Insights into the pathogenic secondary symptoms caused by the primary loss of dystrophin. J. Funct. Morphol. Kinesiol., 2017, 2(4), 44.
[150]
Pelosi, L.; Berardinelli, M.G.; De Pasquale, L.; Nicoletti, C.; D’Amico, A.; Carvello, F.; Moneta, G.M.; Catizone, A.; Bertini, E.; De Benedetti, F.; Musarò, A. Functional and morphological improvement of dystrophic muscle by interleukin 6 receptor blockade. EBioMed, 2015, 2(4), 285-293.


Rights & PermissionsPrintExport Cite as


Article Details

VOLUME: 20
ISSUE: 1
Year: 2019
Page: [24 - 37]
Pages: 14
DOI: 10.2174/1389202920666190116094736
Price: $58

Article Metrics

PDF: 38
HTML: 5
EPUB: 1
PRC: 1