During development, cardiac and skeletal muscle share major transcription factors and sarcomere proteins which were generally regarded as specific to either cardiac or skeletal muscle but not both in terminally differentiated adult cardiac or skeletal muscle. Here, we investigated whether artificial muscle constructed from human skeletal muscle derived stem cells (MDSCs) recapitulates developmental similarities between cardiac and skeletal muscle. We constructed 3-dimensional collagen-based engineered muscle tissue (EMT) using MDSCs (MDSC-EMT) and compared the biochemical and contractile properties with EMT using induced pluripotent stem (iPS) cell-derived cardiac cells (iPS-EMT). Both MDSC-EMT and iPS-EMT expressed cardiac specific troponins, fast skeletal muscle myosin heavy chain, and connexin-43 mimicking developing cardiac or skeletal muscle. At the transcriptional level, MDSC-EMT and iPS-EMT upregulated both cardiac and skeletal muscle-specific genes and expressed Nkx2.5 and Myo-D proteins. MDSC-EMT displayed intracellular calcium ion transients and responses to isoproterenol. Contractile force measurements of MDSC-EMT demonstrated functional properties of immature cardiac and skeletal muscle in both tissues. Results suggest that the EMT from MDSCs mimics developing cardiac and skeletal muscle and can serve as a useful in vitro functioning striated muscle model for investigation of stem cell differentiation and therapeutic options of MDSCs for cardiac repair. 1. Introduction The adult heart is largely a nonregenerative organ. Although cardiomyocytes (CMs), the contractile cells of the heart, have a modest rate of turnover, ranging from 1% in youth to less than 0.5% in old age [1], this level is not enough to compensate for the large number of cardiomyocytes which are lost as a result of heart injury. Combined with the fact that heart disease is the leading cause of death in the United States [2], this has prompted the search for novel therapies to replace damaged myocardium. Muscle derived stem cells (MDSCs) and induced pluripotent (iPS) stem cells are among the types of stem cells under investigation for cardiac repair. MDSCs are a multipotent, somatic stem cell which can be obtained from skeletal muscle via a modified preplate method [3]. MDSCs can be rapidly expanded in vitro to obtain clinically relevant numbers of cells, which can be transplanted as an autologous graft. They are also advantageous because they are resistant to hypoxia, attenuate fibrosis, and readily differentiate into contractile cells [4]. We previously showed that rodent
References
[1]
O. Bergmann, R. D. Bhardwaj, S. Bernard et al., “Evidence for cardiomyocyte renewal in humans,” Science, vol. 324, no. 5923, pp. 98–102, 2009.
[2]
A. S. Go, D. Mozaffarian, V. L. Roger et al., “Heart disease and stroke statistics—2013 update: a report from the American heart association,” Circulation, vol. 127, no. 1, pp. e6–e245, 2013.
[3]
M. Lavasani, A. Lu, S. D. Thompson, P. D. Robbins, J. Huard, and L. J. Niedernhofer, “Isolation of muscle-derived stem/progenitor cells based on adhesion characteristics to collagen-coated surfaces,” Methods in Molecular Biology, vol. 976, pp. 53–65, 2013.
[4]
A. Usas, J. Ma？iulaitis, R. Ma？iulaitis, N. Jakuboniene, A. Mila？ius, and J. Huard, “Skeletal muscle-derived stem cells: implications for cell-mediated therapies,” Medicina, vol. 47, no. 9, pp. 469–479, 2011.
[5]
K. C. Clause, J. P. Tinney, L. J. Liu et al., “A three-dimensional gel bioreactor for assessment of cardiomyocyte induction in skeletal muscle-derived stem cells,” Tissue Engineering C, vol. 16, no. 3, pp. 375–385, 2010.
[6]
K. L. Fujimoto, K. C. Clause, L. J. Liu et al., “Engineered fetal cardiac graft preserves its cardiomyocyte proliferation within postinfarcted myocardium and sustains cardiac function,” Tissue Engineering A, vol. 17, no. 5-6, pp. 585–596, 2011.
[7]
M. Lewitzky and S. Yamanaka, “Reprogramming somatic cells towards pluripotency by defined factors,” Current Opinion in Biotechnology, vol. 18, no. 5, pp. 467–473, 2007.
[8]
K. Takahashi, K. Tanabe, M. Ohnuki et al., “Induction of pluripotent stem cells from adult human fibroblasts by defined factors,” Cell, vol. 131, no. 5, pp. 861–872, 2007.
[9]
L. Yang, M. H. Soonpaa, E. D. Adler et al., “Human cardiovascular progenitor cells develop from a KDR+ embryonic-stem-cell-derived population,” Nature, vol. 453, no. 7194, pp. 524–528, 2008.
[10]
B. Lin, J. Kim, Y. Li et al., “High-purity enrichment of functional cardiovascular cells from human iPS cells,” Cardiovascular Research, vol. 95, no. 3, pp. 327–335, 2012.
[11]
C. Jopling, S. Boue, and J. C. I. Belmonte, “Dedifferentiation, transdifferentiation and reprogramming: three routes to regeneration,” Nature Reviews Molecular Cell Biology, vol. 12, no. 2, pp. 79–89, 2011.
[12]
M. Rajabi, C. Kassiotis, P. Razeghi, and H. Taegtmeyer, “Return to the fetal gene program protects the stressed heart: a strong hypothesis,” Heart Failure Reviews, vol. 12, no. 3-4, pp. 331–343, 2007.
[13]
K. Kuwahara, T. Nishikimi, and K. Nakao, “Transcriptional regulation of the fetal cardiac gene program,” Journal of Pharmacological Sciences, vol. 119, no. 3, pp. 198–203, 2012.
[14]
K. C. Clause, J. Tchao, M. C. Powell et al., “Developing cardiac and skeletal muscle share fast-skeletal myosin heavy chain and cardiac troponin-I expression,” PLoS ONE, vol. 7, no. 7, Article ID e40725, 2012.
[15]
F. S. Apple, “Tissue specificity of cardiac troponin I, cardiac troponin T and creatine kinase-MB,” Clinica Chimica Acta, vol. 284, no. 2, pp. 151–159, 1999.
[16]
L. Saggin, L. Gorza, S. Ausoni, and S. Schiaffino, “Troponin I switching in the developing heart,” The Journal of Biological Chemistry, vol. 264, no. 27, pp. 16299–16302, 1989.
[17]
S. Schiaffino, L. Gorza, and S. Ausoni, “Troponin isoform switching in the developing heart and its functional consequences,” Trends in Cardiovascular Medicine, vol. 3, no. 1, pp. 12–17, 1993.
[18]
B. Zheng, B. Cao, M. Crisan et al., “Prospective identification of myogenic endothelial cells in human skeletal muscle,” Nature Biotechnology, vol. 25, no. 9, pp. 1025–1034, 2007.
[19]
B. Zheng, C. W. Chen, G. Li et al., “Isolation of myogenic stem cells from cultures of cryopreserved human skeletal muscle,” Cell Transplantation, vol. 21, no. 6, pp. 1087–1093, 2012.
[20]
C. W. Chen, M. Corselli, B. Péault, and J. Huard, “Human blood-vessel-derived stem cells for tissue repair and regeneration,” Journal of Biomedicine and Biotechnology, vol. 2012, Article ID 597439, 9 pages, 2012.
[21]
M. Crisan, S. Yap, L. Casteilla et al., “A perivascular origin for mesenchymal stem cells in multiple human organs,” Cell Stem Cell, vol. 3, no. 3, pp. 301–313, 2008.
[22]
L. Grajales, J. Garcia, and D. L. Geenen, “Induction of cardiac myogenic lineage development differs between mesenchymal and satellite cells and is accelerated by bone morphogenetic protein-4,” Journal of Molecular and Cellular Cardiology, vol. 53, no. 3, pp. 382–391, 2012.
[23]
A. Fabiato and F. Fabiato, “Dependence of the contractile activation of skinned cardiac cells on the sarcomere length,” Nature, vol. 256, no. 5512, pp. 54–56, 1975.
[24]
L. M. Hanft and K. S. McDonald, “Length dependence of force generation exhibit similarities between rat cardiac myocytes and skeletal muscle fibres,” The Journal of Physiology, vol. 588, no. 15, pp. 2891–2903, 2010.
[25]
G. Brown, E. Bülbring, and B. D. Burns, “The action of adrenaline on mammalian skeletal muscle,” The Journal of Physiology, vol. 107, pp. 115–128, 1948.
[26]
U. R. Mikkelsen, H. Gissel, A. Fredsted, and T. Clausen, “Excitation-induced cell damage and β2-adrenoceptor agonist stimulated force recovery in rat skeletal muscle,” The American Journal of Physiology—Regulatory Integrative and Comparative Physiology, vol. 290, no. 2, pp. R265–R272, 2006.
[27]
D. C. Andersson, M. J. Betzenhauser, S. Reiken, A. Umanskaya, T. Shiomi, and A. R. Marks, “Stress-induced increase in skeletal muscle force requires protein kinase A phosphorylation of the ryanodine receptor,” The Journal of Physiology, vol. 590, part 24, pp. 6381–6387, 2012.
[28]
K. Tobita, L. J. Liu, A. M. Janczewski et al., “Engineered early embryonic cardiac tissue retains proliferative and contractile properties of developing embryonic myocardium,” The American Journal of Physiology—Heart and Circulatory Physiology, vol. 291, no. 4, pp. H1829–H1837, 2006.
[29]
A. F. Dulhunty and P. W. Gage, “Effects of extracellular calcium concentration and dihydropyridines on contraction in mammalian skeletal muscle,” The Journal of Physiology, vol. 399, pp. 63–80, 1988.
[30]
B. Fraysse, T. Rouaud, M. Millour, J. Fontaine-Pérus, M. Gardahaut, and D. O. Levitsky, “Expression of the Na+/Ca2+ exchanger in skeletal muscle,” The American Journal of Physiology—Cell Physiology, vol. 280, no. 1, pp. C146–C154, 2001.
[31]
M. Arai, K. Otsu, D. H. MacLennan, and M. Periasamy, “Regulation of sarcoplasmic reticulum gene expression during cardiac and skeletal muscle development,” The American Journal of Physiology—Cell Physiology, vol. 262, no. 3, pp. C614–C620, 1992.
[32]
W. Liu, K. Yasui, T. Opthof et al., “Developmental changes of Ca2+ handling in mouse ventricular cells from early embryo to adulthood,” Life Sciences, vol. 71, no. 11, pp. 1279–1292, 2002.
[33]
T. L. Creazzo, J. Burch, and R. E. Godt, “Calcium buffering and excitation-contraction coupling in developing avian myocardium,” Biophysical Journal, vol. 86, no. 2, pp. 966–977, 2004.
[34]
T. S. Klitzner, “Maturational changes in excitation-contraction coupling in mammalian myocardium,” Journal of the American College of Cardiology, vol. 17, no. 1, pp. 218–225, 1991.
[35]
J. P. Louboutin, V. Fichter-Gagnepain, and J. Noireaud, “Comparison of contractile properties between developing and regenerating soleus muscle: influence of external calcium concentration upon the contractility,” Muscle and Nerve, vol. 18, no. 11, pp. 1292–1299, 1995.
[36]
S. O. Winitsky, T. V. Gopal, S. Hassanzadeh et al., “Adult murine skeletal muscle contains cells that can differentiate into beating cardiomyocytes in vitro,” PLoS Biology, vol. 3, no. 4, article e87, 2005.
[37]
O. Binah, “Tetanus in the mammalian heart: studies in the shrew myocardium,” Journal of Molecular and Cellular Cardiology, vol. 19, no. 12, pp. 1247–1252, 1987.
[38]
W. Burridge, “Cardiac tetanus,” The Journal of Physiology, vol. 54, pp. 248–252, 1920.
[39]
D. G. Edmondson, G. E. Lyons, J. F. Martin, and E. N. Olson, “Mef2 gene expression marks the cardiac and skeletal muscle lineages during mouse embryogenesis,” Development, vol. 120, no. 5, pp. 1251–1263, 1994.
[40]
P. A. W. Anderson, N. N. Malouf, A. E. Oakeley, E. D. Pagani, and P. D. Allen, “Troponin T isoform expression in humans: a comparison among normal and failing adult heart, fetal heart, and adult and fetal skeletal muscle,” Circulation Research, vol. 69, no. 5, pp. 1226–1233, 1991.
[41]
Y. Mayer, H. Czosnek, P. E. Zeelon, D. Yaffe, and U. Nudel, “Expression of the genes coding for the skeletal muscle and cardiac actins in the heart,” Nucleic Acids Research, vol. 12, no. 2, pp. 1087–1100, 1984.
[42]
L. Saggin, S. Ausoni, L. Gorza, S. Sartore, and S. Schiaffino, “Troponin T switching in the developing rat heart,” The Journal of Biological Chemistry, vol. 263, no. 34, pp. 18488–18492, 1988.
[43]
C. Cognard, M. Rivet-Bastide, B. Contantin, and G. Raymond, “Progressive predominance of “skeletal” versus “cardiac” types of excitation-contraction coupling during in vitro skeletal myogenesis,” Pflugers Archiv, vol. 422, no. 2, pp. 207–209, 1992.
[44]
T. Tamaki, A. Akatsuka, Y. Okada et al., “Cardiomyocyte formation by skeletal muscle-derived multi-myogenic stem cells after transplantation into infarcted myocardium,” PLoS ONE, vol. 3, no. 3, Article ID e1789, 2008.
[45]
Y. Iijima, T. Nagai, M. Mizukami et al., “Beating is necessary for transdifferentiation of skeletal muscle-derived cells into cardiomyocytes,” The FASEB Journal, vol. 17, no. 10, pp. 1361–1363, 2003.
[46]
G. Invernici, S. Cristini, P. Madeddu et al., “Human adult skeletal muscle stem cells differentiate into cardiomyocyte phenotype in vitro,” Experimental Cell Research, vol. 314, no. 2, pp. 366–376, 2008.
[47]
C. Krueger and F. M. Hoffmann, “Identification of retinoic acid in a high content screen for agents that overcome the anti-myogenic effect of TGF-beta-1,” PLoS ONE, vol. 5, no. 11, Article ID e15511, 2010.
[48]
T. Ryan, J. Liu, A. Chu, L. Wang, A. Blais, and I. S. Skerjanc, “Retinoic acid enhances skeletal myogenesis in human embryonic stem cells by expanding the premyogenic progenitor population,” Stem Cell Reviews and Reports, vol. 8, no. 2, pp. 482–493, 2012.
[49]
H. H. Arnold, C. D. Gerharz, H. E. Gabbert, and A. Salminen, “Retinoic acid induces myogenin synthesis and myogenic differentiation in the rat rhabdomyosarcoma cell line BA-Han-1C,” Journal of Cell Biology, vol. 118, no. 4, pp. 877–887, 1992.
[50]
A. M. Wobus, G. Kaomei, J. Shan et al., “Retinoic acid accelerates embryonic stem cell-derived cardiac differentiation and enhances development of ventricular cardiomyocytes,” Journal of Molecular and Cellular Cardiology, vol. 29, no. 6, pp. 1525–1539, 1997.
[51]
B. R. Keegan, J. L. Feldman, G. Begemann, P. W. Ingham, and D. Yelon, “Retinoic acid signaling restricts the cardiac progenitor pool,” Science, vol. 307, no. 5707, pp. 247–249, 2005.
[52]
S. Crippa, M. Cassano, G. Messina et al., “miR669a and miR669q prevent skeletal muscle differentiation in postnatal cardiac progenitors,” Journal of Cell Biology, vol. 193, no. 7, pp. 1197–1212, 2011.
[53]
I. S. Skerjanc, “Cardiac and skeletal muscle development in P19 embryonal carcinoma cells,” Trends in Cardiovascular Medicine, vol. 9, no. 5, pp. 139–143, 1999.
[54]
E. N. Olson, “Regulation of muscle transcription by the MyoD family: the heart of the matter,” Circulation Research, vol. 72, no. 1, pp. 1–6, 1993.
[55]
J. D. Fu, N. R. Stone, L. Liu, et al., “Direct reprogramming of human fibroblasts toward a cardiomyocyte-like state,” Stem Cell Reports, vol. 1, no. 3, pp. 235–247, 2013.
[56]
S. Crippa, M. Cassano, G. Messina et al., “miR669a and miR669q prevent skeletal muscle differentiation in postnatal cardiac progenitors,” Journal of Cell Biology, vol. 193, no. 7, pp. 1197–1212, 2011.
[57]
L. Tirosh-Finkel, H. Elhanany, A. Rinon, and E. Tzahor, “Mesoderm progenitor cells of common origin contribute to the head musculature and the cardiac outflow tract,” Development, vol. 133, no. 10, pp. 1943–1953, 2006.
[58]
T. K. Kim, J. Sul, N. B. Peternko et al., “Transcriptome transfer provides a model for understanding the phenotype of cardiomyocytes,” Proceedings of the National Academy of Sciences of the United States of America, vol. 108, no. 29, pp. 11918–11923, 2011.
[59]
M. Ieda, J. D. Fu, P. Delgado-Olguin et al., “Direct reprogramming of fibroblasts into functional cardiomyocytes by defined factors,” Cell, vol. 142, no. 3, pp. 375–386, 2010.
[60]
P. Menasché, “Skeletal myoblasts for cardiac repair: act II?” Journal of the American College of Cardiology, vol. 52, no. 23, pp. 1881–1883, 2008.
[61]
K. Suzuki, N. J. Brand, S. Allen et al., “Overexpression of connexin 43 in skeletal myoblasts: relevance to cell transplantation to the heart,” Journal of Thoracic and Cardiovascular Surgery, vol. 122, no. 4, pp. 759–766, 2001.
[62]
O. Tolmachov, Y. L. Ma, M. Themis et al., “Overexpression of connexin 43 using a retroviral vector improves electrical coupling of skeletal myoblasts with cardiac myocytes in vitro,” BMC Cardiovascular Disorders, vol. 6, article 25, 2006.
[63]
H. Reinecke, E. Minami, J. I. Virag, and C. E. Murry, “Gene transfer of connexin43 into skeletal muscle,” Human Gene Therapy, vol. 15, no. 7, pp. 627–636, 2004.
[64]
K. Neef, Y. H. Choi, S. Perumal Srinivasan et al., “Mechanical preconditioning enables electrophysiologic coupling of skeletal myoblast cells to myocardium,” Journal of Thoracic and Cardiovascular Surgery, vol. 144, no. 5, pp. 1176.e1–1184.e1, 2012.
[65]
S. P. Srinivasan, K. Neef, P. Treskes et al., “Enhanced gap junction expression in myoblast-containing engineered tissue,” Biochemical and Biophysical Research Communications, vol. 422, no. 3, pp. 462–468, 2012.
[66]
K. L. Kreutziger and C. E. Murry, “Engineered human cardiac tissue,” Pediatric Cardiology, vol. 32, no. 3, pp. 334–341, 2011.
