Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Incorporation of macrophages into engineered skeletal muscle enables enhanced muscle regeneration

Nature Biomedical Engineering volume 2, pages 942–954 (2018)Cite this article

Subjects

Abstract

Adult skeletal muscle has a robust capacity for self-repair, owing to synergies between muscle satellite cells and the immune system. In vitro models of muscle self-repair would facilitate the basic understanding of muscle regeneration and the screening of therapies for muscle disease. Here, we show that the incorporation of macrophages into muscle tissues engineered from adult-rat myogenic cells enables near-complete structural and functional repair after cardiotoxic injury in vitro. First, we show that—in contrast with injured neonatal-derived engineered muscle—adult-derived engineered muscle fails to properly self-repair after injury, even when treated with pro-regenerative cytokines. We then show that rat bone-marrow-derived macrophages or human blood-derived macrophages resident within the in vitro engineered tissues stimulate muscle satellite cell-mediated myogenesis while significantly limiting myofibre apoptosis and degeneration. Moreover, bone-marrow-derived macrophages within engineered tissues implanted in a mouse dorsal window-chamber model augmented blood vessel ingrowth, cell survival, muscle regeneration and contractile function.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Function and injury response of adult-rat-derived skeletal muscle constructs.
Fig. 2: Structure, function and Ca2+ transient injury response of adult-derived Mu–BMDM constructs.
Fig. 3: Structural, functional and myogenic recovery from CTX-induced in vitro injury in Mu–BMDM constructs.
Fig. 4: Anti-apoptotic effect of BMDMs leads to enhanced regeneration in vitro.
Fig. 5: In vitro regeneration of muscle constructs under shared-media conditions following CTX injury.
Fig. 6: Cytokine analysis following injury of engineered muscle and the effects of TNFα inhibition on recovery.
Fig. 7: Effect of BMDMs on implanted engineered muscle vascularization, function and survival.

Similar content being viewed by others

Data availability

All the data supporting the findings of this study are available within the paper and its Supplementary Information.

References

  1. Charge, S. B. & Rudnicki, M. A. Cellular and molecular regulation of muscle regeneration. Physiol. Rev. 84, 209–238 (2004).

    Article  CAS  PubMed  Google Scholar 

  2. Lepper, C., Partridge, T. A. & Fan, C. M. An absolute requirement for Pax7-positive satellite cells in acute injury-induced skeletal muscle regeneration. Development 138, 3639–3646 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Yin, H., Price, F. & Rudnicki, M. A. Satellite cells and the muscle stem cell niche. Physiol. Rev. 93, 23–67 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Tidball, J. G. & Villalta, S. A. Regulatory interactions between muscle and the immune system during muscle regeneration. Am. J. Physiol. Regul. Integr. Comp. Physiol. 298, R1173–R1187 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Kharraz, Y., Guerra, J., Mann, C. J., Serrano, A. L. & Munoz-Canoves, P. Macrophage plasticity and the role of inflammation in skeletal muscle repair. Mediators Inflamm. 2013, 491497 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Saclier, M. et al. Differentially activated macrophages orchestrate myogenic precursor cell fate during human skeletal muscle regeneration. Stem Cells 31, 384–396 (2013).

    Article  CAS  PubMed  Google Scholar 

  7. Tidball, J. G., Dorshkind, K. & Wehling-Henricks, M. Shared signaling systems in myeloid cell-mediated muscle regeneration. Development 141, 1184–1196 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Turner, N. J. & Badylak, S. F. Regeneration of skeletal muscle. Cell Tissue Res. 347, 759–774 (2012).

    Article  PubMed  Google Scholar 

  9. Blau, H. M., Cosgrove, B. D. & Ho, A. T. The central role of muscle stem cells in regenerative failure with aging. Nat. Med. 21, 854–862 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Sacco, A. et al. Short telomeres and stem cell exhaustion model Duchenne muscular dystrophy in mdx/mTR mice. Cell 143, 1059–1071 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Bhatia, S. N. & Ingber, D. E. Microfluidic organs-on-chips. Nat. Biotechnol. 32, 760–772 (2014).

    Article  CAS  PubMed  Google Scholar 

  12. Clevers, H. Modeling development and disease with organoids. Cell 165, 1586–1597 (2016).

    Article  CAS  PubMed  Google Scholar 

  13. Quarta, M. et al. An artificial niche preserves the quiescence of muscle stem cells and enhances their therapeutic efficacy. Nat. Biotechnol. 34, 752–759 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Cosgrove, B. D. et al. Rejuvenation of the muscle stem cell population restores strength to injured aged muscles. Nat. Med. 20, 255–264 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Gilbert, P. M. et al. Substrate elasticity regulates skeletal muscle stem cell self-renewal in culture. Science 329, 1078–1081 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Juhas, M., Engelmayr, G. C. Jr, Fontanella, A. N., Palmer, G. M. & Bursac, N. Biomimetic engineered muscle with capacity for vascular integration and functional maturation in vivo. Proc. Natl Acad. Sci. USA 111, 5508–5513 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Juhas, M. & Bursac, N. Roles of adherent myogenic cells and dynamic culture in engineered muscle function and maintenance of satellite cells. Biomaterials 35, 9438–9446 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Close, R. Dynamic properties of fast and slow skeletal muscles of rat during development. J. Physiol. 173, 74–95 (1964).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Chen, T. W. et al. Ultrasensitive fluorescent proteins for imaging neuronal activity. Nature 499, 295–300 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Madden, L., Juhas, M., Kraus, W. E., Truskey, G. A. & Bursac, N. Bioengineered human myobundles mimic clinical responses of skeletal muscle to drugs. eLife 4, e04885 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  21. Salva, M. Z. et al. Design of tissue-specific regulatory cassettes for high-level rAAV-mediated expression in skeletal and cardiac muscle. Mol. Ther. 15, 320–329 (2007).

    Article  CAS  PubMed  Google Scholar 

  22. Pelosi, L. et al. Local expression of IGF-1 accelerates muscle regeneration by rapidly modulating inflammatory cytokines and chemokines. FASEB J. 21, 1393–1402 (2007).

    Article  CAS  PubMed  Google Scholar 

  23. 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. 189, 3669–3680 (2012).

    Article  CAS  PubMed  Google Scholar 

  24. Hayashiji, N. et al. G-CSF supports long-term muscle regeneration in mouse models of muscular dystrophy. Nat. Commun. 6, 6745 (2015).

    Article  CAS  PubMed  Google Scholar 

  25. Schleicher, U. & Bogdan, C. Generation, culture and flow-cytometric characterization of primary mouse macrophages. Methods Mol. Biol. 531, 203–224 (2009).

    Article  CAS  PubMed  Google Scholar 

  26. Hamilton, J. A. Colony-stimulating factors in inflammation and autoimmunity. Nat. Rev. Immunol. 8, 533–544 (2008).

    Article  CAS  PubMed  Google Scholar 

  27. Fleetwood, A. J., Lawrence, T., Hamilton, J. A. & Cook, A. D. Granulocyte-macrophage colony-stimulating factor (CSF) and macrophage CSF-dependent macrophage phenotypes display differences in cytokine profiles and transcription factor activities: implications for CSF blockade in inflammation. J. Immunol. 178, 5245–5252 (2007).

    Article  CAS  PubMed  Google Scholar 

  28. Krause, M. P. et al. Impaired macrophage and satellite cell infiltration occurs in a muscle-specific fashion following injury in diabetic skeletal muscle. PLoS ONE 8, e70971 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Soleimani, M. & Nadri, S. A protocol for isolation and culture of mesenchymal stem cells from mouse bone marrow. Nat. Protoc. 4, 102–106 (2009).

    Article  CAS  PubMed  Google Scholar 

  30. Dirks, A. & Leeuwenburgh, C. Apoptosis in skeletal muscle with aging. Am. J. Physiol. Regul. Integr. Comp. Physiol. 282, R519–R527 (2002).

    Article  CAS  PubMed  Google Scholar 

  31. Stratos, I. et al. Inhibition of caspase mediated apoptosis restores muscle function after crush injury in rat skeletal muscle. Apoptosis 17, 269–277 (2012).

    Article  CAS  PubMed  Google Scholar 

  32. Wang, H. et al. Turning terminally differentiated skeletal muscle cells into regenerative progenitors. Nat. Commun. 6, 7916 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Fernando, P., Kelly, J. F., Balazsi, K., Slack, R. S. & Megeney, L. A. Caspase 3 activity is required for skeletal muscle differentiation. Proc. Natl Acad. Sci. USA 99, 11025–11030 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Chazaud, B. et al. Satellite cells attract monocytes and use macrophages as a support to escape apoptosis and enhance muscle growth. J. Cell. Biol. 163, 1133–1143 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Sonnet, C. et al. Human macrophages rescue myoblasts and myotubes from apoptosis through a set of adhesion molecular systems. J. Cell. Sci. 119, 2497–2507 (2006).

    Article  CAS  PubMed  Google Scholar 

  36. Kondo, M. et al. Roles of proinflammatory cytokines and the Fas/Fas ligand interaction in the pathogenesis of inflammatory myopathies. Immunology 128, e589–e599 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  37. Kalovidouris, A. E. & Plotkin, Z. Synergistic cytotoxic effect of interferon-gamma and tumor necrosis factor-alpha on cultured human muscle cells. J. Rheumatol. 22, 1698–1703 (1995).

    CAS  PubMed  Google Scholar 

  38. Reid, M. B. & Li, Y. P. Tumor necrosis factor-alpha and muscle wasting: a cellular perspective. Respir. Res. 2, 269–272 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Pistilli, E. E., Jackson, J. R. & Alway, S. E. Death receptor-associated pro-apoptotic signaling in aged skeletal muscle. Apoptosis 11, 2115–2126 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Geng, Y. J., Wu, Q., Muszynski, M., Hansson, G. K. & Libby, P. Apoptosis of vascular smooth muscle cells induced by in vitro stimulation with interferon-gamma, tumor necrosis factor-alpha, and interleukin-1 beta. Arterioscler. Thromb. Vasc. Biol. 16, 19–27 (1996).

    Article  CAS  PubMed  Google Scholar 

  41. Pedersen, B. K. Exercise-induced myokines and their role in chronic diseases. Brain Behav. Immun. 25, 811–816 (2011).

    Article  CAS  PubMed  Google Scholar 

  42. Pedersen, B. K., Steensberg, A. & Schjerling, P. Muscle-derived interleukin-6: possible biological effects. J. Physiol. 536, 329–337 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Rehman, J. et al. Dynamic exercise leads to an increase in circulating ICAM-1: further evidence for adrenergic modulation of cell adhesion. Brain Behav. Immun. 11, 343–351 (1997).

    Article  CAS  PubMed  Google Scholar 

  44. Villalta, S. A. et al. Interleukin-10 reduces the pathology of mdx muscular dystrophy by deactivating M1 macrophages and modulating macrophage phenotype. Hum. Mol. Genet. 20, 790–805 (2011).

    Article  CAS  PubMed  Google Scholar 

  45. Zeng, L. et al. Insulin-like 6 is induced by muscle injury and functions as a regenerative factor. J. Biol. Chem. 285, 36060–36069 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Munoz-Canoves, P., Scheele, C., Pedersen, B. K. & Serrano, A. L. Interleukin-6 myokine signaling in skeletal muscle: a double-edged sword? FEBS J. 280, 4131–4148 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Jablonski, K. A. et al. Novel markers to delineate murine M1 and M2 macrophages. PLoS ONE 10, e0145342 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  48. Wajant, H., Pfizenmaier, K. & Scheurich, P. Tumor necrosis factor signaling. Cell Death Differ. 10, 45–65 (2003).

    Article  CAS  PubMed  Google Scholar 

  49. Grounds, M. D. & Torrisi, J. Anti-TNFalpha (Remicade) therapy protects dystrophic skeletal muscle from necrosis. FASEB J. 18, 676–682 (2004).

    Article  CAS  PubMed  Google Scholar 

  50. He, M. M. et al. Small-molecule inhibition of TNF-alpha. Science 310, 1022–1025 (2005).

    Article  CAS  PubMed  Google Scholar 

  51. Chen, S. E. et al. Role of TNF-α signaling in regeneration of cardiotoxin-injured muscle. Am. J. Physiol. Cell Physiol. 289, C1179–C1187 (2005).

    Article  CAS  PubMed  Google Scholar 

  52. Cheng, M., Nguyen, M. H., Fantuzzi, G. & Koh, T. J. Endogenous interferon-gamma is required for efficient skeletal muscle regeneration. Am. J. Physiol. Cell Physiol. 294, C1183–C1191 (2008).

    Article  CAS  PubMed  Google Scholar 

  53. Montarras, D. et al. Direct isolation of satellite cells for skeletal muscle regeneration. Science 309, 2064–2067 (2005).

    Article  CAS  PubMed  Google Scholar 

  54. Day, K., Shefer, G., Shearer, A. & Yablonka-Reuveni, Z. The depletion of skeletal muscle satellite cells with age is concomitant with reduced capacity of single progenitors to produce reserve progeny. Dev. Biol. 340, 330–343 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Tierney, M. T. et al. Autonomous extracellular matrix remodeling controls a progressive adaptation in muscle stem cell regenerative capacity during development. Cell Rep. 14, 1940–1952 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Lees, S. J., Zwetsloot, K. A. & Booth, F. W. Muscle precursor cells isolated from aged rats exhibit an increased tumor necrosis factor-alpha response. Aging Cell 8, 26–35 (2009).

    Article  CAS  PubMed  Google Scholar 

  57. Fulle, S., Sancilio, S., Mancinelli, R., Gatta, V. & Di Pietro, R. Dual role of the caspase enzymes in satellite cells from aged and young subjects. Cell Death Dis. 4, e955 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Davis, T. A. & Fiorotto, M. L. Regulation of muscle growth in neonates. Curr. Opin. Clin. Nutr. 12, 78–85 (2009).

    Article  CAS  Google Scholar 

  59. Dogra, C., Changotra, H., Mohan, S. & Kumar, A. Tumor necrosis factor-like weak inducer of apoptosis inhibits skeletal myogenesis through sustained activation of nuclear factor-κB and degradation of MyoD protein. J. Biol. Chem. 281, 10327–10336 (2006).

    Article  CAS  PubMed  Google Scholar 

  60. Bruunsgaard, H., Pedersen, M. & Pedersen, B. K. Aging and proinflammatory cytokines. Curr. Opin. Hematol. 8, 131–136 (2001).

    Article  CAS  PubMed  Google Scholar 

  61. Collins, R. A. & Grounds, M. D. The role of tumor necrosis factor-α (TNF-α) in skeletal muscle regeneration. Studies in TNF-α-/- and TNF-α-/-/LT-α-/- mice. J. Histochem. Cytochem. 49, 989–1001 (2001).

    Article  CAS  PubMed  Google Scholar 

  62. Ochoa, O. et al. Delayed angiogenesis and VEGF production in CCR2−/− mice during impaired skeletal muscle regeneration. Am. J. Physiol. Regul. Integr. Comp. Physiol. 293, R651–R661 (2007).

    Article  CAS  PubMed  Google Scholar 

  63. Chung, E. S. et al. Contribution of macrophages to angiogenesis induced by vascular endothelial growth factor receptor-3-specific ligands. Am. J. Pathol. 175, 1984–1992 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  64. Nucera, S., Biziato, D. & De Palma, M. The interplay between macrophages and angiogenesis in development, tissue injury and regeneration. Int. J. Dev. Biol. 55, 495–503 (2011).

    Article  CAS  PubMed  Google Scholar 

  65. Vignaud, A. et al. Impaired skeletal muscle repair after ischemia–reperfusion injury in mice. J. Biomed. Biotechnol. 2010, 724914 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Lee, S. L., Pevec, W. C. & Carlsen, R. C. Functional outcome of new blood vessel growth into ischemic skeletal muscle. J. Vasc. Surg. 34, 1096–1102 (2001).

    Article  CAS  PubMed  Google Scholar 

  67. Davies, L. C., Jenkins, S. J., Allen, J. E. & Taylor, P. R. Tissue-resident macrophages. Nat. Immunol. 14, 986–995 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Mantovani, A., Biswas, S. K., Galdiero, M. R., Sica, A. & Locati, M. Macrophage plasticity and polarization in tissue repair and remodelling. J. Pathol. 229, 176–185 (2013).

    Article  CAS  PubMed  Google Scholar 

  69. Lavin, Y. et al. Tissue-resident macrophage enhancer landscapes are shaped by the local microenvironment. Cell 159, 1312–1326 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Das, A. et al. Monocyte and macrophage plasticity in tissue repair and regeneration. Am. J. Pathol. 185, 2596–2606 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Forbes, S. J. & Rosenthal, N. Preparing the ground for tissue regeneration: from mechanism to therapy. Nat. Med. 20, 857–869 (2014).

    Article  CAS  PubMed  Google Scholar 

  72. Aurora, A. B. et al. Macrophages are required for neonatal heart regeneration. J. Clin. Invest. 124, 1382–1392 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Kanters, E. et al. Hematopoietic NF-kappaB1 deficiency results in small atherosclerotic lesions with an inflammatory phenotype. Blood 103, 934–940 (2004).

    Article  CAS  PubMed  Google Scholar 

  74. Lesault, P. F. et al. Macrophages improve survival, proliferation and migration of engrafted myogenic precursor cells into MDX skeletal muscle. PLoS ONE 7, e46698 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Stanley, E. R. Murine bone marrow-derived macrophages. Methods Mol. Biol. 75, 301–304 (1997).

    CAS  PubMed  Google Scholar 

  76. Gleissner, C. A., Shaked, I., Little, K. M. & Ley, K. CXC chemokine ligand 4 induces a unique transcriptome in monocyte-derived macrophages. J. Immunol. 184, 4810–4818 (2010).

    Article  CAS  PubMed  Google Scholar 

  77. Flick, D. A. & Gifford, G. E. Comparison of in vitro cell cytotoxic assays for tumor necrosis factor. J. Immunol. Methods 68, 167–175 (1984).

    Article  CAS  PubMed  Google Scholar 

  78. Liddil, J. D., Dorr, R. T. & Scuderi, P. Association of lysosomal activity with sensitivity and resistance to tumor necrosis factor in murine L929 cells. Cancer Res. 49, 2722–2728 (1989).

    CAS  PubMed  Google Scholar 

  79. Bellucci, J. J., Amiram, M., Bhattacharyya, J., McCafferty, D. & Chilkoti, A. Three-in-one chromatography-free purification, tag removal, and site-specific modification of recombinant fusion proteins using sortase A and elastin-like polypeptides. Angew. Chem. Int. Ed. Engl. 52, 3703–3708 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Jetten, N. et al. Anti-inflammatory M2, but not pro-inflammatory M1 macrophages promote angiogenesis in vivo. Angiogenesis 17, 109–118 (2014).

    Article  CAS  PubMed  Google Scholar 

  81. Jackman, C. P., Carlson, A. L. & Bursac, N. Dynamic culture yields engineered myocardium with near-adult functional output. Biomaterials. 111, 66–79 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Hinds, S., Bian, W., Dennis, R. G. & Bursac, N. The role of extracellular matrix composition in structure and function of bioengineered skeletal muscle. Biomaterials 32, 3575–3583 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Ma, L. et al. A novel small-molecule tumor necrosis factor alpha inhibitor attenuates inflammation in a hepatitis mouse model. J. Biol. Chem. 289, 12457–12466 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Palmer, G. M. et al. In vivo optical molecular imaging and analysis in mice using dorsal window chamber models applied to hypoxia, vasculature and fluorescent reporters. Nat. Protoc. 6, 1355–1366 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Palmer, G. M., Fontanella, A. N., Shan, S. & Dewhirst, M. W. High-resolution in vivo imaging of fluorescent proteins using window chamber models. Methods Mol. Biol. 872, 31–50 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We acknowledge C. Jackman, A. Khodabukus, L. Li, I. Shadrin, A. Ganapathi, G. Palmer and G. Hanna for technical assistance, and the Light Microscopy and Optical Molecular Imaging and Analysis core facilities at Duke University for use of their resources. We also thank B. Chazaud for granting a protocol for human macrophage derivation. This study was supported by the National Science Foundation’s Graduate Research Fellowship to M.J., and grants AR070543 and AR065873 from the National Institute of Arthritis and Musculoskeletal and Skin Diseases to N.B.

Author information

Authors and Affiliations

  1. Department of Biomedical Engineering, Duke University, Durham, NC, USA

    Mark Juhas, Nadia Abutaleb, Jason T. Wang, Jean Ye, Zohaib Shaikh, Chaichontat Sriworarat, Ying Qian & Nenad Bursac

  2. Regeneration Next, Duke University, Durham, NC, USA

    Nenad Bursac

Authors
  1. Mark Juhas
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nadia Abutaleb
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jason T. Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jean Ye
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Zohaib Shaikh
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Chaichontat Sriworarat
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ying Qian
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Nenad Bursac
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

M.J. and N.B. conceived and designed the research. M.J., N.A., J.T.W., J.Y., Z.S. and C.S. performed the experiments. Y.Q. performed the implantation surgery. M.J., N.A., J.Y., Z.S. and N.B. analysed the results. M.J. and N.B. wrote the manuscript.

Corresponding author

Correspondence to Nenad Bursac.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Supplementary Information

Supplementary figures and tables.

Reporting Summary

Supplementary Video 1

Real-time assessment of engineered muscle regeneration in vitro.

Supplementary Video 2

Perfused ingrown blood vessels within engineered muscle implants.

Supplementary Video 3

In vivo spontaneous calcium transients in engineered muscle implants.

Supplementary Video 4

Ex vivo electrically induced calcium transients in engineered muscle explants.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Juhas, M., Abutaleb, N., Wang, J.T. et al. Incorporation of macrophages into engineered skeletal muscle enables enhanced muscle regeneration. Nat Biomed Eng 2, 942–954 (2018). https://doi.org/10.1038/s41551-018-0290-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41551-018-0290-2

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research