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Myoblast deactivation within engineered human skeletal muscle creates a transcriptionally heterogeneous population of quiescent satellite-like cells.

Publication ,  Journal Article
Wang, J; Broer, T; Chavez, T; Zhou, CJ; Tran, S; Xiang, Y; Khodabukus, A; Diao, Y; Bursac, N
Published in: Biomaterials
May 2022

Satellite cells (SCs), the adult Pax7-expressing stem cells of skeletal muscle, are essential for muscle repair. However, in vitro investigations of SC function are challenging due to isolation-induced SC activation, loss of native quiescent state, and differentiation to myoblasts. In the present study, we optimized methods to deactivate in vitro expanded human myoblasts within a 3D culture environment of engineered human skeletal muscle tissues ("myobundles"). Immunostaining and gene expression analyses revealed that a fraction of myoblasts within myobundles adopted a quiescent phenotype (3D-SCs) characterized by increased Pax7 expression, cell cycle exit, and activation of Notch signaling. Similar to native SCs, 3D-SC quiescence is regulated by Notch and Wnt signaling while loss of quiescence and reactivation of 3D-SCs can be induced by growth factors including bFGF. Myobundle injury with a bee toxin, melittin, induces robust myofiber fragmentation, functional decline, and 3D-SC proliferation. By applying single cell RNA-sequencing (scRNA-seq), we discover the existence of two 3D-SC subpopulations (quiescent and activated), identify deactivation-associated gene signature using trajectory inference between 2D myoblasts and 3D-SCs, and characterize the transcriptomic changes within reactivated 3D-SCs in response to melittin-induced injury. These results demonstrate the ability of an in vitro engineered 3D human skeletal muscle environment to support the formation of a quiescent and heterogeneous SC population recapitulating several aspects of the native SC phenotype, and provide a platform for future studies of human muscle regeneration and disease-associated SC dysfunction.

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Published In

Biomaterials

DOI

EISSN

1878-5905

Publication Date

May 2022

Volume

284

Start / End Page

121508

Location

Netherlands

Related Subject Headings

  • Satellite Cells, Skeletal Muscle
  • Muscle, Skeletal
  • Melitten
  • Humans
  • Cell Proliferation
  • Cell Differentiation
  • Biomedical Engineering
  • Animals
 

Citation

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Wang, J., Broer, T., Chavez, T., Zhou, C. J., Tran, S., Xiang, Y., … Bursac, N. (2022). Myoblast deactivation within engineered human skeletal muscle creates a transcriptionally heterogeneous population of quiescent satellite-like cells. Biomaterials, 284, 121508. https://doi.org/10.1016/j.biomaterials.2022.121508
Wang, Jason, Torie Broer, Taylor Chavez, Chris J. Zhou, Sabrina Tran, Yu Xiang, Alastair Khodabukus, Yarui Diao, and Nenad Bursac. “Myoblast deactivation within engineered human skeletal muscle creates a transcriptionally heterogeneous population of quiescent satellite-like cells.Biomaterials 284 (May 2022): 121508. https://doi.org/10.1016/j.biomaterials.2022.121508.
Wang, Jason, et al. “Myoblast deactivation within engineered human skeletal muscle creates a transcriptionally heterogeneous population of quiescent satellite-like cells.Biomaterials, vol. 284, May 2022, p. 121508. Pubmed, doi:10.1016/j.biomaterials.2022.121508.
Wang J, Broer T, Chavez T, Zhou CJ, Tran S, Xiang Y, Khodabukus A, Diao Y, Bursac N. Myoblast deactivation within engineered human skeletal muscle creates a transcriptionally heterogeneous population of quiescent satellite-like cells. Biomaterials. 2022 May;284:121508.
Journal cover image

Published In

Biomaterials

DOI

EISSN

1878-5905

Publication Date

May 2022

Volume

284

Start / End Page

121508

Location

Netherlands

Related Subject Headings

  • Satellite Cells, Skeletal Muscle
  • Muscle, Skeletal
  • Melitten
  • Humans
  • Cell Proliferation
  • Cell Differentiation
  • Biomedical Engineering
  • Animals