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Cellular and Molecular Bioengineering

, Volume 10, Issue 5, pp 501–513 | Cite as

Tethered Jagged-1 Synergizes with Culture Substrate Stiffness to Modulate Notch-Induced Myogenic Progenitor Differentiation

  • Helia Safaee
  • Mohsen A. Bakooshli
  • Sadegh Davoudi
  • Richard Y. Cheng
  • Aditya J. Martowirogo
  • Edward W. Li
  • Craig A. Simmons
  • Penney M. GilbertEmail author
Article

Abstract

Introduction

Notch signaling is amongst the key intrinsic mechanisms regulating satellite cell fate, promoting the transition of activated satellite cells to highly proliferative myogenic progenitor cells and preventing their premature differentiation. Although much is known about the biochemical milieu that drives myogenic progression, less is known about the spatial cues providing spatiotemporal control of skeletal muscle repair in the context of Notch signaling.

Methods

Using a murine injury model, we quantified in vivo biophysical changes that occur within the skeletal muscle during regeneration. Employing tunable poly(ethylene glycol)—based hydrogel substrates, we modeled the measured changes in bulk stiffness in the context of Notch ligand signaling, which are present in the regenerative milieu at the time of injury.

Results

Following injury, there is a transient increase in the bulk stiffness of the tibialis anterior muscle that may be explained in part by changes in extracellular matrix deposition. When presented to primary myoblasts, Jagged-1, Jagged-2, and Dll1 in a tethered format elicited greater degrees of Notch activity compared to their soluble form. Only tethered Jagged-1 effects were tuned by substrate stiffness, with the greatest Notch activation observed on stiff hydrogels matching the stiffness of regenerating muscle. When exposed to tethered Jagged-1 on stiff hydrogels, fewer primary myoblasts expressed myogenin, and pharmacological inhibitor studies suggest this effect is Notch and RhoA dependent.

Conclusion

Our study proposes that tethered Jagged-1 presented in the context of transient tissue stiffening serves to tune Notch activity in myogenic progenitors during skeletal muscle repair and delay differentiation.

Keywords

Skeletal muscle Regeneration Biophysical cues Biochemical cues Spatiotemporal Niche Compression testing Extracellular matrix Hydrogel Ligand presentation 

Abbreviations

bFGF

Basic fibroblast growth factor

Dll1

Delta-like 1

DM

Differentiation media

ECM

Extracellular matrix

GM

Growth media

IgG1

Immunoglobulin G subtype 1

Jag1

Jagged-1

Jag2

Jagged-2

MyoG

Myogenin

NICD

Notch intracellular domain

PEG

Polyethylene glycol

PBS

Phosphate buffered saline

ROCK

Rho-associated, coiled-coil containing protein kinase

TBST

Tris-buffered saline plus Tween-20

Notes

Acknowledgments

We are grateful to Dr. Yasuhiro Matsumura (National Cancer Center Hospital, Kashiwa City, Japan) for providing us with his custom antibody to analyze fibrin clot formation in our study.

Author Contributions

HS, MAB, CAS, and PMG conceived the study and designed experiments. HS, SD, RYC, AJM, and EWL performed experiments, analyzed data, performed statistical analyses, and prepared figures. HS, MAB, SD, RYC, AJM, EWL, CAS, and PMG wrote, assembled, and revised the manuscript. All authors reviewed and approved the submission.

Funding

This study was funded by the Natural Sciences and Engineering Research Council (USRA fellowship to H.S., CREATE ToEP fellowship to S.D., RGPIN 327627-06 to C.A.S., RGPIN 435724-13 and Canada Research Chair 950-231201 to P.M.G.); Toronto Musculoskeletal Centre (Graduate Scholarships to M.A.B. and R.Y.C.); Barbara and Frank Milligan Foundation (R.Y.C.); Ontario Provincial Government (OGS-visa to M.A.B., 31390 and ER15-11-073 to P.M.G.); Canada Foundation for Innovation (31390 to P.M.G.); Krembil Foundation (Scholarship to M.A.B.); Toronto Western Arthritis Program (to P.M.G.); and Canadian Institutes of Health Research (MOP-302041 to C.A.S. and ONM-137370 to P.M.G.)

Conflict of interest

All authors declared that they have no conflict of interest.

Ethical Approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. This article does not contain any studies with human participants performed by any of the authors.

Supplementary material

12195_2017_506_MOESM1_ESM.docx (470 kb)
Supplementary material 1 (DOCX 469 kb)

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Copyright information

© Biomedical Engineering Society 2017

Authors and Affiliations

  • Helia Safaee
    • 1
  • Mohsen A. Bakooshli
    • 1
  • Sadegh Davoudi
    • 1
  • Richard Y. Cheng
    • 1
  • Aditya J. Martowirogo
    • 1
  • Edward W. Li
    • 1
  • Craig A. Simmons
    • 1
    • 2
    • 3
  • Penney M. Gilbert
    • 4
    • 5
    • 6
    Email author
  1. 1.Institute of Biomaterials and Biomedical EngineeringUniversity of TorontoTorontoCanada
  2. 2.Translational Biology and Engineering Program, The Ted Rogers Centre for Heart ResearchTorontoCanada
  3. 3.Department of Mechanical & Industrial EngineeringUniversity of TorontoTorontoCanada
  4. 4.Department of BiochemistryUniversity of TorontoTorontoCanada
  5. 5.Donnelly Centre for Cellular and Biomolecular ResearchTorontoCanada
  6. 6.Institute of Biomaterials and Biomedical EngineeringUniversity of TorontoTorontoCanada

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