期刊
CELLULAR AND MOLECULAR BIOENGINEERING
卷 10, 期 5, 页码 501-513出版社
SPRINGER
DOI: 10.1007/s12195-017-0506-7
关键词
Skeletal muscle; Regeneration; Biophysical cues; Biochemical cues; Spatiotemporal; Niche; Compression testing; Extracellular matrix; Hydrogel; Ligand presentation
资金
- Natural Sciences and Engineering Research Council (USRA fellowship)
- Natural Sciences and Engineering Research Council (CREATE ToEP fellowship)
- Natural Sciences and Engineering Research Council [RGPIN 327627-06, RGPIN 435724-13]
- Natural Sciences and Engineering Research Council (Canada Research Chair) [950-231201]
- Toronto Musculoskeletal Centre
- Barbara and Frank Milligan Foundation
- Ontario Provincial Government (OGS-visa) [31390, ER15-11-073]
- Canada Foundation for Innovation [31390]
- Krembil Foundation
- Toronto Western Arthritis Program
- Canadian Institutes of Health Research [MOP-302041, ONM-137370]
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. 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. 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. 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.
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