Cellular and Molecular Bioengineering

, Volume 6, Issue 3, pp 279–286

Combating Adaptation to Cyclic Stretching by Prolonging Activation of Extracellular Signal-Regulated Kinase

  • Justin S. Weinbaum
  • Jillian B. Schmidt
  • Robert T. Tranquillo
Article

DOI: 10.1007/s12195-013-0289-4

Cite this article as:
Weinbaum, J.S., Schmidt, J.B. & Tranquillo, R.T. Cel. Mol. Bioeng. (2013) 6: 279. doi:10.1007/s12195-013-0289-4

Abstract

In developing implantable tissues based on cellular remodeling of a fibrin scaffold, a key indicator of success is high collagen content. Cellular collagen synthesis is stimulated by cyclic stretching but is limited by cellular adaptation. Adaptation is mediated by deactivation of extracellular signal-regulated kinase (ERK); therefore inhibition of ERK deactivation should improve mechanically stimulated collagen production and accelerate the development of strong engineered tissues. The hypothesis of this study is that p38 mitogen activated protein kinase (p38) activation by stretching limits ERK activation and that chemical inhibition of p38 α/γ isoforms with SB203580 will increase stretching-induced ERK activation and collagen production. Both p38 and ERK were activated by 15 min of stretching but only p38 remained active after 1 h. After an effective dose of inhibitor was identified using cell monolayers, 5 μM SB203580 was found to increase ERK activation by two-fold in cyclically stretched fibrin-based tissue constructs. When 5 μM SB203580 was added to the culture medium of constructs exposed to 3 weeks of incremental amplitude cyclic stretch, 2.6 fold higher stretching-induced total collagen was obtained. In conclusion, SB203580 circumvents adaptation to stretching induced collagen production and may be useful in engineering tissues where mechanical strength is a priority.

Keywords

Cell signalingCollagenFibrinFibroblastInhibitionMechanical signalingMitogen-activated protein kinasep38

Abbreviations

DMSO

Dimethylsulfoxide

ERK

Extracellular signal-regulated kinase

MAPK

Mitogen-activated protein kinase

PBS

Phosphate buffered saline

SB

SB203580

SDS-PAGE

Sodium dodecyl sulfate polyacrylamide gel electrophoresis

TBS

Tris buffered saline

Copyright information

© Biomedical Engineering Society 2013

Authors and Affiliations

  • Justin S. Weinbaum
    • 1
    • 3
  • Jillian B. Schmidt
    • 2
  • Robert T. Tranquillo
    • 1
    • 2
  1. 1.Department of Biomedical EngineeringUniversity of MinnesotaMinneapolisUSA
  2. 2.Department of Chemical Engineering & Materials ScienceUniversity of MinnesotaMinneapolisUSA
  3. 3.Center for BioengineeringUniversity of PittsburghPittsburghUSA