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  • The EMBO Journal (2006) 25, 5826 - 5839
  • doi:10.1038/sj.emboj.7601441

Published online: 23 November 2006

TWEAK, via its receptor Fn14, is a novel regulator of mesenchymal progenitor cells and skeletal muscle regeneration

Mahasweta Girgenrath1, Shawn Weng2, Christine A Kostek1, Beth Browning2, Monica Wang2, Sharron AN Brown3, Jeffrey A Winkles3, Jennifer S Michaelson2, Norm Allaire2, Pascal Schneider4, Martin L Scott2, Yen-ming Hsu2, Hideo Yagita5, Richard A Flavell6, Jeffrey Boone Miller1, Linda C Burkly2 and Timothy S Zheng2

  1. Boston Biomedical Research Institute, Watertown, MA, USA
  2. Biogen Idec Inc., 14 Cambridge Center, Cambridge, MA, USA
  3. Departments of Surgery and Physiology, University of Maryland School of Medicine, Baltimore, MD, USA
  4. Department of Biochemistry, University of Lausanne, Ch. Des Boveresses, Epalinges, Switzerland
  5. Department of Immunology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo, Japan
  6. Section of Immunobiology, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT, USA

Correspondence to:

Timothy S Zheng, Biogen Idec Inc., 14 Cambridge Center, Cambridge, MA 02142, USA. Tel.: +1 617 679 3348; Fax: +1 617 679 3208; E-mail: timothy.zheng@biogenidec.com

Received 4 November 2005; Accepted 17 October 2006

Inflammation participates in tissue repair through multiple mechanisms including directly regulating the cell fate of resident progenitor cells critical for successful regeneration. Upon surveying target cell types of the TNF ligand TWEAK, we observed that TWEAK binds to all progenitor cells of the mesenchymal lineage and induces NF-kappaB activation and the expression of pro-survival, pro-proliferative and homing receptor genes in the mesenchymal stem cells, suggesting that this pro-inflammatory cytokine may play an important role in controlling progenitor cell biology. We explored this potential using both the established C2C12 cell line and primary mouse muscle myoblasts, and demonstrated that TWEAK promoted their proliferation and inhibited their terminal differentiation. By generating mice deficient in the TWEAK receptor Fn14, we further showed that Fn14-deficient primary myoblasts displayed significantly reduced proliferative capacity and altered myotube formation. Following cardiotoxin injection, a known trigger for satellite cell-driven skeletal muscle regeneration, Fn14-deficient mice exhibited reduced inflammatory response and delayed muscle fiber regeneration compared with wild-type mice. These results indicate that the TWEAK/Fn14 pathway is a novel regulator of skeletal muscle precursor cells and illustrate an important mechanism by which inflammatory cytokines influence tissue regeneration and repair. Coupled with our recent demonstration that TWEAK potentiates liver progenitor cell proliferation, the expression of Fn14 on all mesenchymal lineage progenitor cells supports a broad involvement of this pathway in other tissue injury and disease settings.

  • Keywords:

    • Fn14,
    • inflammation,
    • muscle,
    • regeneration,
    • TWEAK