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

Abstract

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-jB 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.

Tumor necrosis factor-like weak inducer of apoptosis is a mitogen for liver progenitor cells

“…In CDE-fed Fn14 null mice, the hepatic inflammatory response was delayed, and this is consistent with reduced inflammation in cardiotoxin-treated Fn14 null animals in a model of skeletal muscle regeneration. 16 Collagen deposition correlated with the LPC response, with a reduction evident at 2 but not 3 weeks of CDE feeding. If TWEAK is a direct and selective mitogen for LPCs, this implies that fibrosis follows the LPC response and not the other way around.…”

“…Fn14 KO mice and respective inbred wildtype (WT) animals were used as previously described. 16 For all other experiments, C57BL/6 mice were obtained from ARC (Western Australia). Four-week-old, male mice were administered a CDE diet.…”

Molecular basis of the myogenic profile of aged human skeletal muscle satellite cells during differentiation

“…However, other factors may contribute to failed myogenesis. For instance, the TWEAK receptor, a direct regulator of skeletal muscle regeneration that inhibits terminal differentiation in both the established C2C12 cell line and primary mouse muscle myoblasts, already was up-regulated in early stage of differentiation (Girgenrath et al, 2006).…”

TWEAK Inhibits TRAF2-Mediated CD40 Signaling by Destabilization of CD40 Signaling Complexes

“…Nevertheless, it appears that the TWEAK-Fn14 system is active in processes related to growth and remodeling of tissue and organs during development and tissue repair. In accordance with this, animal studies implicated the TWEAK-Fn14 system in liver progenitor cell proliferation (6,7), regulation of muscle development and muscle regeneration (8)(9)(10)(11), tumor-associated angiogenesis (12), and in various inflammationrelated pathologies including graft-versus-host disease, systemic lupus erythematosus-related nephritis (13), 2,4,6-trinitrobenzene sulfonic acid-induced colitis (14), renal and cerebral ischemia (15)(16)(17)(18), and collagen-induced arthritis (19,20).…”