TWEAK, via its receptor Fn14, is a novel regulator of mesenchymal progenitor cells and skeletal muscle regeneration.
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.
Girgenrath
Mahasweta
M
Boston Biomedical Research Institute, Watertown, MA, USA.
Weng
Shawn
S
Kostek
Christine A
CA
Browning
Beth
B
Wang
Monica
M
Brown
Sharron A N
SA
Winkles
Jeffrey A
JA
Michaelson
Jennifer S
JS
Allaire
Norm
N
Schneider
Pascal
P
Scott
Martin L
ML
Hsu
Yen-ming
YM
Yagita
Hideo
H
Flavell
Richard A
RA
Miller
Jeffrey Boone
JB
Burkly
Linda C
LC
Zheng
Timothy S
TS
D000818:Animals; D002453:Cell Cycle / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004179:Cobra Cardiotoxin Proteins / Q000494:pharmacology; D000074049:Cytokine TWEAK; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007249:Inflammation; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000187:drug effects; D051379:Mice; D008954:Models, Biological; D024510:Muscle Development / Q000187:drug effects; D018482:Muscle, Skeletal / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D032446:Myoblasts / Q000166:cytology / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D012038:Regeneration / Q000187:drug effects; D000074050:TWEAK Receptor; D048069:Tumor Necrosis Factors / Q000235:genetics / Q000378:metabolism*
D004179:Cobra Cardiotoxin Proteins; D000074049:Cytokine TWEAK; D012333:RNA, Messenger; D018124:Receptors, Tumor Necrosis Factor; C000613297:TNFRSF12A protein, human; C109743:TNFSF12 protein, human; D000074050:TWEAK Receptor; C000613299:Tnfrsf12a protein, mouse; C491645:Tnfsf12 protein, mouse; D048069:Tumor Necrosis Factors