Cells migrating to sites of tissue damage in response to the danger signal HMGB1 require NF-kappaB activation.
Tissue damage is usually followed by healing, as both differentiated and stem cells migrate to replace dead or damaged cells. Mesoangioblasts (vessel-associated stem cells that can repair muscles) and fibroblasts migrate toward soluble factors released by damaged tissue. Two such factors are high mobility group box 1 (HMGB1), a nuclear protein that is released by cells undergoing unscheduled death (necrosis) but not by apoptotic cells, and stromal derived factor (SDF)-1/CXCL12. We find that HMGB1 activates the canonical nuclear factor kappaB (NF-kappaB) pathway via extracellular signal-regulated kinase phosphorylation. NF-kappaB signaling is necessary for chemotaxis toward HMGB1 and SDF-1/CXCL12, but not toward growth factor platelet-derived growth factor, formyl-met-leu-phe (a peptide that mimics bacterial invasion), or the archetypal NF-kappaB-activating signal tumor necrosis factor alpha. In dystrophic mice, mesoangioblasts injected into the general circulation ingress inefficiently into muscles if their NF-kappaB signaling pathway is disabled. These findings suggest that NF-kappaB signaling controls tissue regeneration in addition to early events in inflammation.
Palumbo
Roberta
R
Chromatin Dynamics Unit, Stem Cell Research Institute, Istituto Scientifico San Raffaele, 20132 Milan, Italy.
Galvez
Beatriz G
BG
Pusterla
Tobias
T
De Marchis
Francesco
F
Cossu
Giulio
G
Marcu
Kenneth B
KB
Bianchi
Marco E
ME
D000818:Animals; D002460:Cell Line; D054377:Chemokine CXCL12 / Q000378:metabolism; D002633:Chemotaxis / Q000502:physiology*; D005347:Fibroblasts / Q000378:metabolism / Q000502:physiology; D049452:Green Fluorescent Proteins / Q000032:analysis; D024243:HMGB1 Protein / Q000378:metabolism*; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000378:metabolism / Q000502:physiology; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism / Q000502:physiology*; D009336:Necrosis; D010766:Phosphorylation; D011993:Recombinant Fusion Proteins / Q000032:analysis; D015398:Signal Transduction
D054377:Chemokine CXCL12; D024243:HMGB1 Protein; D016328:NF-kappa B; D011993:Recombinant Fusion Proteins; D049452:Green Fluorescent Proteins; D020928:Mitogen-Activated Protein Kinases