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Published online October 8, 2007
doi:10.1083/jcb.200704015
The Journal of Cell Biology, Vol. 179, No. 1, 33-40
The Rockefeller University Press, 0021-9525 $30.00
© 2007 Palumbo et al.
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Cells migrating to sites of tissue damage in response to the danger signal HMGB1 require NF-{kappa}B activation



Roberta Palumbo1, Beatriz G. Galvez2, Tobias Pusterla1, Francesco De Marchis1, Giulio Cossu2,3, Kenneth B. Marcu4,5, and Marco E. Bianchi1,6

1 Chromatin Dynamics Unit and 2 Stem Cell Research Institute, Istituto Scientifico San Raffaele, 20132 Milan, Italy
3 Department of Biology and Centre for Stem Cell Research, University of Milan, 20133 Milan, Italy
4 Centro di Ricerca Biomedica Applicata, Policlinico S. Orsola-Malpighi, Università di Bologna, 40138 Bologna, Italy
5 Biochemistry and Cell Biology Department, Institute for Cell and Developmental Biology, Stony Brook University, Stony Brook, NY 11794
6 Faculty of Medicine, San Raffaele University, 20132 Milan, Italy

Correspondence to Marco E. Bianchi: bianchi.marco{at}hsr.it

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 {kappa}B (NF-{kappa}B) pathway via extracellular signal-regulated kinase phosphorylation. NF-{kappa}B 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-{kappa}B–activating signal tumor necrosis factor {alpha}. In dystrophic mice, mesoangioblasts injected into the general circulation ingress inefficiently into muscles if their NF-{kappa}B signaling pathway is disabled. These findings suggest that NF-{kappa}B signaling controls tissue regeneration in addition to early events in inflammation.

K.B. Marcu and M.E. Bianchi contributed equally to this paper.

Abbreviations used in this paper: {alpha}-SG, {alpha}-sarcoglycan; DRB, 5,6-dichloro-1-ß-D- ribobenzimidazole; ERK, extracellular signal-regulated kinase; fMLP, formyl-met-leu-phe; HMGB1, high mobility group box 1; IKK, I{kappa}B kinase; I{kappa}B{alpha}SR, I{kappa}B{alpha} super-repressor; MEF, mouse embryonic fibroblast; MEK, MAPK/ERK kinase; NF-{kappa}B, nuclear factor {kappa}B; RAGE, receptor for advanced glycation end products; SDF, stromal derived factor; wt, wild type.


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