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Cells migrating to sites of tissue damage in response to the danger signal HMGB1 require NF-B activation

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 B (NF-B) pathway via extracellular signal-regulated kinase phosphorylation. NF-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-B–activating signal tumor necrosis factor . In dystrophic mice, mesoangioblasts injected into the general circulation ingress inefficiently into muscles if their NF-B signaling pathway is disabled. These findings suggest that NF-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: -SG, -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, IB kinase; IBSR, IB super-repressor; MEF, mouse embryonic fibroblast; MEK, MAPK/ERK kinase; NF-B, nuclear factor B; RAGE, receptor for advanced glycation end products; SDF, stromal derived factor; wt, wild type.

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