title: Inflammatory and alternatively activated human macrophages attract vessel-associated stem cells, relying on separate HMGB1- and MMP-9-dependent pathways.
abstract: Inflammatory macrophages recruited at the site of damaged muscles progressively acquire an alternative activation profile. Inflammatory (M1) and alternatively activated (M2) macrophages exert various and even opposite functions. M1 cells amplify tissue damage, and M2 cells dispose of necrotic fibers and deliver survival signals to myogenic precursors, finally supporting healing. A critical step in muscle healing is the recruitment of myogenic stem cells, including vessel-associated stem cells (mesoangioblasts), which have been demonstrated to home to damaged skeletal muscle selectively and preferentially. Little information is available about the signals involved and the role played by infiltrating macrophages. Here, we report that the polarization of macrophages dramatically skews the secretion of high mobility group box 1 (HMGB1), TNF-alpha, vascular endothelial growth factor, and metalloproteinase 9 (MMP-9), molecules involved in the regulation of cell diapedesis and migration. All polarized macrophage populations were strikingly effective at inducing mesoangioblast migration. By means of specific inhibitors, we verified that the recruitment of mesoangioblasts requires the secretion of HMGB1 and TNF-alpha by M1 cells and of MMP-9 by M2 cells. Together, these data demonstrate a feature, unrecognized previously, of macrophages: their ability to attract stem cells, which is conserved throughout their polarization. Moreover, they open the possibility of novel strategies, aimed at interfering selectively with signals that recruit blood-derived stem cells toward pro- or anti-inflammatory macrophages.
authors.affiliation: Clinical Cardiovascular Biology Research Center, H San Raffaele Scientific Institute, Milano, Italy.
authors.forename: Karine
authors.initials: K
authors.lastname: Lolmede
authors.forename: Lara
authors.initials: L
authors.lastname: Campana
authors.forename: Michela
authors.initials: M
authors.lastname: Vezzoli
authors.forename: Lidia
authors.initials: L
authors.lastname: Bosurgi
authors.forename: Rossana
authors.initials: R
authors.lastname: Tonlorenzi
authors.forename: Emilio
authors.initials: E
authors.lastname: Clementi
authors.forename: Marco E
authors.initials: ME
authors.lastname: Bianchi
authors.forename: Giulio
authors.initials: G
authors.lastname: Cossu
authors.forename: Angelo A
authors.initials: AA
authors.lastname: Manfredi
authors.forename: Silvia
authors.initials: S
authors.lastname: Brunelli
authors.forename: Patrizia
authors.initials: P
authors.lastname: Rovere-Querini
mesh_terms: D002465:Cell Movement; D002478:Cells, Cultured; D002633:Chemotaxis; D024243:HMGB1 Protein / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D008262:Macrophage Activation; D008264:Macrophages / Q000378:metabolism / Q000502:physiology*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000166:cytology; D013234:Stem Cells / Q000378:metabolism / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D024243:HMGB1 Protein; D014409:Tumor Necrosis Factor-alpha; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D020780:Matrix Metalloproteinase 9