Published online before print February 5, 2009

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(Journal of Leukocyte Biology. 2009;85:779-787.)
© 2009 Society for Leukocyte Biology

Inflammatory and alternatively activated human macrophages attract vessel-associated stem cells, relying on separate HMGB1- and MMP-9-dependent pathways

Karine Lolmede^*,, Lara Campana^*, Michela Vezzoli^,, Lidia Bosurgi^*, Rossana Tonlorenzi, Emilio Clementi^,||, Marco E. Bianchi^¶, Giulio Cossu^,**, Angelo A. Manfredi^*,¶,1, Silvia Brunelli^, and Patrizia Rovere-Querini^*

^* Cancer Immunotherapy and Gene Therapy Program, Clinical Immunology Unit,
Clinical Cardiovascular Biology Research Center, and
Stem Cell Research Institute, H San Raffaele Scientific Institute, Milano, Italy;
E. Medea Scientific Institute, Bosisio Parini, Italy; Departments of
^|| Preclinical Sciences and
^** Biology, University of Milano, Milano, Italy;
^¶ Università Vita-Salute San Raffaele, Milano, Italy; and
Department of Experimental Medicine, Università di Milano-Bicocca, Monza, Italy

¹ Correspondence: H San Raffaele Institute, DIBIT-3A1, via Olgettina 58, 20132 Milano, Italy. E-mail: manfredi.angelo{at}hsr.it

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-, 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- 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.

Key Words: attraction • inflammation • tissue repair • muscle injury

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