title: Vessel-associated myogenic precursors control macrophage activation and clearance of apoptotic cells.
abstract: Swift and regulated clearance of apoptotic cells prevents the accumulation of cell remnants in injured tissues and contributes to the shift of macrophages towards alternatively activated reparatory cells that sustain wound healing. Environmental signals, most of which are unknown, in turn control the efficiency of the clearance of apoptotic cells and as such determine whether tissues eventually heal. In this study we show that vessel-associated stem cells (mesoangioblasts) specifically modulate the expression of genes involved in the clearance of apoptotic cells and in macrophage alternative activation, including those of scavenger receptors and of molecules that bridge dying cells and phagocytes. Mesoangioblasts, but not immortalized myoblasts or neural precursor cells, enhance CD163 membrane expression in vitro as assessed by flow cytometry, indicating that the effect is specific. Mesoangioblasts transplanted in acutely or chronically injured skeletal muscles determine the expansion of the population of CD163(+) infiltrating macrophages and increase the extent of CD163 expression. Conversely, macrophages challenged with mesoangioblasts engulf significantly better apoptotic cells in vitro. Collectively, the data reveal a feed-forward loop between macrophages and vessel-associated stem cells, which has implications for the skeletal muscle homeostatic response to sterile injury and for diseases in which homeostasis is jeopardized, including muscle dystrophies and inflammatory myopathies.
authors.affiliation: Division of Regenerative Medicine, Stem Cells and Gene Therapy, IRCCS Ospedale San Raffaele, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Bosurgi
authors.forename: S
authors.initials: S
authors.lastname: Brunelli
authors.forename: E
authors.initials: E
authors.lastname: Rigamonti
authors.forename: A
authors.initials: A
authors.lastname: Monno
authors.forename: A A
authors.initials: AA
authors.lastname: Manfredi
authors.forename: P
authors.initials: P
authors.lastname: Rovere-Querini
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D016130:Immunophenotyping; D008262:Macrophage Activation / Q000502:physiology*; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D032446:Myoblasts / Q000378:metabolism* / Q000637:transplantation; D010587:Phagocytosis / Q000502:physiology; D010641:Phenotype
keywords: apoptosis; inflammation; macrophage; phagocytosis
references.citation: Science. 2003 Jul 25;301(5632):487-92
references.pmid: 12855815
references.citation: Nat Immunol. 2013 Oct;14(10):986-95
references.pmid: 24048120
references.citation: Am J Pathol. 2009 Aug;175(2):547-56
references.pmid: 19574425
references.citation: Ann Med. 2004;36(5):347-54
references.pmid: 15478309
references.citation: J Exp Med. 1992 Jul 1;176(1):287-92
references.pmid: 1613462
references.citation: Mediators Inflamm. 2013;2013:491497
references.pmid: 23509419
references.citation: Cell Metab. 2013 Aug 6;18(2):251-64
references.pmid: 23931756
references.citation: Am J Physiol Regul Integr Comp Physiol. 2010 May;298(5):R1173-87
references.pmid: 20219869
references.citation: Proc Natl Acad Sci U S A. 2007 Dec 4;104(49):19446-51
references.pmid: 18042719
references.citation: Nat Immunol. 2010 Oct;11(10):889-96
references.pmid: 20856220
references.citation: J Exp Med. 2007 May 14;204(5):1057-69
references.pmid: 17485518
references.citation: Immunol Cell Biol. 2011 Jan;89(1):130-42
references.pmid: 20514074
references.citation: J Immunol. 1998 Nov 1;161(9):4467-71
references.pmid: 9794367
references.citation: Nat Immunol. 2013 Jan;14(1):14-5
references.pmid: 23238752
references.citation: J Exp Med. 2011 Jan 17;208(1):23-39
references.pmid: 21220455
references.citation: Nat Immunol. 2010 May;11(5):411-8
references.pmid: 20351694
references.citation: Haematologica. 2010 Nov;95(11):1814-22
references.pmid: 20511666
references.citation: Am J Pathol. 2011 Nov;179(5):2651-9
references.pmid: 21924227
references.citation: Immunol Lett. 1999 Jan;65(1-2):15-9
references.pmid: 10065621
references.citation: Haematologica. 2010 Nov;95(11):1801-3
references.pmid: 21037324
references.citation: Circ Res. 2013 Nov 8;113(11):1196-205
references.pmid: 24036496
references.citation: Proc Natl Acad Sci U S A. 2009 Oct 13;106(41):17475-80
references.pmid: 19805133
references.citation: Antioxid Redox Signal. 2013 Jun 10;18(17):2254-63
references.pmid: 22793784
references.citation: J Immunol. 2012 Jun 15;188(12):6267-77
references.pmid: 22573810
references.citation: Eur J Immunol. 2010 Aug;40(8):2296-307
references.pmid: 20468007
references.citation: J Leukoc Biol. 2009 May;85(5):779-87
references.pmid: 19197071
references.citation: Br Med Bull. 1997;53(3):491-508
references.pmid: 9374033
references.citation: J Exp Med. 2012 Jun 4;209(6):1219-34
references.pmid: 22615129
references.citation: Nature. 2005 Jul 14;436(7048):266-71
references.pmid: 16015332
references.citation: Proc Natl Acad Sci U S A. 2002 Feb 5;99(3):1503-8
references.pmid: 11805289
references.citation: Antioxid Redox Signal. 2013 Jun 10;18(17):2352-63
references.pmid: 22900885
references.citation: Nat Immunol. 2013 Jan;14(1):41-51
references.pmid: 23179077