Monocytes/macrophages cooperate with progenitor cells during neovascularization and tissue repair: conversion of cell columns into fibrovascular bundles.
The potential of monocytes/macrophages (MC/Mph) to contribute to neovascularization has recently become a topic of intense scrutiny. Here, we characterized the behavior of MC/Mph in cellular infiltrates, with emphasis on their spatial organization and localization in newly formed microvessels. To this end, we studied MC/Mph migration and assembly in basic fibroblast growth factor-supplemented Matrigel plugs placed in transgenic Tie2-beta-galactosidase mice for up to 4 weeks. In these plugs, along with Nile Red-positive adipocytes, we found MC/Mph distributed in cell cords, also containing various mature and progenitor tissue cells; and functional Tie2-positive or -negative microvessels embedded in bundles of fibrillar collagen surrounded by F4/80-positive MC/Mph. At earlier stages of infiltration, we found tubular destruction of the matrix (tunnels) and MC/Mph-lined capillary-like structures occasionally containing erythrocytes, indicating their propensity for endothelial trans-differentiation. We also analyzed in vitro the MCP-1-induced chemotactic migration of fluorescently labeled peritoneal MC/Mph incorporated in Matrigel-containing fluorescent protease substrates. Many of these MC/Mph produced MMP-12- and TIMP-1-dependent tunnels coupled with acquisition of a lumen. In conclusion, long-term implantation of Matrigel plugs qualifies as a novel experimental model of tissue regeneration, in which neovascularization intimately couples with fibrosis and organogenesis and in which cells of MC/Mph phenotype play a key structural role.
Anghelina
Mirela
M
Department of Internal Medicine/Cardiology, Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH 43210, USA.
Krishnan
Padma
P
Moldovan
Leni
L
Moldovan
Nicanor I
NI
D000818:Animals; D002454:Cell Differentiation; D002465:Cell Movement; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000494:pharmacology; D002633:Chemotaxis; D003094:Collagen / Q000378:metabolism; D004338:Drug Combinations; D004730:Endothelium, Vascular / Q000166:cytology*; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D007797:Laminin / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000502:physiology*; D053508:Matrix Metalloproteinase 12; D008666:Metalloendopeptidases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009000:Monocytes / Q000502:physiology*; D018919:Neovascularization, Physiologic; D011509:Proteoglycans / Q000378:metabolism; D042787:Receptor, TIE-2 / Q000235:genetics / Q000502:physiology; D012038:Regeneration; D013234:Stem Cells / Q000502:physiology*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D001616:beta-Galactosidase
D018932:Chemokine CCL2; D004338:Drug Combinations; D007797:Laminin; D011509:Proteoglycans; D019715:Tissue Inhibitor of Metalloproteinase-1; D016222:Fibroblast Growth Factor 2; C059485:matrigel; D003094:Collagen; D042787:Receptor, TIE-2; D001616:beta-Galactosidase; D008666:Metalloendopeptidases; C507122:MMP12 protein, human; D053508:Matrix Metalloproteinase 12