slug Controls Fibro‐Vascular Differentiation of Monocytes/Macrophages‐Containing Cell Columns

Recently we described the conversion of monocytes/macrophages (MC/Mph)‐based inflammatory cell columns into fibrovascular bundles (Am. J. Pathol., 2006;168:). Here, we studied the role in this process of the differentiation factor Slug, which functions in the signaling pathway of CD117/c‐kit. Methods. Distribution of MC/Mph and of LacZ positive cells in bFGF‐supplemented Matrigel in vivo was assessed in subcutaneous implants placed in transgenic mice expressing this marker gene under the promoters of either the endothelial angiopoietin receptor Tie2 , or under that of slug . Peritoneal macrophages and c‐kit + bone marrow cells from slug knock‐in mice were compared in culture with wild‐type counterparts for survival and cell cords formation. Results. We found that slug is actively expressed in cell columns at one week, but no more at one month. Titration of slug by LacZ knocking‐in reduced the penetration of the plugs by inflammatory cells and the number of columns, as compared with wild type controls. After one month, in the plugs placed in control mice we detected cell cords containing F4/80 + MC/Mph and LacZ + endothelial progenitors, along with microvessels embedded in fibrillar collagen bundles. In homozygous slug knock‐in mice, organization of microvessels present at the core of fibrovascular bundles appeared deficient, leading to erythrocytes extravasation. In vitro, we found that survival and cord formation by cells derived from slug‐ LacZ mice were impaired. Conclusion. Maturation of MC/Mph‐ and progenitor cells‐containing columns into fibro‐vascular bundles is regulated by the differentiation factor slug . Supported by NIH HL‐65983 (to NIM).