BackgroundMacrophages and fibroblasts are two major players in tissue repair and fibrosis. Despite the relevance of macrophages and fibroblasts in tissue homeostasis, remarkably little is known whether macrophages are able to influence the properties of fibroblasts. Here we investigated the role of paracrine factors secreted by classically activated (M1) and alternatively activated (M2) human macrophages on human dermal fibroblasts (HDFs).ResultsHDFs stimulated with paracrine factors from M1 macrophages showed a 10 to > 100-fold increase in the expression of the inflammatory cytokines IL6, CCL2 and CCL7 and the matrix metalloproteinases MMP1 and MMP3. This indicates that factors produced by M1 macrophages induce a fibroblast phenotype with pro-inflammatory and extracellular matrix (ECM) degrading properties. HDFs stimulated with paracrine factors secreted by M2 macrophages displayed an increased proliferation rate. Interestingly, the M1-activated pro-inflammatory fibroblasts downregulated, after exposure to paracrine factors produced by M2 macrophages or non-conditioned media, the inflammatory markers as well as MMPs and upregulated their collagen production.ConclusionsParacrine factors of M1 or M2 polarized macrophages induced different phenotypes of HDFs and the HDF phenotypes can in turn be reversed, pointing to a high dynamic plasticity of fibroblasts in the different phases of tissue repair.

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A previous immunophenotyping study in the fetal uterine cervix provided evidence for the existence of 2 subpopulations of reserve cells, one giving rise to glandular epithelium and the other to squamous epithelium (5). In this study, we investigated whether the adult uterine cervix also harbors different populations of reserve cells on the basis of their marker profile and distribution pattern. Sagittal sections from 10 normal uteri, comprising the region from ectocervix to lower uterine cavity, were histologically examined and immunostained for p63, bcl-2 and cytokeratins (CKs) 5, 7, 8, and 17. The endocervical canal consists of three regions, that is, a part lined with squamous epithelium, a part lined with endocervical cells and a part lined with tubal type epithelial cells. Histologically, we found reserve cells in all 10 investigated cervices, with an abundancy in the area beneath the endocervical columnar epithelium close to the squamo-columnar junction, and high in the endocervical canal where the invaginations consist of tubal type epithelium. In between, an area lined with endocervical columnar cells without reserve cells was identified. No reserve cells were detected in the endometrial epithelium. We defined the end of the endocervix as the point where the surface of the cervical canal and the invaginations are completely lined with tubal type epithelium. From this point, reserve cells were no longer found. Reserve cells show strong expression for p63, CKs 5 and 7, and moderate expression for bcl-2. CK17 is strongly expressed in the reserve cells at the squamo-columnar junction and to a lesser extent in the reserve cells close to the endometrium. Endocervical columnar cells usually express CKs 7 and 8 and sporadically also p63 and CK5. CK17 was only found in endocervical cells in the vicinity of CK17-positive subcolumnar reserve cells. Tubal-type epithelium was present in all samples and contained bcl-2, along with CKs 5, 7, and 8. As a result, bcl-2 and CK5 expression distinguishes tubal epithelium from endocervical columnar cells. We conclude that reserve cells are present in all investigated cervices along the entire cervical canal. The concentration of subglandular reserve cells is highest close to the squamo-columnar junction and in the upper third of the cervix. The marker profile of reserve cells is the same in all parts of the cervix, except for CK17, which shows a decreasing gradient from distal to proximal, indicating a subpopulation of distal reserve cells as progenitor for squamous and columnar epithelium, and proximal reserve cells that can serve as progenitor cells for columnar epithelium.