Mesenchymal Cells of the Intestinal Lamina Propria – PMC – NCBI

Molecular Markers

Conventionally, myofibroblasts have been identified by their expression of various in-tracellular cytoskeletal proteins—the microfilament α-smooth muscle actin (α-SMA), type 3 intermediate filaments such as vimentin or desmin, and collagen type 1 maturation enzymes such as prolyl-4 hydroxylase—and by the absence of epithelial cytokeratins (3, 10). Although various combinations of these markers have been used to demonstrate the plasticity of myofibroblasts, operationally intestinal myofibroblasts are defined by their expression of α-SMA together with their location and structure and are considered activated fibroblasts. α-SMA remains the best single (but not exclusive or absolutely specific) marker of the subepithelial myofibroblast network and of the other mesenchymal elements of the lamina propria, i.e., mural cells (pericytes; please see related side bar) (1, 11), bone marrow-derived stromal stem cells (11, 12), the muscularis mucosae (13), and the smooth muscle of the small intestinal villus core (14). All express α-SMA. Although the stromal stem cells are difficult to identify by routine histology of tissue sections, the lamina propria smooth muscle fibers of the small intestine are prominent. When histological sections are properly aligned, these smooth muscle fibers of the small intestinal villus are closely associated with the lymphatic lacteals (Figure 1), a conclusion supported by comparing α-SMA-stained histological sections with published scanning electron micrographs of corrosion casts of intestinal lacteals (15) and immunohistochemical sections stained with antibodies against the lymphatic endothelium (LYVE1, a hyaluronan receptor) (16). The idea that these villus core smooth muscle cells surround the lacteal and through piston-like contractions propel lymph to lymph nodes and eventually to the thoracic duct was first proposed in the late 1960s, and the physiology of this system was reviewed in 1989 (17). Intermediate filament stains differentiate the myofibroblasts and mural cells from the muscularis mucosae and the lymphatic lacteal. The muscularis mucosa and the smooth muscle of the villus core stain poorly with antibodies against vimentin but react strongly to desmin antibodies, whereas the myofibroblasts and mural cells stain weakly (if at all) for desmin (13, 14, 18). The intestine of the α-SMA-null mouse has not been studied in detail. These animals have no difficulty feeding or reproducing but have impaired vascular contractility and blood pressure control (19), suggesting that other actin isoforms can substitute for some functions in the digestive and urogenital tracts. Interferon-γ (IFN-γ) downregulates α-SMA (20), suggesting caution when one identifies myofibroblasts in intestinal inflammatory states.

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To facilitate identification of the mesenchymal elements of the lamina propria, novel markers have been sought. In the human intestine, both fibroblasts and myofibroblasts express CD90 (cluster of differentiation 90), also known as Thy-1 (thymocyte differentiation antigen-1). Thy-1 is a 25-37-kDa, extracellular glycosylphosphatidylinositol-linked glycoprotein that is expressed by subsets of fibroblasts, myofibroblasts, mesangial cells, vascular pericytes, hematopoietic and mesenchymal stem cells (MSCs), and activated endothelial cells. It is also expressed by some murine neurons and murine T cells (21, 22). There is also a soluble form of Thy-1, which is either secreted or cleaved from the surface of producing cells. We used antibodies against this surface protein to identify the human intestinal myofibroblast-fibroblast-pericyte network. Diffuse staining of the matrix associated with the network suggests that the extracellular matrix may capture soluble Thy-1 (23). In both human myometrium and orbit, Thy-1+ and Thy-1− fibroblasts exist. Only Thy-1+ fibroblasts can differentiate into myofibroblasts after treatment with transforming growth factor (TGF)β, whereas only Thy-1− fibroblasts differentiate into lipofibroblasts upon exposure to 15-deoxy-δ-prostaglandin J2 (24). Thy-1 subtypes in other tissues show different abilities to secrete cytokines, eicosanoids, and collagens or to express major histocompatibility complex (MHC) class II molecules upon stimulation (25). We conclude that the human intestinal stromal cell compartment can be identified but not exclusively defined by the reaction to Thy-1 antibodies.

Antibodies against intracellular components of thymus stromal cells (reticular fibroblasts) such as monoclonal antibody clones ER-TR7 (26, 27) and TE-7 (28) have immunoreactivity with fibroblasts, myofibroblasts, pericytes, and lymphatic stromal cells. Preliminary studies in our laboratory show reactivity of Thy-1, ER-TR7, and α-SMA against these mesenchymal elements of the lamina propria, and confocal microscopic merged images give promise that the combination may be useful in demonstrating the villus smooth muscle (lymphatics) and the subepithelial myofibroblast network. Furthermore, an extensive study of 72 different markers suggests that ER-TR7 and TE-7 may be useful in differentiating fibroblasts from tissue macrophages, monocytes, and fibrocytes (stromal stem cells) (29).

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