What is the difference between stroma and matrix

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Evidence for circulating bone marrow-derived endothelial cells. Detection of stromal cells in peripheral blood progenitor cell collections from breast cancer patients. Bone Marrow Transplantation, Failure to detect spindle-shaped fibroblastoid cell progenitors in PBPC collections. Co-cultures mostly consisted of stromal and epithelial cells from the same patient. Typically, stromal cells were plated at 10 5 cells per well of a 24 well plate and all conditions were performed in triplicate.

Stromal and epithelial cells in co-culture were identified and visualized by cell specific staining of cytoskeletal proteins. Cultures or tissue sections were rinsed with PBS and fixed with 3.

Controls included samples treated with no primary antibody, but treated with secondary fluorescent antibodies. Samples were rinsed three times with PBS. Fluorescence was visualized using a Nikon Microphot FXA fluorescent microscope with triple-band-pass filter cube containing ultraviolet, rhodamine and fluorescein filters Omega Optical Inc.

DNA synthesis was determined using tritiated thymidine incorporation, as a measure of cell proliferation. Epithelial cells were plated in triplicate in monoculture or co-cultured, as described.

After 4 or 7 days of growth, tritiated 3 H thymidine was added in culture media at a final concentration of 2. After 24 h, the medium was removed. The cells were solublized with 0. Isolated DNA was quantified by spectrophotometric absorbency at nm. To compare indices of differentiated function in mono- and co-cultures of human endometrial epithelium with or without stromal cells, we used the epithelial gene product glycodelin PP Media were assayed for glycodelin using an immunofluorometric assay Koistinen et al.

The immunofluorometric assay used monoclonal antibodies to glycodelin for coating the microtitre wells and secondary labelling with europium III chelate, as previously described Rittinen et al. Plates were incubated overnight at room temperature.

Samples were washed and the secondary antibody, europium III chelate, was added to each well and incubated at room temperature for 2 h. The wells were washed and a fluorescence enhancement solution containing 2-naphtoyltrifluoroacetone and tri-n-octylphosphine oxide was added.

Fluorescence was measured using a fluorometer. For comparison of two populations, a two-sample Student's t -test was used. This model system, as presented, provided the opportunity to examine stromal effects on epithelial growth and differentiation that have not previously been reported. The effect of the BME substrate on stromal and epithelial cell proliferation after 5 days in culture is depicted in Figure 3.

In addition to differences in rate of growth, the morphology of epithelial and stromal cells was dependent on the substrate provided. On plastic, endometrial stromal cells had a characteristic spindled shape, which progressed to a tight fibroblastic growth pattern at confluence Figure 4a. This appearance is similar to that seen in endometrial tissue sections by immunofluorescence Figure 4c , immunofluorescent.

Stromal cells within the tissue also appear singular and stellate with irregular cell borders. Epithelial cells cultured on plastic initially maintained a polyhedral or whorled pattern typical of epithelial cells Figure 4d Satyaswaroop et al. Culture of primary endometrial epithelial cells was limited to less than 2 weeks when cultured on plastic; cell integrity deteriorated as evidenced by intracellular vacuoles and squamoid morphology.

These cells assumed three-dimensional spherical and tubular structures Figure 4f. Since a distinction between cell types in co-culture was difficult using phase microscopy alone Figure 5a , epithelial cells were labelled using anti-cytokeratin antibodies and Texas Red fluorochrome and stromal cells with vimentin antibodies and using fluorescein FITC-green fluorochrome.

The nuclei of all cells were stained blue with DAPI. As shown in Figure 5b—f , the dynamic nature of epithelial cell—stromal cell interaction is mediated in part by the presence of this extracellular matrix. In cross-section and at higher power this was more evident Figure 5d. The cytoplasmic projections from single stromal cells sometimes appeared to project towards specific epithelial cells Figure 5e. When endometrial epithelial and stromal cells were co-cultured on plastic, this higher order of organized association was not apparent Figure 5g.

Finally, to determine if the presence of stromal cells could modulate specific gene expression by endometrial epithelial cells, we studied the secretion patterns of glycodelin as a biomarker of endometrial epithelial cell differentiation. Glycodelin was measured in media obtained from endometrial epithelial cells in both monoculture and in co-culture. In the present study, we have utilized the now established methods of isolation and culture of primary endometrial epithelial and stromal cells, but applied to those methods a novel modification that restores a more normal and physiological cell—cell interaction.

Using this model we have demonstrated three-dimensionally organized epithelial—stromal interactions, regulation of cell proliferation, and induction of differentiated epithelial gene expression. By exposing stromal cells to basement membrane material, we find that the adjacent epithelial cells display a reduction in proliferation and an increased expression of the epithelial gene product, glycodelin.

By restoring the three-dimensional milieu of the extracellular matrix, we believe that we have recreated what occurs in living tissues, namely a paracrine relationship between stromal and epithelial cells both interacting with a basement membrane.

Attempts to demonstrate stromal regulation of epithelial cell function have been explored in other tissues with the development of various cell culture models.

In collagen gels, fibroblasts induced epithelial tubular morphogenesis in MDCK kidney cells Montesano et al. Media conditioned by stromal cells was shown to inhibit proliferation of prostate epithelial cells in vitro Kooistra et al. Stromal induction of prostatic epithelial differentiated function has also been studied by Chung et al.

Chung et al. Co-culture models have also been developed for keratinocytes Konig and Bruckner-Tderman, ; Fusenig, and for mammary cells in which stromal cells were found to regulate epithelial function through interaction with extracellular matrix constituents Haslam, ; Haslam and Counterman, Few in-vitro studies using human endometrial cells have been successful at demonstrating such differences in epithelial proliferation or regulation of differentiated cell function that are dependent on the presence of stromal cells.

The human endometrium is a very relevant tissue for investigating the influence of the tissue micro-environment on epithelial growth and differentiation. In the adult, the endometrium undergoes cyclic developmental changes that can be studied in the context of endocrine, paracrine and extracellular influences. Methods to separate and culture endometrial stromal and epithelial elements have now been well established, and the purity and morphology have been described Kirk et al. The importance of the extracellular matrix for epithelial polarization has previously been demonstrated for endometrial cells Schatz et al.

Epithelial cells in culture express endometrial specific secretory products Wegner and Carson, and can respond to the ovarian steroid hormones Astrahantseff and Morris, ; Osteen et al. The configuration of cell co-culture used in this study is the first that we are aware of to place stromal cells in direct contact with basement membrane material.

Our data suggest that optimal configuration for stromal growth inhibitory effect in co-culture was when stromal cells were not only in the presence of BME but also in direct proximity to the epithelial cells.

Whereas much of the extracellular matrix of the interstitial stroma is primarily comprised of fibronectin Fazleabas et al. Endometrial epithelial cells attach to the basement membrane proteins and become polarized through specific interactions with cell adhesion molecules Davis and Camarillo, ; Strunck and Vollmer, ; Fukushima et al. What has not been appreciated is the effect basement membrane proteins may have on the cells that reside on the side opposite to the epithelial cells, namely the stroma.

Since stromal cells are now suspected of having major roles in epithelial growth and differentiation in adult tissues Cunha et al. Basement membrane itself, which has two sides, may be the stimulus required for a differentiation of stromal cells toward this paracrine role. Only the stromal cells adjacent to basement membrane expressed this growth factor, while stromal cells away from the basement membrane and epithelial cells displayed little if any HB—EGF expression B.

Lessey et al. To investigate further the paracrine effects of stromal cells on epithelial cell function, several gene products were considered as potential markers of differentiation. This glycoprotein has an extensive carbohydrate content and may have contraceptive potential by inhibiting binding of human spermatozoa to the zona pellucida in vitro Dell et al.

Glycodelin has also been demonstrated to exhibit immunosuppressive activity Okamoto et al. While the exact function of glycodelin remains to be elucidated, its synthesis increases in endometrium around the time of implantation and early pregnancy, suggesting a role in the establishment of pregnancy Klentzeris et al.

Glycodelin can be assayed readily using immunofluorometric techniques as described in the present study. As such, the use of this hormone-regulated endometrial gene product was ideal for examining the effect of stromal cells on epithelial differentiation in our co-culture model system.

The regulation of glycodelin expression has previously been used to assess differentiation in endometrial epithelial cells in vitro. Preliminary data by White et al.

White et al. Mixed endometrial cell cultures grown on a plastic substrate were reported to exhibit glycodelin concentrations that rapidly declined in culture within the first week Chatzaki et al. It was noted that this decrease in glycodelin was associated with a parallel increase in epithelial cell senescence.

As with any model, this co-culture system has both advantages as well as limitations. While we would like to recreate conditions in vivo as much as possible, we have not included other endometrial cellular components such as endothelial cells, immunological cells or myometrium; all of these cells may play a role in the function of this complex tissue. It was, perhaps, fortuitous that inclusion of only isolated epithelial and stromal cells demonstrated the restoration of epithelial responsiveness.

Stromal cells, epithelial cells and contact with basement membrane proteins may be the minimal requirements for in-vitro restoration of endometrial growth and differentiation. For endometrium, this model will have significant impact for the investigation of implantation and the establishment of uterine receptivity as well as elucidating factors that favour the development of endometrial hyperplasia or cancer. Furthermore, the important relationships between cells, endocrine and paracrine responses, and the extracellular matrix can now be more logically dissected and analysed.

The model proposed here, in which stromal cells encounter BME, illustrates the importance of the tissue micro-environment and its effect on cell function. This simple alteration to the traditional methods for endometrial cell culture yields striking new results and provides potentially new insights into important questions in cell biology. Schematic showing the strategy for isolation of endometrial stromal and epithelial components from primary tissues.

This technique of using collagenase followed by sequential sieves to isolate glandular epithelium and stroma is based on the work of Satyaswaroop and colleagues Satyaswaroop et al. Digested endometrium passed over the sieves effectively separates glandular structures from the individual stromal cells and red blood cells. Monoculture and co-culture configurations used to demonstrate paracrine and extracellular matrix mediated effects of stromal cells. Basement membrane extract BME alone was used to culture glandular epithelial cells in monoculture A.

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