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The Journal of Clinical Endocrinology & Metabolism Vol. 88, No. 2 844-849
Copyright © 2003 by The Endocrine Society

Contractile Activity of Human Decidual Stromal Cells

María Kimatrai, Carmen Oliver, Ana Clara Abadía-Molina, José Marcos García-Pacheco and Enrique G. Olivares

Unidad de Inmunología, Facultad de Medicina, Universidad de Granada (M.K., C.O., A.C.A.-M., E.G.O.), 18012 Granada, Spain; and Unidad de Inmunología y Biología Molecular, Hospital do Meixoeiro (J.M.-G.-P.), 36200 Vigo, Spain

Address all correspondence and requests for reprints to: Dr. Enrique G. Olivares, Unidad de Inmunología, Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad de Granada, 18012 Granada, Spain. E-mail: engarcia{at}ugr.es.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
We previously demonstrated that human decidual stromal cells (DSC), the main cellular component of the decidua, are similar in antigen phenotype and structure to myofibroblasts, cells with contractile activity. In this work we isolated and maintained DSC in fibroblast medium, in which these cells show a stable phenotype similar to that of DSC in vivo. Flow cytometric observations showed that most DSC expressed {alpha}-smooth muscle ({alpha}-SM) actin, an intermediate filament that is considered a marker of myofibroblasts and is responsible for the contractile activity of these cells. {alpha}-SM actin mRNA was detected by RT-PCR in these cells. The contractile activity of DSC was determined by the gel contraction assay; we found that TGFß1 and platelet-derived-growth factor, cytokines that are known to be inducers of myofibroblast contractility, also induced contractility of DSC. IL-2, a Th1 cytokine-related with spontaneous abortion, also activated DSC contractility. Our results confirmed that DSC are phenotypically and functionally related with myofibroblast.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
DECIDUAL TISSUE, THE maternal component of the maternal-fetal interface, is composed predominantly of typical stromal-type cells as well as glandular cells and leukocytes (1). Decidual stromal cells (DSC) constitute a distinctive cell class that originates from the proliferation and differentiation (decidualization) of a fibroblast-like stromal cell precursor (preDSC) already detected in the endometrium (2). During the luteal phase of the menstrual cycle or if pregnancy takes place, preDSC are induced to decidualize by progesterone (3). Decidualized cells become rounder, express desmin in their cytoplasm, and secrete PRL (4, 5, 6). Although their function, cell lineage, and origin are not fully understood, human and murine DSC or endometrial stromal cells (ESC), the DSC counterpart in nongestating endometrium, have been shown to be involved in different immune functions, such as the production of cytokines (7, 8, 9, 10), antigen presentation (11), and phagocytosis (12). These cells also express antigens associated with hemopoietic cells (11, 13, 14). Furthermore, inflammatory and Th1 cytokines inhibit decidualization (15, 16, 17). The immune activities of DSC together with their bone marrow origin have led some researchers to propose that DSC might be true immune cells (18). Nevertheless, we have demonstrated in humans that DSC are related to the bone marrow stromal precursors rather than to the hemopoietic lineage (19), and their morphology and phenotype are similar to those of myofibroblasts (20), fibroblastic cells with contractile activity that are involved in wound retraction. Here we investigate the contractile activity of DSC to confirm the relationships of these cells with myofibroblasts. We also studied the effect of IL-2, a Th1 cytokine that blocks the decidualization of DSC (17) and is related to spontaneous abortion (21), on DSC contractility.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Tissues

Eighteen samples from elective vaginal terminations of first trimester pregnancy (6–11 wk) from healthy patients, aged 20–30 yr, were used. In 14 patients this was their first pregnancy, and of the 4 patients who had prior pregnancies (1, 1, 3, and 3 pregnancies) only 1 had had one previous spontaneous abortion. We excluded women receiving any medication or with infectious, autoimmune, or other systemic or local diseases. None of the abortions was pharmacologically induced. The specimens were obtained by vaginal curettage at the Clínica El Sur (Málaga, Spain), Clínica los Cármenes (Granada, Spain), and Hospital Universitario de San Cecilio (Granada, Spain). Informed consent was obtained from each patient. This study was approved by the research and ethics committee of Hospital Universitario de San Cecilio.

Fibroblast medium

According to the information provided by the manufacturer (Sigma-Aldrich, St. Louis, MO), fibroblast medium contains fibroblast basal medium (a modified version of the culture medium MCDB 105) supplemented with 2% fetal calf serum (FCS), and unspecified amounts of basic fibroblast growth factor, heparin, epidermal growth factor, and hydrocortisone.

Isolation and culture of DSC

Decidual tissues were examined histologically to exclude the presence of infection or inflammatory infiltration. Samples of decidua from different patients were not mixed so as to avoid the induction of cytokine secretion as a result of the allogeneic reaction of leukocytes that initially contaminate DSC cultures. Tissues were thoroughly washed in PBS solution, and the decidua was carefully freed from the trophoblast. Decidual fragments were finely minced between two scalpels in a small volume of RPMI 1640 medium with 100 U/ml penicillin and 50 µg/ml gentamicin, and put in a solution of 0.5% trypsin and 0.2% EDTA (Sigma-Aldrich) for 15 min at 37 C. The reaction was stopped by adding cold RPMI with 20% FCS (Life Technologies, Inc., Paisley, UK); the suspension was filtered through gauze and centrifuged at 425 x g for 10 min. The supernatant was discarded, and the cell pellet was suspended in RPMI and centrifuged on Ficoll-Paque (Pharmacia Biotech, Uppsala, Sweden) for 20 min at 600 x g. Cells were collected from the interface, suspended in PBS, and washed. This suspension, containing mainly DSC and leukocytes, was incubated in culture flasks for 1 h in complete RPMI with 10% FCS to allow macrophages, granulocytes, and gland cells to adhere to the flask. The supernatant, containing DSC and lymphocytes, was washed and incubated in fibroblast medium with 100 U/ml penicillin and 50 µg/ml gentamicin. After overnight incubation to allow DSC to adhere to the flask, lymphocytes in the supernatant were discarded. The remaining adherent cells were mainly DSC. Fibroblast medium was then replaced and changed twice a week, and after 2–4 wk, adherent cells covered the whole surface of the 25-cm2 culture flask. Proliferating DSC overgrew other possible contaminant cells, thus further guaranteeing the purity of the cultures. Purity was further confirmed using flow cytometry to detect the coexpression of CD10 and CD13 and the lack of CD45 antigens by DSC (11, 12, 13, 14, 19, 20, 23). In fibroblast medium, cells proliferated for 8–12 wk; during this period their antigen phenotype was stable (19). Supernatants from confluent cultures were collected, concentrated 10-fold in a Miniplus concentrator (Amicon, Beverly, MA), and analyzed for the presence of PRL with an electrochemiluminescence immunoassay (Roche, Indianapolis, IN).

Monoclonal antibodies (mAb)

The mAb used in this study are shown in Table 1Go.


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  		Table 1. mAb used in this study

 
Flow cytometry

Decidual stromal cells were detached from the culture flask by treatment with 0.04% EDTA at 37 C. Cells were centrifuged, the supernatant was discarded, and the pellet was suspended in PBS at 106 cells/ml. For direct staining, 100 µl of the cell suspension was incubated with 10 µl of the appropriate monoclonal antibody for 30 min at 4 C in the dark. Cells were washed, suspended in 1 ml PBS, and immediately analyzed in a flow cytometer (Ortho-Cytoron, Ortho Diagnostic Systems, Raritan, NJ). To identify dead cells we incubated DSC with propidium iodide (Sigma-Aldrich). The percentage of cells that were antibody positive was calculated by comparison with the appropriate isotype control (Table 1Go). For double labeling, we followed the same procedure, except that a second mAb with a different fluorescent marker from the first mAb was also added. For indirect labeling, FITC-labeled goat antimouse immunoglobulin was added after the first mAb. For intracytoplasmic labeling, DSC were fixed with 4% paraformaldehyde for 20 min at 4 C and permeabilized with cold acetone for 10 min before the mAb was added.

PCR primers

Primers used in this study are shown in Table 2Go. They were designed according to sequences available from GenBank (http://www2.ncbi.nlm.nih.gov/) and synthesized by Genset (Paris, France). To prevent the amplification of contaminant genomic DNA, sense and antisense primers were designed, when possible, from sequences located far apart on different exons and tested in PCR reactions with RNA used in cDNA synthesis.


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  		Table 2. Primer sequences used for RT-PCR

 
RT-PCR

Total RNA from cells was extracted by the Ultraspec RNA isolation method according to the manufacturer’s protocol (Biotecx Laboratories, Inc., Houston, TX). A single-strand cDNA copy was made from total RNA using random hexamers (Pharmacia Biotech) and Moloney murine leukemia virus H- ribonuclease reverse transcriptase (Promega Corp., Madison, WI). After heating to 65 C for 5 min and quickly cooling to 4 C in a thermal cycler (Geneamp PCR System 9600, PerkinElmer/Cetus, Norwalk, CT) for denaturation, RT was performed for 1 h at 37 C. Starting with the equivalent of 75 ng RNA, amplification was carried out in a total volume of 12.5 µl of the amplification mix, 10 mM Tris-Cl (pH 8.4), 50 mM KCl, 2 mM MgCl2, 0.01% gelatin, 0.2 mM deoxy-NTPs, 5% glycerol, 0.25 mM of each primer, and 0.02 U/ml Taq DNA polymerase (Promega Corp.). After incubation for 5 min at 96 C, each cycle consisted of 94 C for 30 sec, 57 C for 30 sec, and 72 C for 30 sec, for a total of 32 cycles. One microliter of the first round product was used for the second 32-cycle round. The PCR products were size-separated on ethidium bromide-stained 2% agarose gels, and a 100-bp DNA ladder was included in each run.

Cytokines

TGFß1, platelet-derived-growth factor BB (PDGF-BB) and IL-2 were purchased from Sigma.

Gel contraction assay

Cellular collagen gel contraction assays were performed as previously described (22). A sterile solution of purified, pepsin-solubilized bovine dermal collagen (Vitrogen, Cohesion Technologies, Inc., Palo Alto, CA) was prepared according to the manufacturer’s instructions and combined with 25 x 104 DSC. The collagen/cell mixture (100 µl/well) was dispensed into culture plates and allowed to polymerize at 37 C for 30 min. Immediately after polymerization, 2 ml fibroblast medium with or without the appropriate cytokine was added to each well. After incubation for 24 h, the height (h) and diameter (d) of each gel were measured with a microscope micrometer, and the volume (V) of each gel was calculated with the following formula: V = 1/24 x {pi} x h x (3 x d2 + h2). The mean of the measurements (n = 3 for each sample) taken at each concentration point was used to estimate gel volume. The data are presented as the percent gel contraction of cytokine-treated DSC compared with that of cells cultured in the absence of cytokine calculated with the following formula: cell contractility (%) = 100 x (V with no cytokine - V with cytokine)/V with no cytokine. As a negative control for cell contractility in gel, we used the Ramos cell B lymphoma line. These cells are unable to adhere to surfaces (plastic or gel). They are therefore unable to contract gels, because this activity depends on adhesion to the gel matrix. Ramos cells were cultured in RPMI 1640 medium with 100 U/ml penicillin, 50 µg/ml gentamicin, and 10% FCS before the assay.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
DSC lines

DSC lines with fibroblast-like morphology (Fig. 1Go) were obtained in fibroblast medium 2–4 wk after the primary culture. With flow cytometry we observed that most DSC expressed CD10 and CD13, but lacked CD45 (Fig. 2Go). This matches the basic antigen phenotype of human ESC and DSC, as reported by several researchers (11, 12, 13, 14, 19, 20, 23). Moreover, CD10 is considered a marker for these cells (24). These results confirmed the purity of the cultures and the absence of contaminant hemopoietic cells. Also, as previously reported (19), most cultured DSC were positive for alkaline phosphatase (ALP), and some lines expressed human leukocyte antigen DR (HLA-DR). {alpha}-Smooth muscle ({alpha}-SM) actin, a marker for myofibroblasts (25), was detected in most DSC (Fig. 2Go).



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  		Figure 1. DSC lines cultured in fibroblast medium showed fibroblast-like morphological features.

 


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  		Figure 2. Flow cytometric analysis of the antigens expressed by cultured DSC. Each mAb was matched with its respective isotype control.

 
Detection of {alpha}-SM actin mRNA in cultured DSC

The expression of {alpha}-SM actin was confirmed by RT-PCR. {alpha}-SM actin mRNA, together with CD10, CD13, ALP mRNAs, were detected in all DSC lines (Fig. 3Go). Because PRL is secreted by DSC only when they are cultured with progesterone (6), and our cultures lacked this hormone, we did not detect PRL in the supernatants (results not shown). Nevertheless, small amounts of PRL mRNA were detected in some lines. As found for HLA-DR expression detected by flow cytometry, some, but not all, DSC lines expressed HLA-DRB mRNA (Fig. 3Go). Although DSC cultured in fibroblast medium show a stable antigen phenotype equivalent to that displayed by these cells in vivo (11, 14, 19, 20, 23), and we did not observe any significant change in the expression of the antigens during this study, the detection of HLA-DR-positive and HLA-DR-negative DSC lines may indicate that HLA-DR is modulated negatively in culture.



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  		Figure 3. Expression of CD10, CD13, {alpha}-SM actin, ALP, PRL, and HLA-DRB mRNAs by two different lines of DSC (GR-1 and MA-3) examined by RT-PCR.

 
Contractile activity of cultured DSC

To determine whether the expression of {alpha}-SM actin by DSC correlated with a functional phenotype, we examined the effects of TGF-ß1 and PDGF, two cytokines with the capacity to induce cell contractility in fibroblast cells (26), on DSC plated on collagen. Both cytokines induced cell contractility in DSC in a dose-response manner (Fig. 4Go). IL-2, a cytokine able to block decidualization (17) and related to spontaneous abortion (21), also induced cell contractility in cultured DSC. None of these cytokines, however, showed any effect in the Ramos cells used as a negative control (Fig. 4Go).



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  		Figure 4. Induction of contractility in lines of DSC by TGFß1, PDGF, and IL-2, determined by the collagen gel contraction assay. Each curve (•, {square}, {blacktriangleup}, {diamond}, {triangleup}, {triangledown}, {blacksquare}, and {diamondsuit}) represents the contractile activity of a different DSC line. As a negative control for gel contraction we used Ramos cells ({circ}). The mean of measurements (n = 3 for each sample) taken at each concentration point was used to estimate contractility. The data are presented as the percent gel contraction ± SD of cytokine-treated DSC compared with that of cells cultured in the absence of cytokine.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Although the many immune activities of DSC and their probable bone marrow origin led some researchers to propose that these cells belonged to the hemopoietic lineage (18), we recently demonstrated that human DSC are related to the bone marrow stromal precursors, multipotent stromal cells that differentiate into different types of mesenchymal cell (19). Furthermore, the cytoskeletal filament phenotype and ultrastructural morphology of DSC are similar to those of myofibroblasts (20). In this study we show that cultured DSC express {alpha}-SM actin and mRNA for {alpha}-SM actin, a microfilament that is considered a marker of myofibroblasts (25). Because DSC were able to contract collagen gel matrixes, we conclude that they are also functionally related to myofibroblast. Furthermore, like DSC, fibroblasts and myofibroblasts express antigens associated with hemopoietic cells (27, 28), secrete cytokines (29), costimulate T lymphocyte proliferation (30), and appear to be involved in transplant rejection (31). Under the regulation of local cytokines, both DSC and myofibroblasts produce matrix metalloproteinases, enzymes that degrade the interstitial matrix. In intestinal myofibroblasts, this degradation leads to the shedding and epithelial renewal of the intestinal mucosa (32); in the ESC, the process leads to the loss of integrity of blood vessels, destruction of the endometrial interstitial matrix, and the resultant bleeding characteristic of menstruation (33). The contractile activity of ESC may favor expulsion of the endometrium during menstruation.

TGFß1 and PDGF, two cytokines reported to induce contraction in myofibroblasts (26), also activated the contractility of DSC. The fact that these cytokines also inhibit decidualization (34) suggests that contractile activity is carried out mainly by preDSC. In this connection our cultured DSC are related to preDSC rather than to decidualized DSC (19). After primary culture, only DSC with the ability to proliferate are positively selected. In the absence of progesterone in the culture medium, these cells can be assumed to correspond to preDSC (5, 6, 19). In fact, like preDSC, DSC cultured in fibroblast medium did not secrete PRL (results not shown). The fact that preDSC are located around the vessels (35) suggests that these contractile cells may play a role in blood flow regulation.

TGFß1 and PDGF also stimulated DSC proliferation, probably by affecting preDSC, in view of the antidecidualizing effect of these cytokines (34). In humans, decidual tissue has been shown to express TGFß1 mRNA (36) and mRNA for PDGF-A and PDGF-B (37). PDGF receptors were found on both DSC (37) and ESC (38), and TGF type II receptor was detected on ESC (39). Furthermore, PDGF and TGFß1 have been detected in ESC (38, 39), and these cells were reported to be the source of these cytokines (40, 41), although TGFß1 is also produced by epithelial cells (41), suggesting that autocrine and paracrine mechanisms take place in the induction of DSC or ESC contractility.

Another functional role of the contractile activity of DSC may be in trophoblast expulsion during spontaneous abortion. There is increasing evidence that the immune system is involved in normal pregnancy and abortion (42). In mice and humans, normal pregnancy is related to the local and peripheral production of Th2 cytokines (43), whereas abortion is associated with Th1 cytokine production (21, 43). Progesterone up-regulates the production of Th2 cytokines by lymphocytes (44) and inhibits the production of Th1 cytokines (45). Decidual stromal cells show membrane receptor for IL-2 (46), a Th1 cytokine. IL-2, like TGFß1 and PDGF, inhibited decidualization (17) and, as shown by our findings, also induced DSC contractility. Progesterone, the hormone that favors pregnancy, differentiates DSC to a progestation status and blocks their immune activities (7, 12), whereas cytokines such as TGFß1, PDGF, and IL-2 inhibit decidualization (17, 34) and favor the contractile activity of DSC, which may lead to expulsion of the trophoblast. The fact that levels of IL-2 (21) and TGFß1 (47) are elevated in spontaneous abortion supports this view and suggests the existence of an immunological-endocrinological cross-talk involving DSC, which may lead to either normal pregnancy or spontaneous abortion.


   Acknowledgments
 
We are grateful to Drs. S. Jordán and C. Sánchez from the Clínica el Sur (Málaga) for providing us with decidual specimens. We thank K. Shashok for improving our use of English in this manuscript.


   Footnotes
 
This work was supported by grants from the Fondo de Investigaciones Sanitarias de la Seguridad Social (Spanish Ministry of Health).

Abbreviations: ALP, Alkaline phosphatase; DSC, decidual stromal cell; ESC, endometrial stromal cell; FCS, fetal calf serum; HLA, human leukocyte antigen; mAb, monoclonal antibody; PDGF, platelet-derived-growth factor; preDSC, decidual stromal cell precursor; {alpha}-SM, {alpha}-smooth muscle.

Received August 2, 2002.

Accepted November 18, 2002.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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