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The Journal of Clinical Endocrinology & Metabolism Vol. 82, No. 10 3319-3323
Copyright © 1997 by The Endocrine Society

Original Studies

Keratinocyte Growth Factor Expression in the Mesenchymal Cells of Human Amnion1

M. Linette Casey and Paul C. MacDonald

The Cecil H. and Ida Green Center for Reproductive Biology Sciences and the Departments of Obstetrics-Gynecology and Biochemistry, The University of Texas Southwestern Medical School, Dallas, Texas 75335

Address all correspondence and requests for reprints to: M. Linette Casey, Cecil H. and Ida Green Center for Reproductive Biology Sciences, University of Texas Southwestern Medical School, 5323 Harry Hines Boulevard, Dallas, Texas 75335. E-mail: casey{at}grnctr.swmed.edu


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Amnion epithelial and mesenchymal cells were separated by differential protease treatment, and the separated cells were maintained in monolayer culture. Keratinocyte growth factor (KGF) messenger RNA (mRNA) was readily detected by Northern analysis of amnion mesenchymal cell total RNA (10 µg) but not in amnion epithelial cells. Treatment of the amnion mesenchymal cells in serum-free medium with tetradecanoyl phorbol acetate (1 nM) caused an increase in the level of KGF mRNA. Forskolin treatment also caused an increase in KGF mRNA but not to the levels attained with tetradecanoyl phorbol acetate treatment. Dexamethasone (1 nM) treatment of these cells effected a reduction in the level of KGF mRNA. Prolonged maintenance of mesenchymal cells in serum-free medium also was associated with an increase in the level of KGF mRNA. Treatment with a variety of other agents, viz., interleukin (IL)-1, IL-6 plus or minus IL-6 soluble receptor, IL-11, oncostatin M , epidermal growth factor (EGF), and transforming growth factor-ß did not modify the level of KGF mRNA. Treatment of amnion epithelial cells with KGF caused an increase in the rate of [3H]thymidine incorporation, but the rate of cell replication induced by KGF was less than that induced by treatment with EGF. Transforming growth factor-ß treatment inhibited basal and EGF- and KGF-stimulated amnion epithelial cell replication. The findings of this study are indicative that KGF is expressed in human amnion mesenchymal cells, and that KGF may act on the epithelial cells of this tissue.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
THE HUMAN amnion is a unique avascular tissue that contributes the principal resistance of the fetal membranes to rupture and tearing, and the interstitial collagens of the amnion are the primary source of this tensile strength (1). Preterm premature rupture of the fetal membranes (PT-PROM) is the direct antecedent of preterm delivery in upwards of 40% of pregnancies delivered before 34 weeks gestation (2, 3, 4). Unfortunately, however, very little is known about either the cellular processes that maintain the structural integrity of the amnion, and thereby the tensile strength of this tissue, or the cause(s) of PT-PROM.

There are two principal cell types of the human amnion, i.e. the epithelial cells, which create a continuous lining adjacent to the amniotic fluid, and the sparsely distributed mesenchymal cells, which form a loosely connected cellular network between the zona compacta and the zona spongiosa. In addition, there are a few fetal macrophages in this tissue, but there are no smooth muscle, lymphatic, vascular, or nerve tissue components in human amnion (5). Early in embryogenesis, before 8 weeks gestation, the amnionic membrane is comprised of a layer of mesenchymal cells that lie immediately beneath the layer of epithelial cells. At this stage of development, there are approximately equal numbers of epithelial and mesenchymal cells that comprise a two-cell layer amnionic membrane (6). By 10–14 weeks gestation, the mesenchymal cells have been separated from the epithelium by interstitial collagens that are deposited between the two layers of amnion cells in the formation of the zona compacta. After the first trimester of pregnancy, the epithelial cells replicate at a very slow rate sufficient to accommodate expansion of the amnionic sac so that a continuous layer of contiguous epithelial cells is maintained; but by the third trimester of pregnancy, there are only about 1/10th as many mesenchymal as epithelial cells as the mesenchymal cells have become widely dispersed (7).

Very few studies have been conducted to define mesenchymal-epithelial cell interactions in the amnion; indeed, the mesenchymal cells of this tissue have been largely ignored. Perhaps this has been the case because of the prominence of the amnion epithelium and its specialized microvillous structure together with the ease of separation of epithelial cells in vitro as a highly purified preparation. In any event, virtually all studies of amnion cellular function have been conducted with epithelial cells. It has been demonstrated recently, however, that critical functions of the amnion are vested in the mesenchymal cells. For example, the interstitial collagens, which make up the zona compacta of the amnion (the source of amnion tensile strength), are synthesized/processed exclusively in the mesenchymal cells (7). The enzyme lysyl oxidase, which catalyzes the initial reaction in the cross-linking of interstitial collagen fibrils, also is expressed primarily in the mesenchymal cells (8). In addition, the tissue inhibitor of metalloproteinase-1 is produced preferentially in the amnion mesenchymal cells (9). The cytokines, interleukin (IL)-6 and -8, and monocyte chemoattractant protein-1 are produced preferentially in the mesenchymal cells, and the amnion mesenchymal cells are responsive to phagocytic challenge (Ref. 5 and Casey and MacDonald, unpublished observations).

In this study, the amnion mesenchymal cells were evaluated as a potential source of keratinocyte growth factor [(KGF) also referred to as fibroblast growth factor-7], a unique member of the fibroblast growth factor family that is believed to act exclusively on epithelial cells (10, 11, 12). KGF acts on epithelial cells to effect mitogenesis and differentiation (11, 13) and to prevent epithelial cell apoptosis (14, 15, 16). These functions of KGF, if operative in human amnion, could be important in mesenchymal-epithelial cell interactions in the maintenance of the physical and functional integrity of this tissue.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Collection of amnion tissues and isolation and culture of epithelial and mesenchymal cells

Human amnion tissues were obtained from normal term pregnancies at the time of cesarean section conducted before the onset of labor. The reflected amnion and chorion laeve were separated by blunt dissection. The amnion epithelial and mesenchymal cells were isolated by differential enzymatic dispersion of reflected amnion tissue. The epithelial cells were isolated as described previously after incubation of amnion tissue pieces with trypsin (7, 17). Mesenchymal cells were isolated by incubation of the epithelial cell-depleted pieces of amnion tissue with collagenase as described (7). The separated amnion epithelial and mesenchymal cells were plated separately in plastic culture dishes. Viability of both cell types, determined by evaluation of trypan blue exclusion, was >98%. The cells were maintained in culture in Ham’s F12:DMEM (1:1, vol/vol) that contained heat-inactivated FBS (10%, vol/vol; Gibco BRL, Gaithersburg, MD) and penicillin (200 U/mL), streptomycin (200 µg/mL), and Fungizone (Gibco BRL; 0.5 µg/mL). Twenty-four hours after plating and every 2 days thereafter, the culture medium was changed. The cells were maintained in primary monolayer culture in a humidified atmosphere of air and CO2 (5%) at 37 C and became confluent in 7–14 days. Confluent cells in primary culture were used for all experiments.

Northern analysis

Total RNA was isolated from amnion cells in culture by the guanidinium isothiocyanate/cesium chloride ultracentrifugation method of Chirgwin et al. (18). The cells were solubilized in guanidinium isothiocyanate (4 M), and the mixture was centrifuged over cesium chloride (5.7 M) at 238,000 x g overnight. Total RNA was quantified, size-fractionated by electrophoresis on formaldehyde-agarose (1.1%) gels, transferred electrophoretically to Hybond-N+ membrane (Amersham, Arlington Heights, IL), then fixed to the nylon membrane by exposure to ultraviolet light (Stratalinker; Stratagene, La Jolla, CA). Prehybridization was conducted at 42 C in buffer comprised of formamide (50%), 5x SSC [NaCl (3 M), sodium citrate (0.3 M), pH 7.0], 10x Denhardt, NaH2PO4 (0.05 M), dextran sulfate (5%), and salmon sperm DNA (0.5 mL/mL). KGF complementary DNA (cDNA) was radiolabeled with [{alpha}-32P]deoxycytidine triphosphate using Klenow and random hexamer primers. Hybridization was conducted at 42 C in buffer that contained formamide (50%), 5x SSC, 2x Denhardt, NaH2PO4 (0.02 M), dextran sulfate (10%), and salmon sperm DNA (0.25 mg/mL). After hybridization, the blots were washed twice with 0.1x SSC and SDS (0.1%, wt/vol) for 15 min at room temperature, twice with 0.1x SSC and SDS (0.1%, wt/vol) for 15 min at 42 C, and twice with 0.1x SSC and SDS (0.1%, wt/vol) for 15 min at 55 C. Thereafter, the membranes were exposed to Kodak X-Omat AR film (Eastman Kodak, Rochester, NY) at -80 C for autoradiography. The KGF cDNA was 592 bp of the cDNA reported by Finch et al. (19), synthesized by RT-PCR; the glyceraldehyde 3-phosphate dehydrogenase (G3PDH) oligonucleotide and hybridization conditions have been described previously (8). The presence of equal amounts of total RNA in each lane was assessed by visualization of 28S and 18S ribosomal RNA subunits and by analysis of the levels of G3PDH messenger RNA (mRNA). Each study was conducted with cells derived from amnion tissue of one pregnancy; each study (or a similar study) was conducted on two to four occasions with similar findings.

[3H]Thymidine incorporation into amnion epithelial cells

Confluent isolated amnion epithelial or mesenchymal cells in 24-well dishes were treated for 24 h with medium that contained serum; 24 h later, the medium was changed to serum-free medium. After 24 h in serum-free medium, the cells (replicates of four wells) were treated with serum-free medium that contained test agents for 22 h before the addition of [3H]thymidine (3 µCi/well). Two hours later, the medium was removed, and the cells were rinsed with a solution of NaCl (0.15 M). Distilled water (0.5 mL/well) was added to each well, and the cells were sonicated. Aliquots (in duplicate) of the homogenates were placed on 3-mm filter paper discs (2.4 cm diameter; Whatman International, Maidstone, England), and DNA was precipitated by immersion of the discs in trichloracetic acid (TCA) (20%, wt/vol). The discs were washed extensively and successively in TCA (10%, wt/vol), distilled water, ethanol, and acetone, and then dried; radioactivity on each disc was quantified by scintillation spectrometry.

Materials

Dexamethasone, forskolin, H7, and tetradecanoyl phorbol acetate (TPA) were purchased from Sigma Chemical Co., (St. Louis MO). Transforming growth factor-ß (TGF-ß) from human platelets, recombinant human ILs-1{alpha}, -6, -11, IL-6 soluble receptor, recombinant human epidermal growth factor (EGF), KGF, and oncostatin M were purchased from R & D Systems (Minneapolis, MN) or Becton Dickinson (Bedford, MA).


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
KGF mRNA in amnion epithelial and mesenchymal cells

KGF mRNA was readily detected by Northern analysis of total RNA (10 µg) in separated amnion mesenchymal cells maintained in monolayer culture but was not detected in total RNA from epithelial cells (Fig. 1Go). Treatment of amnion mesenchymal cells with forskolin (10 µM) or TPA (1 nM) for 16 h caused an increase in the level of KGF mRNA. Treatment with H7 (30 µM), an inhibitor of protein kinase A, caused a decrease in the level of KGF mRNA and prevented the increase effected by forskolin (Fig. 1Go). Neither forskolin nor TPA caused an increase in KGF mRNA in amnion epithelial cells.



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  		Figure 1. Northern analysis of KGF mRNA in human amnion epithelial and mesenchymal cells in monolayer culture. Confluent cells in serum-free medium were treated with forskolin (Fsk) (10 µM) for 16 h; some cells were pretreated with H7 (30 µM) for 30 min before treatment with or without forskolin. Total RNA (10 µg applied to each lane) was probed for KGF mRNA (upper panel) or G3PDH (middle panel). A photograph of ethidium-bromide stained 28 S ribosomal RNA subunit is presented in lower panel. Ctl, Untreated cells (control).

 
Treatment of amnion epithelial or mesenchymal cells in serum-free medium with IL-1{alpha} (10 U/mL), IL-6 (20 ng/mL) ± IL-6 soluble receptor (20 ng/mL), IL-11 (10 ng/mL), oncostatin M (10 ng/mL), or TGF-ß (1 ng/mL) for 4 h did not affect the level of KGF mRNA (data not shown).

Effect of TPA on levels of mRNA in amnion mesenchymal cells

Treatment of amnion mesenchymal cells with TPA (1 nM) caused a time-dependent increase in the level of KGF mRNA, which was clearly evident after 4–8 h of TPA treatment and was still greater after 24 h (Fig. 2Go). There was no detectable KGF mRNA in amnion epithelial cells isolated from the same amnion tissue before or during TPA treatment (data not shown).



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  		Figure 2. Northern analysis of KGF mRNA in human amnion mesenchymal cells. Confluent mesenchymal cells in serum-free medium were treated with TPA (1 nM) for 1, 2, 4, 8, or 24 h. Total RNA (10 µg applied to each lane) was evaluated for KGF mRNA (upper panel) and G3PDH (lower panel).

 
Effect of cell starvation and forskolin treatment on levels of KGF mRNA in amnion mesenchymal cells

The level of KGF mRNA increased in a time-dependent manner during maintenance of the cells in serum-free medium without added test agents (Fig. 3Go). The increase in KGF mRNA with forskolin (10 µM) treatment was somewhat greater than that attained in serum-free medium, but the increases were parallel in time, and maximum levels of KGF mRNA were observed after 120 h of treatment (Fig. 3Go). KGF mRNA was not observed in amnion epithelial cells isolated from the same amnion tissue and treated in an identical manner (data not shown).



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  		Figure 3. Northern analysis of KGF mRNA in human amnion mesenchymal cells. Confluent cells in serum-free medium were treated with forskolin (10 µM) for 2, 6, 24, or 120 h. Total RNA (10 µg applied to each lane) was probed for KGF mRNA (upper panel) or G3PDH (lower panel).

 
Effect of serum and dexamethasone on levels of KGF mRNA in amnion mesenchymal cells

Amnion mesenchymal cells were treated without or with serum (10%, vol/vol) plus or minus dexamethasone (1 nM) for 4 and 24 h (Fig. 4Go). Under all conditions of study (without or with serum in the medium), dexamethasone caused a reduction in the level of KGF mRNA.



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  		Figure 4. Northern analysis of KGF mRNA in human amnion epithelial and mesenchymal cells in culture. Confluent cells in serum-free medium were treated for 24 h with dexamethasone (Dex) (1 nM). Total RNA (10 µg applied to each lane) was evaluated for KGF mRNA (upper panel) or G3PDH (lower panel).

 
Effect of KGF on amnion epithelial cell replication

Treatment of amnion epithelial cells with KGF caused an increase in [3H]thymidine incorporation, but KGF was not as effective as EGF in stimulating mitogenesis (Fig. 5Go). Neither EGF nor KGF effected an increase in [3H]thymidine incorporation in amnion mesenchymal cells (Fig. 5Go).



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  		Figure 5. Thymidine incorporation into DNA of human epithelial and mesenchymal cells in monolayer culture. Confluent cells in serum-free medium were treated with EGF (filled bars) or KGF (open bars) for 24 h; [3H]thymidine was present during last 2 h of treatment. [3H]Thymidine incorporation into trichloroacetic acid-precipitable material was quantified, and data, normalized to total cell protein, are presented as mean ± SEM for replicates of 4 wells of cells treated identically.

 
In six experiments, EGF (10–15 ng/mL) effected an increase in [3H]thymidine incorporation of 28.7 ± 11.8-fold (mean ± SEM; range 4.6–72.6-fold) in amnion epithelial cells, whereas KGF effected an increase of 6.6 ± 3.7-fold (range = 1.1–24.8-fold). In all of these studies, the effect of EGF on thymidine incorporation into TCA-precipitable material of amnion epithelial cells isolated from a given amnion tissue was greater than that of KGF (P < 0.03, Wilcoxon signed rank test), even though there was considerable variation among epithelial cells from different pregnancies in the fold increase effected by EGF or KGF. The data from one experiment are presented in Fig. 6Go. The rate of thymidine incorporation into amnion epithelial cells was stimulated 6.7-fold by EGF (10 ng/mL), 3.2-fold by KGF (10 ng/mL), and 5-fold by KGF + EGF (P < 0.05, ANOVA); the effect of each agent was different (P < 0.05) from the other agents tested (Dunn’s post hoc pairwise analysis). In this study, TGF-ß (1 ng/mL) inhibited thymidine incorporation by 73% and completely prevented the stimulatory effect of EGF or KGF (P < 0.05, ANOVA). The stimulatory effects of EGF and KGF on [3H]thymidine incorporation into DNA of amnion epithelial cells were not additive (Fig. 6Go).



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  		Figure 6. Thymidine incorporation into DNA of human amnion epithelial cells in culture. Confluent cells in serum-free medium were treated with EGF (10 ng/mL), KGF (10 ng/mL), TGF-ß (1 ng/mL) or combinations thereof for 24 h; [3H]thymidine was present during last 2 h of incubation. Incorporation of [3H]thymidine into TCA-precipitable material was quantified and data were normalized to total cell protein. Data are expressed as mean ± SEM for replicates of four wells of cells treated in an identical manner; data for all treatment conditions are different from control (P < 0.05, ANOVA), whether change effected was an increase or a decrease.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
KGF has been implicated in important reproductive functions: KGF is expressed in the stromal cells of the secretory endometrium in a progesterone-dependent fashion (20, 21, 22), and it acts to prevent apoptosis of the basilar endometrial epithelial cells at the time of progesterone withdrawal during infertile ovarian cycles (15, 16). KGF also is expressed in human myometrial smooth muscle and leiomyomata cells (21). KGF is produced in mesenchymal cells of the human placenta, and KGF receptor expression has been demonstrated in syncytiotrophoblast (23). KGF, produced in ovarian theca cells, acts to effect replication of granulosa cells (24). KGF has been referred to as a progestomedin (20) and as an andromedin (25), implying that KGF, produced in mesenchymal cells in response to progesterone or androgen, may act as an intermediate agent in promoting the actions of these steroid hormones on the epithelium of a given tissue (20, 25, 26, 27).

In this study, we found that, as in other tissues, KGF is expressed in the mesenchymal cells but not in the epithelial cells of human amnion. Treatment of amnion mesenchymal cells with TPA, forskolin, and serum-free medium caused an increase in the level of KGF mRNA. Treatment of these cells with dexamethasone caused a decrease in the level of KGF mRNA. In a survey of other agents that might modify the levels of KGF in amnion mesenchymal cells, IL-1, IL-6, IL-6 soluble receptor, IL-6 + IL-6 soluble receptor, IL-11, oncostatin M, and TGF-ß did not effect a change in the level of KGF mRNA. KGF mRNA was not detected by Northern analysis of total RNA in treated or nontreated amnion epithelial cells. These findings are indicative that KGF is expressed in the amnion mesenchymal cells, and that the levels of KGF mRNA can be altered by treatments that evoke an increase in protein kinases A and C. An increase in KGF expression in response to both protein kinases A and C has been demonstrated previously in dermal fibroblasts (28, 29); others also have observed that glucocorticosteroids caused a decrease in KGF expression, e.g. in dermal fibroblasts (30, 31).

In other mesenchymal cells [human embryonic fibroblasts (M426), and foreskin and adult dermal fibroblasts], however, IL-1 as well as PDGF, IL-6, and TGF-{alpha} caused an increase in the levels of KGF mRNA (32, 33) as does serum (29). Therefore, amnion mesenchymal cell expression of KGF appears to be regulated in a manner different from that in other cells examined heretofore in that serum, IL-1, and IL-6 did not cause an increase in the levels of KGF mRNA in these cells.

KGF treatment caused a significant increase in the rate of [3H]thymidine incorporation in amnion epithelial cells, but this effect was less than that evoked by treatment with EGF. TGF-ß acted to attenuate the effect of EGF and KGF on amnion epithelial cell replication.

The loss of epithelial cells in an anatomically specific area of the amnion has been associated with PT-PROM, and can be caused by amnion injury (fetal-induced) (5), apoptosis (34), or by anatomically defined/restricted abnormalities, e.g. the dependent or cervical portion of the membranes (5). KGF is believed to serve important functions in restoring epithelium in wound healing, e.g. in skin (35, 36), lung (37, 38), and kidney (39). Within 1 day of experimental wounding, a 160-fold increase in the level of KGF mRNA, localized to the dermal cells, was observed (40). In addition to the mitogenic effect, other actions of KGF appear to be important in wound healing, viz. migration of epithelial cells along the wound bed. Under selected conditions, KGF acts to increase the expression of matrix metalloproteinase (MMP)-9 and urokinase plasminogen activator (41) and, in association with heparin, interstitial collagenase MMP-1 (42). MMP-9 and urokinase plasminogen activator are induced in wound tissue and are believed to act to promote epithelial cell detachment and thereby facilitate epithelial cell migration during wound healing. KGF of amnion mesenchymal cell origin may function normally to effect repair of the amnion epithelium and to prevent apoptosis. It can be envisioned that the inappropriate formation of KGF could give rise to excessive formation of MMP-9, and thereby the untimely loss of amnion epithelium. Vadillo-Ortega, Lei, Strauss and colleagues have shown that MMP-9 (92-kDa gelatinase) expression is increased strikingly in amnion of the rat and human at parturition (43, 44), and that there is an increase in MMP-9 in amniotic fluid during labor and with PT-PROM (45). Moreover, they identified increased MMP-1 and MMP-1 actions in rat amnion with labor (34, 46). The regulation of KGF expression and action near term may be important in the regulation of amnion epithelial cell replication and function. Studies are in progress to investigate further the regulation of the expression and action of KGF in amnion and to identify factors that may be involved in the regulation of this gene in vivo.


   Footnotes
 
1 This work was supported, in part, by United States Public Health Service Grant 5-P50-HD11149. Back

Received March 31, 1997.

Revised June 24, 1997.

Accepted July 7, 1997.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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D. H.-K. Ma, L.-C. See, S.-B. Liau, and R. J.-F. Tsai
Amniotic membrane graft for primary pterygium: comparison with conjunctival autograft and topical mitomycin C treatment
Br J Ophthalmol, September 1, 2000; 84(9): 973 - 978.
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