KGF mRNA Research Articles

Hair Growth Promoting Effect of Trichoxidil<up>TM</up>: A New Natural Compound for Hair Loss

Background: Androgenetic alopecia (AGA) is a most common condition of hair loss. Thus, the present study aimed to investigate the effect of TrichoxidilTM, a phytocomplex obtained from a blend of essential oils, in the treatment of hair loss caused by AGA. Methods: The CCD1072Sk cells were cultured for the 24-hour cell viability assessment and cytotoxicity of TrichoxidilTM. The expression of mRNA levels from KGF, IGF-1, and VEGF in fibroblasts was evaluated by RT-qPCR. Thirty-three volunteers, diagnosed with AGA, men and women, aged between 25 and 50 years, were divided into Control group, without treatment (n = 5); TrichosolTM vehicle group, without active (n = 5); Hydroalcoholic vehicle group, without active (n = 4); TrichosolTM vehicle group, with 2.5% minoxidil (n = 5); Hydroalcoholic vehicle group, with 2.5% minoxidil (n = 5); TrichosolTM group with 2.5% TrichoxidilTM (n = 5) and Hydroalcoholic vehicle group with 2.5% TrichoxidilTM (n = 4) to dermoscopic and histologic. Results: Fibroblasts exhibited higher proliferation when treated with higher concentrations of TrichoxidilTM. TrichoxidilTM significantly increased the expression of KGF, IGF-1, and VEGF mRNA in fibroblasts cells. Analysis of the capillary density showed that TrichoxidilTM associated with TrichosolTM vehicle, was the most effective association. In addition, it was observed an increased more effectively the percentage of anagen phase and reduction of the telogen when compared to other formulations. Conclusion: TrichoxidilTM promoted proliferative effects and positively modulated the expression of growth factors IGF-1, VEGF, and KGF, being a promising candidate for the treatment of hair loss caused by AGA.

Action Mechanism of Natural Plant Extracts for Hair Loss Prevention and Hair Growth Promotion in C57BL/6 Mice

The Natural Plant Extracts (NPE), produced by mixing seven natural plant extracts including sweet flag, contains asacurin 100 as its main ingredient and shows improvement in skin, but no hair growth effect has been reported. This study was conducted to evaluate the effects of NPE on mouse hair loss prevention and hair growth promotion and to determine the mechanism of action of NPE. Thirty male C57BL/6 mice were randomized into three treatment groups of 10 mice each: Control group (saline), NPE and minoxidil 5% application. For the NPE application group, the first hair growth was observed on day 9 and the density, length and thickness of their hair were significantly higher than those of the control group. Compared to the control group, the anagen hair growth in the C57BL/6 mice of the NPE application group was significantly stimulated. Compared to the control group, the expression of VEGF and KGF mRNA was up-regulated in the NPE and minoxidil 5% application groups, but the expression of TGF-β1 mRNA was down regulated on the contrary. This result suggests that NPE promotes hair growth while inducing anagen hair growth in animals through genetic regulation while, simultaneously preventing hair loss.

Topical Application of Oleuropein Induces Anagen Hair Growth in Telogen Mouse Skin.

We observed that oleuropein, the main constituent of the leaves and unprocessed olive drupes of Olea europaea, protected mice from high-fat diet-induced adiposity by up-regulation of genes involved in Wnt10b-mediated signaling in adipose tissue. The activation of Wnt/β-catenin pathway is also well established to positively regulate the anagen phase of hair growth cycle in mice skin.Methodology and Principal FindingsOleuropein promoted cultured human follicle dermal papilla cell proliferation and induced LEF1 and Cyc-D1 mRNA expression and β-catenin protein expression in dermal papilla cells. Nuclear accumulation of β-catenin in dermal papilla cells was observed after oleuropein treatment. Topical application of oleuropein (0.4 mg/mouse/day) to C57BL/6N mice accelerated the hair-growth induction and increased the size of hair follicles in telogenic mouse skin. The oleuropein-treated mouse skin showed substantial upregulation of Wnt10b, FZDR1, LRP5, LEF1, Cyc-D1, IGF-1, KGF, HGF, and VEGF mRNA expression and β-catenin protein expression.Conclusions and SignificanceThese results demonstrate that topical oleuroepin administration induced anagenic hair growth in telogenic C57BL/6N mouse skin. The hair-growth promoting effect of oleuropein in mice appeared to be associated with the stimulation of the Wnt10b/β-catenin signaling pathway and the upregulation of IGF-1, KGF, HGF, and VEGF gene expression in mouse skin tissue.

Mechanisms of thymic recovery and T cell reconstitution following sublethal ionizing radiation (104.21)

Abstract Proper thymic function is important for maintaining lifelong peripheral homeostasis of naïve and memory T cells. Age-induced thymic involution is chronic and does not recover. Acute thymus involution in settings of stress can spontaneously recover. The goal of this research was to define mechanisms of thymic damage and recovery following acute stress (irradiation). Young and old BALB/c mice were sublethaly irradiated (≤ 125 rad).Thymus function was monitored by thymus weight, cellularity, and TCR gene re-arrangement (mTREC). In young, irradiation significantly reduced thymocyte number and depleted mTREC levels by day 7, followed by full recovery (day 42). In old, radiation did not cause further decrease in thymocyte number or mTREC compared to that induced by age. To define mechanisms of thymic involution/recovery expression of thymostimulatory factors and indicators of healthy thymus were analyzed.While IL-7 and FoxN1 mRNA levels were not impacted in the young, KGF and AIRE mRNA expression levels were significantly reduced during irradiation-induced involution. These levels restored to baseline 21 days prior to full thymus functional recovery. Thus, suggesting a critical role of thymic-stromal derived KGF in promoting stroma/thymocyte crosstalk to mediate thymus recovery. Overall, these findings may lead to a better understanding of mechanisms involved in thymus recovery from damage and inform development of strategies to restore thymic function in the aged.

Keratinocyte growth factor promotes preadipocyte proliferation via an autocrine mechanism

Keratinocyte growth factor (KGF; also known as FGF-7) is a well-characterized paracrine growth factor for tissue growth and regeneration. However, its role in adipose tissue, which is known to undergo tremendous expansion in obesity, is virtually unknown. Given that we previously identified KGF as one of the up-regulated growth factors in adipose tissue of an early-life programmed rat model of visceral obesity, the present study was undertaken to examine the hypothesis that KGF promotes adipogenesis. Using 3T3-L1 and rat primary preadipocytes as in vitro model systems, we demonstrated that (1) KGF stimulated preadipocyte proliferation in a concentration-dependent manner with a maximal effect at 2.5 ng/ml (approximately 2-fold increase); (2) KGF mRNA was highly expressed in rat adipocytes and preadipocytes as well as 3T3-L1 cells; (3) treatment of preadipocytes with a neutralizing antibody against KGF and siRNA-mediated knockdown of KGF led to a 50% reduction in their proliferative capacity; (4) KGF activated the protein kinase Akt, and the PI3 kinase inhibitor LY294002 blocked KGF stimulation of preadipocyte proliferation; and (5) KGF did not promote differentiation of preadipocytes to mature adipocytes. Together, these results reveal adipocytes and their precursor cells as novel sites of KGF production. Importantly, they also demonstrate that KGF promotes preadipocyte proliferation by an autocrine mechanism that involves activation of the PI3K/Akt signaling pathway. Aberrant KGF expression may have consequences not only for normal adipose tissue growth but also for the pathogenesis of obesity.

46 ACUTE RESPIRATORY DISTRESS SYNDROME ALVEOLAR FLUID INDUCES MYOFIBROBLAST GENES BUT SUPPRESSES KERATINOCYTE GROWTH FACTOR IN NORMAL HUMAN LUNG FIBROBLASTS.

<h3>Rationale</h3> Alveolar repair is critical to ARDS outcome. Myofibroblast induction is integral to healing by facilitating wound apposition (α-smooth muscle actin (α-SMA), secreting matrix (collagens 1 and 3), cytokines (TGF-β1 and connective tissue growth factor [CTGF]), and epithelial mitogens (keratinocyte growth factor [KGF]). We hypothesized that bronchoalveolar lavage fluid (BALF) from ARDS patients would induce multiple features of myofibroblasts. <h3>Methods</h3> ARDS BALF was collected within 48 hours of intubation. Patients with cardiogenic pulmonary edema were included as negative controls. ARDS and control BALF were incubated with normal human lung fibroblasts for 24 hours, and α-SMA, collagens 1 and 3, CTGF, TGF-β1, and KGF mRNA was measured by real-time RT-PCR. <h3>Results</h3> Ten ARDS patients and five negative controls were enrolled. The average age for ARDS patients was 53 ± 16 years. The average PaO₂/ FiO₂ ratio, compliance, and APACHE 2 scores were 118 ± 70, 21 ± 10, and 28 ± 8, respectively. ARDS BALF induced 110% more α-SMA (<i>p</i> &lt; .05) and 85% more CTGF (<i>p</i> &lt; .05) than controls. In addition, ARDS BALF induced 43% more collagen 1 (<i>p</i> = .11) and 52% more collagen 3 (<i>p</i> = .08) than controls. In contrast, control BALF induced 70% more KGF (<i>p</i> &lt; .03) than ARDS BALF. There was a significant inverse correlation between ARDS induction of α-SMA and KGF (<i>r</i> = −.78, <i>p</i> &lt; .01). The TGF-β1 receptor inhibitor SB431542 significantly reduced ARDS BALF induction of α-SMA, CTGF, and collagens 1 and 3 (<i>p</i> &lt; .05 for all) but had no impact on KGF expression (<i>p</i> = .33). <h3>Conclusion</h3> Early ALI/ARDS BALF has predominant profibrotic characteristics and suppresses epithelial mitogen induction.

KERATINOCYTE GROWTH FACTOR AND ITS RECEPTOR CORRELATE WITH VENOUS INVASION VIA MATRIX METALLOPROTEINASE-9 (MMP-9) IN PANCREATIC CANCER

Background: MMP-9 is known to participate in the degradation of type IV collagen, which is one of the major components of vascular basement membranes, and expression of MMP-9 has been associated with venous invasion and hematogenous metastasis in various cancer tissues. We previously reported that co-expression of KGFR and KGF in pancreatic cancer showed a significant association with venous invasion and poor prognosis. In the present study, we investigated the expression of KGFR, KGF and MMP-9 in pancreatic cancer cell lines and their correlations with clinicopathological factors in human pancreatic cancer tissues. Methods: Expression of KGFR, KGF and MMP-9 were examined in eight of human pancreatic cancer cell lines. Immunohistochemical analyses using anti-KGFR, KGF or MMP-9 antibodies were performed on fifty-three cases of pancreatic cancer. Moreover, the correlation with KGFR, KGF or MMP-9, and clinicopathological factors in pancreatic cancer cases was evaluated. Results: KGFR and MMP-9 mRNA were detected in all pancreatic cancer cell lines. In contrast, KGF mRNA was detected in 7 of 8 pancreatic cancer cell lines. KGFR, KGF and MMP-9 were localized in pancreatic cancer cells in 22 of the 53 cases (41.5%), 18 of the 53 cases (34.0%) and 22 of the 53 cases (41.5%), respectively. Clinicopathologically, KGFR, KGF or MMP-9 expression was highly correlated with venous invasion. Moreover, co-expression of KGFR and KGF correlated significantly with venous invasion, MMP-9 expression and poor prognosis. However, survival rates of the MMP-9-positive group and MMP-9-negative group were not significantly different. Conclusion: These findings suggest that co-expression of KGFR and KGF might play an important role in enhancing venous invasion via MMP-9 in pancreatic cancer cases. KGF/KGFR system may lead to the development of new therapeutic strategies for human pancreatic cancer.

Effects of perinatal exposure to flutamide on sex hormone responsiveness in F1 male rats.

Pregnant rats were administered flutamide (0 and 10 mg/kg, p.o.) from gestation Day 14 to post-parturition Day 3 and effects on responsiveness to androgens (testosterone propionate, TP; dihydrotestosterone, DHT) in male offspring were examined with a Hershberger assay. Male pups of each group were assigned to 6 subgroups as follows: Group 1, castration and euthanized at postnatal Day 46 (PND 46); Group 2, castration + vehicle; Group 3, castration + TP; Group 4, castration + DHT; Group 5, vehicle; Group 6, DHT. After castrations were conducted at PND 36, animals were treated with TP (2 mg/kg in corn oil, s.c.) or DHT (1.25 mg/kg in corn oil, s.c.) once a day for 10 days, beginning at PND 46. At PND 56, the following organs/tissues were removed and weighed: ventral prostate, dorso-lateral prostate, seminal vesicles with coagulating glands, levator ani muscle plus bulbocavernosus muscle, Cowper's gland, and glands penis. Analysis of serum testosterone, LH and FSH in Groups 2, 3, 4, 5 and 6, and RT-PCR using prostate tissue from Groups 2, 3 and 4 were carried out. Perinatal exposure to flutamide caused decreased weights of androgen-dependent organs. Responses to androgens were recognized in organs of all castrated groups, with increased organ weights, especially in animals administered TP where values were essentially equal to or greater than those of intact animals in both the control and the 10 mg/kg group. On the other hand, the degree of weight increase of the ventral prostate and seminal vesicles with TP or DHT treatment in castrated animals was smaller in the flutamide administration group than in the controls. In hormone assays, castrated + vehicle animals showed higher serum LH than the other groups. Serum FSH was high in the castrated groups (Group 2>Group 4>Group 3), while in the noncastrated group a constant level was noted, with or without flutamide. No effect of flutamide administration was observed regarding sex hormone. RT-PCR using ventral prostate tissue revealed no significant differences in expression of AR, C3, VEGF, TGF-beta1, beta2, KGF and CK8 mRNA after androgen treatment between the control and flutamide treatment groups. C3 mRNA was increased in androgen-treated animals, whereas AR, TGF-beta and KGF mRNAs were decreased. Perinatal exposure to anti-androgen causes irreversible abnormalities in male pups. Concerning the responsiveness to TP and DHT, the degrees of weight changes in ventral prostate and seminal vesicles in castrated animals were decreased. However, the other organ weights, the sex hormone levels and androgen-reactive gene expression in the ventral prostate were not influenced by perinatal flutamide treatment in the present study.

Analysis of the cellular basis of keratinocyte growth factor overexpression in inflammatory bowel disease

BACKGROUNDKeratinocyte growth factor (KGF) stimulates gastrointestinal epithelial cells in vivo, and is protective against gastrointestinal injury and colitis. Endogenous KGF is increased in inflammatory bowel disease (IBD), and may be...

Interactions between stromal cell--derived keratinocyte growth factor and epithelial transforming growth factor in immune-mediated crypt cell hyperplasia.

Immune reactions in the gut are associated with increased epithelial cell proliferation. Here we have studied the role of keratinocyte growth factor (KGF; FGF7) and transforming growth factor-alpha (TGF-alpha) in the epithelial cell hyperplasia seen in explants of fetal human small intestine after activation of lamina propria T cells with the superantigen Staphylococcus aureus enterotoxin B (SEB). After the addition of SEB to the explants there is a 10-fold increase in KGF mRNA by 72 h of culture. KGF transcripts were abundant in the lamina propria using in situ hybridization and the culture supernatants contained elevated amounts of KGF protein. SEB had no direct effect on KGF mRNA and protein production by cultured lamina propria mesenchymal cells, but both were upregulated by TNF-alpha. Accompanying the increase in KGF there was also an increase in TGF-alpha precursor proteins in the culture supernatants and the phosphorylated form of the EGFR receptor was also detected in the tissue. Increased TGF-alpha precursor proteins were also detected in the supernatants of control explants stimulated with KGF alone. The direct addition of KGF and TGF-alpha enhanced epithelial cell proliferation and antibodies against KGF and TGF-alpha partially inhibited SEB-induced crypt hyperplasia. These results suggest molecular cross-talk between the KGF/KGFR and the TGF-alpha/EGFR in immune-mediated crypt cell hyperplasia.

Estrogen-induced keratinocyte growth factor mRNA expression in normal and cancerous human breast cells.

The local recurrence rate of breast cancer has been reported to be unusually high at the surgical scar. Such breast cancer recurrence is believed to be triggered by the release of growth factors into the healing wound. Observations from an animal model have also demonstrated that KGF expression is dramatically induced by creation of full thickness wounds in mouse skin. Since KGF is an epithelial cell-specific mitogen in rat mammary epithelium, it is reasonable to speculate that KGF may be also involved in regulating human breast cancer cell growth. The purpose of the present study was to determine the effect of estradiol-17 on KGF gene expression in normal human breast stromal cells, as well as in human breast cancer stromal cells, and the mechanisms by which estradiol-17 regulates breast epithelial proliferation. Our results show that KGF expression was not effected by estradiol-17 treatment in normal human breast stromal cells. In contrast, KGF expression was stimulated by estradiol-17 in human breast cancer stromal cells. KGF mRNA levels have also been examined in normal human breast stromal cells and human breast cancer stromal cells. An interesting correlation was found between KGF expression and estradiol-17 regulation in these cell types. Normal human breast stromal cells which do not response to estradiol-17 have lower KGF mRNA level than the cancer cells which KGF expression is stimulated by estradiol-17. Our data also demonstrate that recombinant human KGF significantly stimulate normal human breast and human breast cancer epithelial cell proliferation in a dose-dependent manner. Since we have shown that estradiol-17 induces KGF mRNA expression in human breast cancer stromal cells, KGF may be involved at least in part in the stimulatory pathway that is initiated by estradiol-17 in human breast cancer epithelial cells.

Induction of KGF, Basic FGF, and TGFa mRNA Expression During Healing of Experimental TM Perforations

KGF (KGF), synthesized and secreted exclusively by stromal cells in epithelialized organs, specifically promotes proliferation of cells of epithelial origin, including keratinocytes. A related peptide, basic fibroblast growth factor (bFGF), has mitogenic properties for fibroblasts and endothelial cells. KGF expression is stimulated markedly in the skin during wound healing. To investigate the physiologic action of KGF in the healing of TM (TM) perforations, we examined KGF and KGF receptor (KGFR) mRNA transcript levels as well as those of bFGF and transforming growth factor-

Keratinocyte growth factor expression in hormone insensitive prostate cancer.

Cellular interactions between stroma and epithelium are important in the growth and proliferation of prostate cancer. Peptide growth factors may facilitate the progression of prostate cancer as autocrine and/or paracrine factors. Keratinocyte Growth Factor (KGF or FGF7) has a differentiative and proliferative effect on the epithelium of the developing rat prostate. We investigated if KGF may act as a paracrine agent in human prostate cancer and examined the expression of KGF and Fibroblast Growth Factor Receptors (FGFRs) (IIIb and IIIc isoforms of the FGFR1 and FGFR2 genes). Sixty-five percent (11 out of 17 informative cases) of prostate cancers (CaP) expressed KGF mRNA by RT-PCR, while KGF expression was not detected in benign prostatic hyperplasia (BPH) (n = 6). Upregulation of KGF expression was related to hormone insensitive tumours (P<0.05). Tumour grade and stage were not associated with KGF expression. The source of KGF expression was further characterised using an in vitro primary culture model, showing its restriction to the prostatic stroma. The FGFR1IIIb isoform was expressed in all cases of prostate cancer (n = 17), and FGFR1IIIc mRNA was not detected. In the BPH group, FGFR1IIIb transcripts were detected in four out of six cases. FGFR2IIIb expression was detected in five of six cases of BPH and twelve out of seventeen (71%) cases of prostate cancer. In CaP, though not reaching statistical significance, the persistence of FGFR2IIIb expression appeared to be associated with hormone insensitive tumours (P=0.052). FGFR2IIIc expression was present in eleven of seventeen tumours but was absent in all six cases of BPH. Functional assessment of recombinant KGF in a proliferation assay demonstrated a mitogenic effect of up to 100% on cultured prostatic epithelial cells.

Analysis of growth factor and receptor mRNA levels during development of the rat seminal vesicle and prostate.

Development of the mammalian male accessory sexual organs requires both androgens and mesenchymal/epithelial interactions. Paracrine acting factors whose expression is mesenchymal and androgen dependent have been proposed to regulate development of these organs, although the identity of these paracrine mediators is unknown. Keratinocyte growth factor (Kgf) has been shown to play an important role in the development of the mouse seminal vesicle and rat ventral prostate. Also, Kgf is expressed in mesenchymal cells and has been shown to be regulated by androgens in prostatic cells grown in vitro. Thus Kgf has been proposed as a mediator of androgen action. We have investigated the expression of Kgf mRNA during development of the rat seminal vesicle and prostate, both in vitro and in vivo. Additionally we have examined mRNAs for Kgf receptor (KgfR), transforming growth factor alpha (Tgf alpha), epidermal growth factor receptor (EgfR) and cytokeratin 19 (CK19). The levels of growth factor and receptor mRNAs fluctuated during androgen-regulated development; however, these changes reflected variations in the mesenchymal/epithelial ratio rather than regulation by testosterone. Expression of Kgf is mesenchymal, while KgfR is epithelial and Tgf alpha is predominantly epithelial. The changes in the levels of mRNAs for these factors correlated well with changes in the level of an epithelial marker, CK19, suggesting they were due to alterations in the relative abundance of tissue compartments in which they were expressed. Kgf has been shown to mimic androgen action in explant cultures of seminal vesicle and prostate. We demonstrate here that anti-androgens are able to block Kgf stimulated development, suggesting that Kgf and androgen receptor signalling pathways may interact. Taken together our data suggest that, in vivo, Kgf may interact with androgen receptor signalling but it is not a direct target of androgen action.

Androgen Regulation of the Rat Keratinocyte Growth Factor (KGF/FGF7) Promoter

Keratinocyte Growth Factor (KGF/FGF7) is a candidate andromedin in normal embryonic development of male accessory sex glands, such as the prostate and seminal vesicles. The expression of KGF mRNA and protein is androgen-responsive. To elucidate the regulation of expression of the KGF gene, we isolated the first two exons of the KGF gene and approximately 15 kb upstream sequences. The major transcription start site was mapped. It is preceded by a CAAT-box and a TATA-box. Transient transfections in LNCaP cells revealed that, upon treatment with the synthetic androgen R1881, KGF promoter activity is upregulated 6 to 11 fold, indicating androgen regulation of the KGF promoter in the region from position −1900 to −1200. The longest construct (BH-pLuc: −4700 to +901) has a much higher basal activity than the shorter constructs, indicating that in the region −4700 to −2700 additional activating sequences are present.

Expression of mRNA for keratinocyte growth factor and its receptor in human endometrium.

The aim of the present study was to evaluate the expression of mRNA for the keratinocyte growth factor and the keratinocyte growth factor receptor in human endometrium at different stages of the menstrual cycle. The role of estrogen and progesterone in regulating the expression of the mRNAs encoding keratinocyte growth factor and its receptor was further examined by studying the effect of continuous progestin (endometrium exposed to levonorgestrel releasing intrauterine contraceptive device), and continuous estrogen (endometrium hyperplasia) on the endometrium. The expression of mRNA in endometrial samples was evaluated using reverse transcriptase polymerase chain reaction. The expression of KGF mRNA was found to vary during the menstrual cycle, with the highest levels in the progesterone-dominated late-secretory stage endometrium. Keratinocyte growth factor mRNA expression was low in both the endometrium that had been under the influence of continuous progestin (atrophic endometrium) and continuous estrogen (hyperplastic endometrium). The highest level of keratinocyte growth factor receptor mRNA expression was seen in late-proliferative stage of the menstrual cycle and in hyperplasia when the estrogen exposure to endometrium is high. A low receptor mRNA level was found in endometrium exposed to continuous progestin. The results suggest that keratinocyte growth factor mRNA expression is progesterone dependent, whereas keratinocyte growth factor receptor mRNA expression seems to be more estrogen than progesterone dependent.

Progesterone-dependent expression of keratinocyte growth factor mRNA in stromal cells of the primate endometrium: keratinocyte growth factor as a progestomedin.

In vitro studies have shown that keratinocyte growth factor (KGF, also known as FGF-7) is secreted by fibroblasts and is mitogenic specifically for epithelial cells. Therefore, KGF may be an important paracrine mediator of epithelial cell proliferation in vivo. Because stromal cells are thought to influence glandular proliferation in the primate endometrium, we investigated the hormonal regulation and cellular localization of KGF mRNA expression in the rhesus monkey uterus. Tissues were obtained both from naturally cycling monkeys in the follicular and luteal phases of the cycle, and from spayed monkeys that were either untreated or treated with estradiol (E2) alone, E2 followed by progesterone (P), E2 plus P, or E2 plus P plus an antiprogestin (RU 486). Northern blot analysis of total RNA with 32P-labeled probes revealed that the level of KGF mRNA in the endometrium was 70-100-fold greater in the luteal phase or after P treatment than in untreated, E2-treated, or follicular phase animals. Northern analysis also showed that KGF mRNA was present in the myometrium but was unaffected by hormonal state. RU 486 treatment prevented the P-induced elevation of endometrial KGF mRNA. P-dependent elevation of endometrial KGF expression was confirmed by measurement of KGF protein in tissue extracts using a two-site enzyme-linked immunosorbent assay. In situ hybridization with nonradioactive digoxigenin-labeled cDNA probes revealed that the KGF mRNA signal, which was present only in stromal and smooth muscle cells, was substantially increased by P primarily in the stromal cells located in the basalis region. Smooth muscle cells in the myometrium and the walls of the spiral arteries also expressed KGF mRNA, but the degree of this expression did not differ with hormonal state. P treatment led to increased proliferation in the glandular epithelium of the basalis region and to extensive growth of the spiral arteries. We conclude that the P-dependent increase in endometrial KGF resulted from a dual action of P: (a) a P-dependent induction of KGF expression in stromal cells, especially those in the basalis (zones III and IV), and (b) a P-dependent increase in the number of KGF-positive vascular smooth muscle cells caused by the proliferation of the spiral arteries. KGF is one of the first examples in primates of a P-induced, stromally derived growth factor that might function as a progestomedin.