OR36-6 Aberrant Activation of Stem Cell-Associated Regulatory Pathways and Pro-Inflammatory Cytokine Expression with Absence of Endometrial Krüppel-Like Factor 9 (KLF9) in a Mouse Model of Endometriosis

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: OR36-Ovarian & Uterine Function
Monday, June 17, 2013: 11:15 AM-12:45 PM
Presentation Start Time: 12:30 PM
Room 104 (Moscone Center)
Melissa Emma Heard*1, Frank A Simmen2 and Rosalia C M Simmen3
1University of Ark for Med Scienc, Little Rock, AR, 2University of Arkansas for Medical Sciences, Little Rock, AR, 3Univ of Arkansas for Med Sci &, Little Rock, AR
Endometriosis is a benign gynecological disorder associated with reduced fertility, uterine bleeding and chronic pelvic pain. Emerging data suggests the potential contribution of stem and progenitor cell dysfunction in its genesis. The transcription factor KLF9 mediates cellular differentiation, proliferation, and apoptosis in the uterus and has been linked to the control of signaling pathways involved in adult stem cell maintenance. We previously reported that loss of KLF9 expression in eutopic endometrium of women with vs. without endometriosis was associated with dysregulated gene networks implicated in endometriosis and infertility. Further, using immune-competent wildtype (WT) mice injected with minced endometrium from donor WT and KLF9 null (Klf9 KO) mice, we showed 100% incidence of ectopic lesions in recipients of Klf9 KO tissues (n=18), while recipients of WT tissues had significantly lower incidence (65%; n=17). Here, we report potential mechanisms for the promotion of lesion establishment with KLF9 loss-of-expression. Pathway profiling indicated differences in transcript levels of Notch signaling components in ectopic lesions from donor WT and Klf9 KO endometria. Klf9 null lesions had increased sonic hedgehog and hedgehog signaling components Smo, Gli1, and Stil; up-regulated Jag2 and Hes1; and down-regulated delta-like 3 transcripts, than WT lesions. Klf9 KO lesions also displayed greater expression of proliferative markers Cyclin D1, Wnt11, and Pparγ, consistent with their greater percentage of Ki67-staining cells. Antibody array analyses of peritoneal fluids from mice with ectopic lesions showed increased levels of pro-inflammatory cytokines IL-6, TNF-α, sTNFR1 and IFN-γ in those of Klf9 null than WT donor mice. KLF13, the highly related KLF family member, was also evaluated for its role in ectopic lesion establishment. While all recipient mice (n=11) developed ectopic lesions with donor Klf13 KO endometria, resultant lesions showed distinct Notch/hedgehog signaling component expression and lower numbers of Ki67-staining cells from those of Klf9 KO lesions. Peritoneal fluids from mice with Klf13 KO lesions had higher IL-6, TNF-α and sTNFR1 levels than from donor WT fluids. Thus, loss of endometrial expression of KLF9 but not of KLF13 may trigger dysfunctions in pathways required for stem cell maintenance while loss of both KLFs may coordinately activate pro-inflammatory and immune signaling, for ectopic lesion establishment and progression.

Nothing to Disclose: MEH, FAS, RCMS

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: Supported in part by Arkansas Biosciences Institute/Arkansas Children’s Hospital Research Institute Intramural Grant Program.
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