O soro de mulheres com endometriose altera os níveis de citocinas produzidas pelas células estromais e endoteliais uterinas cocultivadas em sistema 3D.

BORGATO, C.G. Serum from women with endometriosis altering the levels of cytokines produced by stromal and endothelial endometrial cells in 3D co - culture system. 2016 119 f. Dissertation (Masther thesis in Cell and Tissue Biology) – Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, 2016. Endometriosis is a chronic inflammatory disease characterized by the presence and growth of ectopic endometrial tissue. It affects 10% to 15% of women in reproductive age and is associated with severe inflammatio n and infertility. The altered profile of systemic immunological factors seems to be linked to infertility in this disease, regardless of the severity of the endometriosis lesions. In this study, through a three -dimensional (3D) co - culture system of a part ially reconstituted endometrium, we explored the possibility that factors present in the serum of women with endometriosis affect the profile of cytokines produced by the endometrium, determining changes that can affect fertility. Samples were collected after obtaining written informed consent (the Research Ethics Committee of USP Human Beings, no. 692457). Endometrial biopsies (n = 15) and serum (n = 15) were collected from patients without endometriosis from Huntington Reproductive Medicine Clinical, São Paulo, Brazil. The serum of patients with endometriosis (using contraceptives, n = 10 and untreated, post-surgery n = 5) was obtained from this clinic and Hospital of Medical School of the University of São Paulo, SP. Biopsies were digested with collagenas e II / DNAase I and filtered to retention of endometrial glands. Magnetic beads anti -CD105 (MACS) were used for positive and negative selection of endothelial cells and stromal cells, respectively. The cells were resuspended in supplemented medium (DMEM / F12). To construct the 3D environment, 0.1 x 106 stromal cells in the medium were added to a mixture of extracellular matrix components (fibronectin and collagen V, I and III) and plated in 48 well plates. After 12 hours in culture conditions (37°C with 5% CO2), the endothelial cells were added to the system (0.1 x 106 cells) on the surface of the gelled culture. After 24 hours, the medium was either replaced by serum of women with endometriosis or healthy, as follows (n = 3 -8): i) serum from healthy women, without endometriosis; ii) serum from patients with endometriosis; iii) serum of patients with endometriosis using contraceptives. The system remained in culture conditions for further 24 and 48 h. The homogenate of the cells was collected to assess the c ytokine profile by CBA (Cytometric Bead Array). The reconstituted endometrium was morphologically examined and characterized by immunofluorescence using specific markers for mesenchymal, decidual, endothelial and epithelial cells showing a typical stromal-endothelial organization. It also showed to be able to respond to the cytokines present in sera, producing cytokines involved in the regulation of immune response, with a predominance of IL -2, IL -6, IL -10, IFN -g, and TNF -a, with an inflammatory tendency. I n comparison with this group, the group of sera from treated patients showed a cytokine profile, which tended to a non -exacerbating inflammatory profile (IL -4, IL-6, and IL -8). The experimental model, here explained, proved to be an elegant tool that can b e used in numerous studies involving the uterine environment, enabling future strategies for analysis of endometrial pathophysiology in impactful conditions like those affected by diseases such as endometriosis, leading to infertility

Co-culture. 3D culture. Endometrium. Endometriosis. Cytokines. 4 INTRODUÇÃO 5 A infertilidade é atribuída a várias causas, dentre elas diversos fatores relacionados a falhas de implantação e qualidade embrionária (DE ZIEGLER et al., 2016) . Apesar dos muitos estudos já descritos na literatura, as causas e alterações que levam a essas falhas ainda não foram totalmente elucidadas . A importância do tecido uterino nesse complexo processo é ímpar. Estudos têm mostrado que a inabilidade uterina em manter um ambiente adequado para o estabelecimento da receptividade endometrial, para a implan tação embrionária ou para o desenvolvimento embrionário é uma das causas que prevalece nas perdas embrionárias recorrentes (NORWITZ; SCHUST; FISHER, 2001). Dentre as patologias que levam a perdas embrionárias recorrentes, destacam-se aquelas sem causa apa rente e a endometriose (YOVICH et al., 1988). Particularmente a endometriose, caracterizada pelo crescimento de tecido endometrial fora do útero, é uma doença que afeta milhões de mulheres na fase reprodutiva em todo o mundo (MEULEMAN et al., 2009). Mulher es com endometriose apresentam , entre outros sintomas, dores pélvicas c rônicas e subfertilidade (VIGANÒ et al., 2004). A diminuição da fertilidade nesta patologia se deve principalmente à redução da qualidade oocitária e à perda da receptividade endometrial durante a janela de implantação, causadas por alterações do perfil inflamatório destas pacientes tanto na cavidade pélvica quanto no sangue periférico, sugerindo uma possível base imunológica (GIUDICE et al., 2002; GIUDICE; KAO, 2004; LEBOVIC et al., 2001). Além disso, evidências também apontam para alterações no endométrio eutópico dessas mulheres, no que diz respeito à estrutura, atividade proliferativa, componentes imunológicos e, produção e responsividade a citocinas (MINICI et al., 2008 ; SHARPE -TIMMS, 2001 ), sugerindo que a endometriose pode afetar a receptividade uterina (KLEMMT et al., 2006). Embora os estudos não sejam completamente concordantes, têm se observado na endometriose alterações no repertório de células NK, linfócitos T e macrófagos e também, nos níveis de citocinas (GM -CSF, IL-1, IL-4, IL-6, IL-8, IL-10 e TNF-α entre outras) e de fatores de crescimento (TGF-β, IGF-1, HGF e VEGF). Essas alterações podem estar associadas a mudanças no perfil do endométrio e na sua capacidade de propiciar atividade adequada por parte das 6 células imunológicas, vitais para o sucesso implantaci onal e gestacional (KRÁLÍČKOVÁ; VETVICKA, 2015). Também foram observadas alterações nos biomarcadores da decidualização no endométrio eutópico das pacientes com endometriose (KLEMMT et al., 2006; MINICI et al., 2008). A decidualização estudada in vitro sob a influência do fluido peritoneal de pacientes com endometriose mostrou -se comprometida, sugerindo a influência do meio endometriótico sobre a fisiologia endometrial (MINICI et al., 2008). Em ensaios em que o TNF -α foi inibido (positivamente correlacionado com a severidade da endometriose; RICHTER et al., 2005) as alterações geradas pelo fluido endometriótico no processo de decidualização mostraram-se atenuadas, enfatizando o papel das citocinas inflamatórias na perda de qualidade do endométrio eutópico (MINICI et al., 2008). Por outro lado, o endométrio é uma mucosa complexa, cujos componentes agem em sintonia por meio de diferentes respostas e mecanismos para permitir a implantação e desenvolvimento do embrião. Um desses componentes, muitas vezes negligenciado ou estudado de forma isolada, com intensa capacidade de resposta a alterações do meio são as células endoteliais (LUK et al., 2010). Devido a sua posição estratégica, células endoteliais endometriais estão expostas a mudanças do perfil sistêmico, seja devido a presenç a de patógenos ou de mediadores solúveis, como, por exemplo, os mediadores inflamatórios liberados pelas células do sistema imunológico na patologia da endometriose. As células endoteliais são também uma importante fonte de mediadores inflamatórios e quimi otáxicos, podendo responder a uma ampla gama de estímulos biológicos (SANTORO et al., 2014). Desta forma, na vigência de um processo inflamatório como se caracteriza a endometriose, estas células devem ser consideradas como parceiros endometriais ativos e relevantes. No contexto destes achados e, a fim de contribuir com informações sobre a possível influência do ambiente endometriótico sobre a fisiologia endometrial, este estudo utilizou culturas tridimensionais de células estromais uterinas revestidas por endotélio (microambiente uterino reconstituído) para a avaliação 7 do perfil de citocinas em resposta ao soro de pacientes saudáveis ou com endometriose. 8 CONCLUSÕES 9  O modelo experimental de cocultivo 3D permite mimetizar as relações estroma-capilar endometrial e, de forma mais completa do que com culturas 2D, a análise da influência do ambiente sobre a fisiologia endometrial.  Os diferentes nívei s de citocinas produzidos pelo endométrio reconstituído frente ao perfil sérico das pacientes que fazem uso ou não de anticoncepcionais, mostram a capacidade das células endometriais de responder a um perfil específico de citocinas.  As células endometria is apresentaram uma resposta exacerbada no perfil de IL -2, IL -6, IL -10, IFN - e TNF -α quando expostas ao soro de mulheres com endometriose sem uso de anticoncepcionais, ou seja, com um perfil mais inflamatório, o que sugere que estas células podem contribuir com o perfil sistêmico inflamatório encontrado em mulheres com endometriose.  Células endometriais expostas ao soro de mulheres com endometriose, porém tratadas com anticoncepcionais, apresentaram uma expressão elevada diferencial das citocina pró -inflamatória IL-6, da quimiocina IL -8 e da citocina anti -inflamatória IL -4, o que pode estar relacionado à tentativa de recrutar células imunes para o local inflamado (Tregs) e com a regulação da inflamação.  Nossos achados sugerem que o uso de cocultivos de células estromais e endoteliais endometriais como ferramenta de estudo, ao associar a possibilidade de interações mutuas entre tipos celulares que compartilham o mesmo tecido e condições, amplia a compreensão dos mecanismos que ocorrem in vivo. 10 REFERÊNCIAS* ABRÃO, M. 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