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Gerald R Cunha - One of the best experts on this subject based on the ideXlab platform.
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human urogenital sinus mesenchyme is an inducer of prostatic epithelial development
American journal of clinical and experimental urology, 2021Co-Authors: Gerald R Cunha, Mei Cao, Amber Derpinghaus, Laurence S. BaskinAbstract:OBJECTIVE To determine whether human fetal urogenital sinus mesenchyme (UGM) can induce prostatic development in a responsive mouse Epithelium. METHOD Male and female human fetal UGM was combined with mouse urinary bladder Epithelium (BLE), and the resultant human UGM + mouse BLE tissue recombinants were grown under renal capsules of male athymic mice. Human male and female UGM was derived from reproductive tracts 9 and 14 weeks of gestation obtained following elective termination of pregnancy. At these ages prostatic ducts had already emerged from the urogenital sinus Epithelium, and the human UGM remained contaminated with human prostatic Epithelium. This unavoidable problem was tolerated because the induced mouse prostatic Epithelium could be distinguished from contaminating human prostatic Epithelium. RESULTS The simple columnar Epithelium induced from mouse bladder Epithelium by human male and female UGM resembled mouse prostatic Epithelium by: (a) histology, (b) the pattern of basal cell distribution, (c) Hoechst dye nuclear staining, (d) expression of NKX3.1, (e) the pattern of androgen receptor expression and (f) the expression of probasin, a mouse prostatic secretory protein. Summary/Interpretation: These findings provide validation for mouse as a model of human prostatic development as the molecular dialogue involved in mesenchymal-epithelial interactions are sufficiently conserved that human UGM can induce mouse bladder Epithelium to undergo prostatic development.
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new insights into human female reproductive tract development
Differentiation, 2017Co-Authors: Stanley J Robboy, Laurence S. Baskin, Takeshi Kurita, Gerald R CunhaAbstract:We present a detailed review of the embryonic and fetal development of the human female reproductive tract utilizing specimens from the 5th through the 22nd gestational week. Hematoxylin and eosin (H&E) as well as immunohistochemical stains were used to study the development of the human uterine tube, endometrium, myometrium, uterine cervix and vagina. Our study revisits and updates the classical reports of Koff (1933) and Bulmer (1957) and presents new data on development of human vaginal Epithelium. Koff proposed that the upper 4/5ths of the vagina is derived from Mullerian Epithelium and the lower 1/5th derived from urogenital sinus Epithelium, while Bulmer proposed that vaginal Epithelium derives solely from urogenital sinus Epithelium. These conclusions were based entirely upon H&E stained sections. A central player in human vaginal epithelial development is the solid vaginal plate, which arises from the uterovaginal canal (fused Mullerian ducts) cranially and squamous Epithelium of urogenital sinus caudally. Since Mullerian and urogenital sinus Epithelium cannot be unequivocally identified in H&E stained sections, we used immunostaining for PAX2 (reactive with Mullerian Epithelium) and FOXA1 (reactive with urogenital sinus Epithelium). By this technique, the PAX2/FOXA1 boundary was located at the extreme caudal aspect of the vaginal plate at 12 weeks. During the ensuing weeks, the PAX2/FOXA1 boundary progressively extended cranially such that by 21 weeks the entire vaginal Epithelium was FOXA1-reactive and PAX2-negative. This observation supports Bulmer's proposal that human vaginal Epithelium derives solely from urogenital sinus Epithelium. Clearly, the development of the human vagina is far more complex than previously envisioned and appears to be distinctly different in many respects from mouse vaginal development.
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roles of p63 in the diethylstilbestrol induced cervicovaginal adenosis
Development, 2004Co-Authors: Takeshi Kurita, Alea A Mills, Gerald R CunhaAbstract:Women exposed to diethylstilbestrol (DES) in utero develop abnormalities, including cervicovaginal adenosis that can lead to cancer. We report that transient disruption of developmental signals by DES permanently changes expression of p63, thereby altering the developmental fate of Mullerian duct Epithelium. The cell fate of Mullerian Epithelium to be columnar (uterine) or squamous (cervicovaginal) is determined by mesenchymal induction during the perinatal period. Cervicovaginal mesenchyme induced p63 in Mullerian duct Epithelium and subsequent squamous differentiation. In p63(-/-) mice, cervicovaginal Epithelium differentiated into uterine Epithelium. Thus, p63 is an identity switch for Mullerian duct Epithelium to be cervicovaginal versus uterine. P63 was also essential for uterine squamous metaplasia induced by DES-exposure. DES-exposure from postnatal day I to 5 inhibited induction of p63 in cervicovaginal Epithelium via epithelial ERalpha. The inhibitory effect of DES was transient, and most cervicovaginal epithelial cells recovered expression of p63 by 2 days after discontinuation of DES-treatment. However, some cervicovaginal epithelial cells failed to express p63, remained columnar and persisted into adulthood as adenosis.
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paracrine regulation of apoptosis by steroid hormones in the male and female reproductive system
Cell Death & Differentiation, 2001Co-Authors: Takeshi Kurita, Yuzhuo Wang, Annemarie A Donjacour, C Zhao, John P Lydon, Bert W Omalley, John T Isaacs, Rajvir Dahiya, Gerald R CunhaAbstract:In males, androgens are essential in maintaining the integrity of the prostate. Androgen-ablation induces apoptosis of the prostatic Epithelium. In females, ovariectomy induces apoptosis in uterine Epithelium while progesterone inhibits this process. The objective of this study was to determine whether androgen and progesterone inhibit apoptosis, respectively, in mouse prostatic and uterine epithelia via steroid receptors in the Epithelium or in the stroma. To address this question, prostatic tissue recombinants were prepared with rat urogenital sinus mesenchyme plus bladder Epithelium from wild-type or testicular feminization mutant (Tfm) mice. Thus, prostatic tissue was generated having androgen receptor (AR) in both Epithelium and stroma or in the stroma only. Castration of hosts induced apoptosis in the AR-negative Tfm prostatic Epithelium with an epithelial apoptotic index virtually identical to prostatic tissue recombinants containing wild-type Epithelium. Moreover, this castration-induced prostatic epithelial apoptosis was blocked by testosterone and dihydrotestosterone in both wild-type and Tfm prostatic tissue recombinants. Likewise, uterine tissue recombinants were prepared in which Epithelium and/or stroma was devoid of progesterone receptor (PR) by using uterine Epithelium and stroma of wild-type and PR knockout mice. Progesterone inhibited uterine epithelial apoptosis only in tissue recombinants prepared with PR-positive stroma. The PR status of the Epithelium did not affect epithelial apoptotic index. Therefore, the apoptosis in prostatic and uterine epithelia is regulated by androgen and progesterone via stromal AR and PR, respectively. In both cases, epithelial AR or PR is not required for hormonal regulation of epithelial apoptosis in prostatic and uterine Epithelium.
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paracrine regulation of epithelial progesterone receptor by estradiol in the mouse female reproductive tract
Biology of Reproduction, 2000Co-Authors: Takeshi Kurita, Paul S Cooke, Julia A Taylor, Dennis B Lubahn, Gerald R CunhaAbstract:Regulation of progesterone receptor (PR) by estradiol-17b (E 2) in mouse uterine and vaginal epithelia was studied. In ovariectomized mice, PR expression was low in both vaginal stroma and Epithelium, but high in uterine Epithelium. E 2 induced PR in vaginal Epithelium and stroma, but down-regulated PR in uterine Epithelium. Analysis of estrogen receptor a (ERa) knockout (ERKO) mice showed that ERa is essential for E 2-induced PR expression in both vaginal Epithelium and stroma, and for E 2induced down-regulation, but not constitutive expression of PR in uterine Epithelium. Regulation of PR by E 2 was studied in vaginal and uterine tissue recombinants made with Epithelium and stroma from wild-type and ERKO mice. In the vaginal tissue recombinants, PR was induced by E 2 only in wild-type Epithelium and/or stroma. Hence, in vagina, E 2 induces PR directly via ERa within the tissue. Conversely, E 2 down-regulated epithelial PR only in uterine tissue recombinants constructed with wildtype stroma. Therefore, down-regulation of uterine epithelial PR by E 2 requires stromal, but not epithelial, ERa. In vitro, isolated uterine epithelial cells retained a high PR level with or without E 2, which is consistent with an indirect regulation of uterine epithelial PR in vivo. Thus, E 2 down-regulates PR in uterine Epithelium through paracrine mechanisms mediated by stromal ERa.
Takeshi Kurita - One of the best experts on this subject based on the ideXlab platform.
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new insights into human female reproductive tract development
Differentiation, 2017Co-Authors: Stanley J Robboy, Laurence S. Baskin, Takeshi Kurita, Gerald R CunhaAbstract:We present a detailed review of the embryonic and fetal development of the human female reproductive tract utilizing specimens from the 5th through the 22nd gestational week. Hematoxylin and eosin (H&E) as well as immunohistochemical stains were used to study the development of the human uterine tube, endometrium, myometrium, uterine cervix and vagina. Our study revisits and updates the classical reports of Koff (1933) and Bulmer (1957) and presents new data on development of human vaginal Epithelium. Koff proposed that the upper 4/5ths of the vagina is derived from Mullerian Epithelium and the lower 1/5th derived from urogenital sinus Epithelium, while Bulmer proposed that vaginal Epithelium derives solely from urogenital sinus Epithelium. These conclusions were based entirely upon H&E stained sections. A central player in human vaginal epithelial development is the solid vaginal plate, which arises from the uterovaginal canal (fused Mullerian ducts) cranially and squamous Epithelium of urogenital sinus caudally. Since Mullerian and urogenital sinus Epithelium cannot be unequivocally identified in H&E stained sections, we used immunostaining for PAX2 (reactive with Mullerian Epithelium) and FOXA1 (reactive with urogenital sinus Epithelium). By this technique, the PAX2/FOXA1 boundary was located at the extreme caudal aspect of the vaginal plate at 12 weeks. During the ensuing weeks, the PAX2/FOXA1 boundary progressively extended cranially such that by 21 weeks the entire vaginal Epithelium was FOXA1-reactive and PAX2-negative. This observation supports Bulmer's proposal that human vaginal Epithelium derives solely from urogenital sinus Epithelium. Clearly, the development of the human vagina is far more complex than previously envisioned and appears to be distinctly different in many respects from mouse vaginal development.
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roles of p63 in the diethylstilbestrol induced cervicovaginal adenosis
Development, 2004Co-Authors: Takeshi Kurita, Alea A Mills, Gerald R CunhaAbstract:Women exposed to diethylstilbestrol (DES) in utero develop abnormalities, including cervicovaginal adenosis that can lead to cancer. We report that transient disruption of developmental signals by DES permanently changes expression of p63, thereby altering the developmental fate of Mullerian duct Epithelium. The cell fate of Mullerian Epithelium to be columnar (uterine) or squamous (cervicovaginal) is determined by mesenchymal induction during the perinatal period. Cervicovaginal mesenchyme induced p63 in Mullerian duct Epithelium and subsequent squamous differentiation. In p63(-/-) mice, cervicovaginal Epithelium differentiated into uterine Epithelium. Thus, p63 is an identity switch for Mullerian duct Epithelium to be cervicovaginal versus uterine. P63 was also essential for uterine squamous metaplasia induced by DES-exposure. DES-exposure from postnatal day I to 5 inhibited induction of p63 in cervicovaginal Epithelium via epithelial ERalpha. The inhibitory effect of DES was transient, and most cervicovaginal epithelial cells recovered expression of p63 by 2 days after discontinuation of DES-treatment. However, some cervicovaginal epithelial cells failed to express p63, remained columnar and persisted into adulthood as adenosis.
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paracrine regulation of apoptosis by steroid hormones in the male and female reproductive system
Cell Death & Differentiation, 2001Co-Authors: Takeshi Kurita, Yuzhuo Wang, Annemarie A Donjacour, C Zhao, John P Lydon, Bert W Omalley, John T Isaacs, Rajvir Dahiya, Gerald R CunhaAbstract:In males, androgens are essential in maintaining the integrity of the prostate. Androgen-ablation induces apoptosis of the prostatic Epithelium. In females, ovariectomy induces apoptosis in uterine Epithelium while progesterone inhibits this process. The objective of this study was to determine whether androgen and progesterone inhibit apoptosis, respectively, in mouse prostatic and uterine epithelia via steroid receptors in the Epithelium or in the stroma. To address this question, prostatic tissue recombinants were prepared with rat urogenital sinus mesenchyme plus bladder Epithelium from wild-type or testicular feminization mutant (Tfm) mice. Thus, prostatic tissue was generated having androgen receptor (AR) in both Epithelium and stroma or in the stroma only. Castration of hosts induced apoptosis in the AR-negative Tfm prostatic Epithelium with an epithelial apoptotic index virtually identical to prostatic tissue recombinants containing wild-type Epithelium. Moreover, this castration-induced prostatic epithelial apoptosis was blocked by testosterone and dihydrotestosterone in both wild-type and Tfm prostatic tissue recombinants. Likewise, uterine tissue recombinants were prepared in which Epithelium and/or stroma was devoid of progesterone receptor (PR) by using uterine Epithelium and stroma of wild-type and PR knockout mice. Progesterone inhibited uterine epithelial apoptosis only in tissue recombinants prepared with PR-positive stroma. The PR status of the Epithelium did not affect epithelial apoptotic index. Therefore, the apoptosis in prostatic and uterine epithelia is regulated by androgen and progesterone via stromal AR and PR, respectively. In both cases, epithelial AR or PR is not required for hormonal regulation of epithelial apoptosis in prostatic and uterine Epithelium.
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paracrine regulation of epithelial progesterone receptor by estradiol in the mouse female reproductive tract
Biology of Reproduction, 2000Co-Authors: Takeshi Kurita, Paul S Cooke, Julia A Taylor, Dennis B Lubahn, Gerald R CunhaAbstract:Regulation of progesterone receptor (PR) by estradiol-17b (E 2) in mouse uterine and vaginal epithelia was studied. In ovariectomized mice, PR expression was low in both vaginal stroma and Epithelium, but high in uterine Epithelium. E 2 induced PR in vaginal Epithelium and stroma, but down-regulated PR in uterine Epithelium. Analysis of estrogen receptor a (ERa) knockout (ERKO) mice showed that ERa is essential for E 2-induced PR expression in both vaginal Epithelium and stroma, and for E 2induced down-regulation, but not constitutive expression of PR in uterine Epithelium. Regulation of PR by E 2 was studied in vaginal and uterine tissue recombinants made with Epithelium and stroma from wild-type and ERKO mice. In the vaginal tissue recombinants, PR was induced by E 2 only in wild-type Epithelium and/or stroma. Hence, in vagina, E 2 induces PR directly via ERa within the tissue. Conversely, E 2 down-regulated epithelial PR only in uterine tissue recombinants constructed with wildtype stroma. Therefore, down-regulation of uterine epithelial PR by E 2 requires stromal, but not epithelial, ERa. In vitro, isolated uterine epithelial cells retained a high PR level with or without E 2, which is consistent with an indirect regulation of uterine epithelial PR in vivo. Thus, E 2 down-regulates PR in uterine Epithelium through paracrine mechanisms mediated by stromal ERa.
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paracrine regulation of epithelial progesterone receptor by estradiol in the mouse female reproductive tract
Biology of Reproduction, 2000Co-Authors: Takeshi Kurita, Paul S Cooke, Julia A Taylor, Dennis B Lubahn, Kijun Lee, Gerald R CunhaAbstract:Regulation of progesterone receptor (PR) by estradiol-17beta (E(2)) in mouse uterine and vaginal epithelia was studied. In ovariectomized mice, PR expression was low in both vaginal stroma and Epithelium, but high in uterine Epithelium. E(2) induced PR in vaginal Epithelium and stroma, but down-regulated PR in uterine Epithelium. Analysis of estrogen receptor alpha (ERalpha) knockout (ERKO) mice showed that ERalpha is essential for E(2)-induced PR expression in both vaginal Epithelium and stroma, and for E(2)-induced down-regulation, but not constitutive expression of PR in uterine Epithelium. Regulation of PR by E(2) was studied in vaginal and uterine tissue recombinants made with Epithelium and stroma from wild-type and ERKO mice. In the vaginal tissue recombinants, PR was induced by E(2) only in wild-type Epithelium and/or stroma. Hence, in vagina, E(2) induces PR directly via ERalpha within the tissue. Conversely, E(2) down-regulated epithelial PR only in uterine tissue recombinants constructed with wild-type stroma. Therefore, down-regulation of uterine epithelial PR by E(2) requires stromal, but not epithelial, ERalpha. In vitro, isolated uterine epithelial cells retained a high PR level with or without E(2), which is consistent with an indirect regulation of uterine epithelial PR in vivo. Thus, E(2) down-regulates PR in uterine Epithelium through paracrine mechanisms mediated by stromal ERalpha.
Magali Saint-geniez - One of the best experts on this subject based on the ideXlab platform.
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Identification of a synergistic interaction between endothelial cells and retinal pigment Epithelium
Journal of Cellular and Molecular Medicine, 2017Co-Authors: Carrie Spencer, Stephanie Abend, Kevin J. Mchugh, Magali Saint-geniezAbstract:The retinal pigment Epithelium located between the neurosensory retina and the choroidal vasculature is critical for the function and maintenance of both the photoreceptors and underlying capillary endothelium. While the trophic role of retinal pigment Epithelium on choroidal endothelial cells is well recognized, the existence of a reciprocal regulatory function of endothelial cells on retinal pigment Epithelium cells remained to be fully characterized. Using a physiological long-term co-culture system, we determined the effect of retinal pigment Epithelium-endothelial cell heterotypic interactions on cell survival, behaviour and matrix deposition. Human retinal pigment Epithelium and endothelial cells were cultured on opposite sides of polyester transwells for up to 4 weeks in low serum conditions. Cell viability was quantified using a trypan blue assay. Cellular morphology was evaluated by H&E staining, S.E.M. and immunohistochemistry. Retinal pigment Epithelium phagocytic function was examined using a fluorescent bead assay. Gene expression analysis was performed on both retinal pigment Epithelium and endothelial cells by quantitative PCR. Quantification of extracellular matrix deposition was performed on decellularized transwells stained for collagen IV, fibronectin and fibrillin. Our results showed that presence of endothelial cells significantly improves retinal pigment Epithelium maturation and function as indicated by the induction of visual cycle-associated genes, accumulation of a Bruch's membrane-like matrix and increase in retinal pigment Epithelium phagocytic activity. Co-culture conditions led to increased expression of anti-angiogenic growth factors and receptors in both retinal pigment Epithelium and endothelial cells compared to monoculture. Tube-formation assays confirmed that co-culture with retinal pigment Epithelium significantly decreased the angiogenic phenotype of endothelial cells. These findings provide evidence of critical interdependent interactions between retinal pigment Epithelium and endothelial cell involved in the maintenance of retinal homeostasis.
Machiko Iida - One of the best experts on this subject based on the ideXlab platform.
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loss of stemness emt and supernumerary tooth formation in cebpb runx2 murine incisors
Scientific Reports, 2018Co-Authors: Kazuyuki Saito, Boyen Huang, Katsu Takahashi, Honoka Kiso, Yumiko Togo, Hiroko Tsukamoto, Masakazu Asahara, Sayaka Mishima, Masaki Nagata, Machiko IidaAbstract:Adult Cebpb KO mice incisors present amelogenin-positive Epithelium pearls, enamel and dentin allopathic hyperplasia, fewer Sox2-positive cells in labial cervical loop Epitheliums, and reduced Sox2 expression in enamel epithelial stem cells. Thus, Cebpb acts upstream of Sox2 to regulate stemness. In this study, Cebpb KO mice demonstrated cementum-like hard tissue in dental pulp, loss of polarity by ameloblasts, enamel matrix in ameloblastic layer, and increased expression of epithelial-mesenchymal transition (EMT) markers in a Cebpb knockdown mouse enamel epithelial stem cell line. Runx2 knockdown in the cell line presented a similar expression pattern. Therefore, the EMT enabled disengaged odontogenic epithelial stem cells to develop supernumerary teeth. Cebpb and Runx2 knockdown in the cell line revealed higher Biglycan and Decorin expression, and Decorin-positive staining in the periapical region, indicating their involvement in supernumerary tooth formation. Cebpb and Runx2 acted synergistically and played an important role in the formation of supernumerary teeth in adult incisors.
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Loss of Stemness, EMT, and Supernumerary Tooth Formation in Cebpb −/− Runx2 +/− Murine Incisors
Nature Publishing Group, 2018Co-Authors: Kazuyuki Saito, Boyen Huang, Katsu Takahashi, Honoka Kiso, Yumiko Togo, Hiroko Tsukamoto, Masakazu Asahara, Sayaka Mishima, Masaki Nagata, Machiko IidaAbstract:Abstract Adult Cebpb KO mice incisors present amelogenin-positive Epithelium pearls, enamel and dentin allopathic hyperplasia, fewer Sox2-positive cells in labial cervical loop Epitheliums, and reduced Sox2 expression in enamel epithelial stem cells. Thus, Cebpb acts upstream of Sox2 to regulate stemness. In this study, Cebpb KO mice demonstrated cementum-like hard tissue in dental pulp, loss of polarity by ameloblasts, enamel matrix in ameloblastic layer, and increased expression of epithelial-mesenchymal transition (EMT) markers in a Cebpb knockdown mouse enamel epithelial stem cell line. Runx2 knockdown in the cell line presented a similar expression pattern. Therefore, the EMT enabled disengaged odontogenic epithelial stem cells to develop supernumerary teeth. Cebpb and Runx2 knockdown in the cell line revealed higher Biglycan and Decorin expression, and Decorin-positive staining in the periapical region, indicating their involvement in supernumerary tooth formation. Cebpb and Runx2 acted synergistically and played an important role in the formation of supernumerary teeth in adult incisors
Carrie Spencer - One of the best experts on this subject based on the ideXlab platform.
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Identification of a synergistic interaction between endothelial cells and retinal pigment Epithelium
Journal of Cellular and Molecular Medicine, 2017Co-Authors: Carrie Spencer, Stephanie Abend, Kevin J. Mchugh, Magali Saint-geniezAbstract:The retinal pigment Epithelium located between the neurosensory retina and the choroidal vasculature is critical for the function and maintenance of both the photoreceptors and underlying capillary endothelium. While the trophic role of retinal pigment Epithelium on choroidal endothelial cells is well recognized, the existence of a reciprocal regulatory function of endothelial cells on retinal pigment Epithelium cells remained to be fully characterized. Using a physiological long-term co-culture system, we determined the effect of retinal pigment Epithelium-endothelial cell heterotypic interactions on cell survival, behaviour and matrix deposition. Human retinal pigment Epithelium and endothelial cells were cultured on opposite sides of polyester transwells for up to 4 weeks in low serum conditions. Cell viability was quantified using a trypan blue assay. Cellular morphology was evaluated by H&E staining, S.E.M. and immunohistochemistry. Retinal pigment Epithelium phagocytic function was examined using a fluorescent bead assay. Gene expression analysis was performed on both retinal pigment Epithelium and endothelial cells by quantitative PCR. Quantification of extracellular matrix deposition was performed on decellularized transwells stained for collagen IV, fibronectin and fibrillin. Our results showed that presence of endothelial cells significantly improves retinal pigment Epithelium maturation and function as indicated by the induction of visual cycle-associated genes, accumulation of a Bruch's membrane-like matrix and increase in retinal pigment Epithelium phagocytic activity. Co-culture conditions led to increased expression of anti-angiogenic growth factors and receptors in both retinal pigment Epithelium and endothelial cells compared to monoculture. Tube-formation assays confirmed that co-culture with retinal pigment Epithelium significantly decreased the angiogenic phenotype of endothelial cells. These findings provide evidence of critical interdependent interactions between retinal pigment Epithelium and endothelial cell involved in the maintenance of retinal homeostasis.
