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Comprehensive analysis of leukocytes, vascularization and matrix metalloproteinases in human menstrual xenograft model.

Guo Y, He B, Xu X, Wang J - PLoS ONE (2011)

Bottom Line: Human CD45+ cells showed a peak of increase 28 days post-transplantation.Three days after progesterone withdrawal, mouse CD45+ cells increased rapidly in number and were significantly greater than human CD45+ cell counts.After progesterone withdrawal, the expression levels of matrix metalloproteinases (MMP) 1, 2, and 9 were increased.

View Article: PubMed Central - PubMed

Affiliation: Graduate School, Peking Union Medical College, Beijing, People's Republic of China.

ABSTRACT
In our previous study, menstrual-like changes in mouse were provoked through the pharmacologic withdrawal of progesterone with mifepristone following induction of decidualization. However, mouse is not a natural menstruation animal, and the menstruation model using external stimuli may not truly reflect the occurrence and development of the human menstrual process. Therefore, we established a model of menstruation based on human endometrial xenotransplantation. In this model, human endometrial tissues were transplanted subcutaneously into SCID mice that were ovarectomized and supplemented with estrogen and progestogen by silastic implants with a scheme imitating the endocrinological milieu of human menstrual cycle. Morphology, hormone levels, and expression of vimentin and cytokeratin markers were evaluated to confirm the menstrual-like changes in this model. With 28 days of hormone treatment, transplanted human endometrium survived and underwent proliferation, differentiation and disintegration, similar to human endometrium in vivo. Human CD45+ cells showed a peak of increase 28 days post-transplantation. Three days after progesterone withdrawal, mouse CD45+ cells increased rapidly in number and were significantly greater than human CD45+ cell counts. Mouse CD31+ blood vascular-like structures were detected in both transplanted and host tissues. After progesterone withdrawal, the expression levels of matrix metalloproteinases (MMP) 1, 2, and 9 were increased. In summary, we successfully established a human endometrial xenotransplantation model in SCID mice, based on the results of menstrual-like changes in which MMP-1, 2 and 9 are involved. We showed that leukocytes are originated from in situ proliferation in human xenografts and involved in the occurrence of menstruation. This model will help to further understand the occurrence, growth, and differentiation of the endometrium and the underlying mechanisms of menstruation.

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Histological examination of xenotransplanted human endometrial tissues.(A) Human endometrial tissues before transplantation. Endometrial tissues showed simple columnar epithelium and dense stroma, which characterized a typical human early proliferative phase endometrium. (B) Control group without hormone treatment. The tissue fragments were small in size and increased in lumen diameter. (C) 14d group (E2 provided alone). Glandular epithelium was in high columnar form with a significant pseudostratification of the nuclei. (D) 21d group (E2 provided for 21 days of which P4 provided for last 7 days). Glandular epithelial cells were changed into low columnar. Subnuclear vacuolation was clearly visible in the glandular epithelial cells with nuclei close to the basilar membrane, whereas stromal cell density was decreased. (E) 28d group (E2 provided for 28 days of which P4 provided for last 14 days). The cell-cavity surface with irregular margins contained a large number of small secretion bubbles. Interstitial edema was observed, stromal cells were enlarged, and the nuclei clearly showed a typical decidual-like stromal change. (F) 31d group (hormones were provided for 28 days and then no hormone support for the remaining 3 days). A large number of leukocytes were infiltrated, and the endometrial tissue structure was disintegrated with erythrocyte leakage. Original magnification: 400× (H&E).
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pone-0016840-g002: Histological examination of xenotransplanted human endometrial tissues.(A) Human endometrial tissues before transplantation. Endometrial tissues showed simple columnar epithelium and dense stroma, which characterized a typical human early proliferative phase endometrium. (B) Control group without hormone treatment. The tissue fragments were small in size and increased in lumen diameter. (C) 14d group (E2 provided alone). Glandular epithelium was in high columnar form with a significant pseudostratification of the nuclei. (D) 21d group (E2 provided for 21 days of which P4 provided for last 7 days). Glandular epithelial cells were changed into low columnar. Subnuclear vacuolation was clearly visible in the glandular epithelial cells with nuclei close to the basilar membrane, whereas stromal cell density was decreased. (E) 28d group (E2 provided for 28 days of which P4 provided for last 14 days). The cell-cavity surface with irregular margins contained a large number of small secretion bubbles. Interstitial edema was observed, stromal cells were enlarged, and the nuclei clearly showed a typical decidual-like stromal change. (F) 31d group (hormones were provided for 28 days and then no hormone support for the remaining 3 days). A large number of leukocytes were infiltrated, and the endometrial tissue structure was disintegrated with erythrocyte leakage. Original magnification: 400× (H&E).

Mentions: Before transplantation, endometrial tissues showed simple columnar epithelium, small glandular lumen, and dense stromal cells with most of them being spindle-like, which characterized a typical human early proliferative phase endometrium (Fig. 2A). After transplantation and hormone treatment, the endometrial tissue fragments increased in volume and were surrounded by a connective tissue capsule with a clear boundary. In the absence of hormones, the tissue fragments of the control group did not grow, and were significantly smaller than those of the hormone-treated groups, although the lumen was enlarged (Fig. 2B). After 14 days of 17β-estradiol (17β-E2) treatment (14d group), the following features were shown: tissue volume increased significantly; glandular epithelium was in high columnar form with a significant pseudostratification of the nuclei; glandular lumen was expanded, stromal cells were mostly spindle or round in shape; the cell cytoplasm was scarce (Fig. 2C). In the 21d group, the glandular lumen was expanded more, with cavities contained secretions and exfoliated epithelial cells in the cavity. Glandular epithelial cells were changed into low columnar in appearance. Subnuclear vacuolation was clearly visible in the glandular epithelial cells with nuclei close to the basilar membrane, whereas stromal cell density was decreased (Fig. 2D). In the 28d group, the cell-cavity surface with irregular margins contained a large number of small secretion bubbles. The interstitial edema was very observed, and stromal cells were enlarged with nuclei clearly showing a typical decidual-like stromal change (Fig. 2E). In the 31d group, a large number of leukocytes were infiltrated, and the endometrial tissue structure was disintegrated with erythrocyte leakage (Fig. 2F).


Comprehensive analysis of leukocytes, vascularization and matrix metalloproteinases in human menstrual xenograft model.

Guo Y, He B, Xu X, Wang J - PLoS ONE (2011)

Histological examination of xenotransplanted human endometrial tissues.(A) Human endometrial tissues before transplantation. Endometrial tissues showed simple columnar epithelium and dense stroma, which characterized a typical human early proliferative phase endometrium. (B) Control group without hormone treatment. The tissue fragments were small in size and increased in lumen diameter. (C) 14d group (E2 provided alone). Glandular epithelium was in high columnar form with a significant pseudostratification of the nuclei. (D) 21d group (E2 provided for 21 days of which P4 provided for last 7 days). Glandular epithelial cells were changed into low columnar. Subnuclear vacuolation was clearly visible in the glandular epithelial cells with nuclei close to the basilar membrane, whereas stromal cell density was decreased. (E) 28d group (E2 provided for 28 days of which P4 provided for last 14 days). The cell-cavity surface with irregular margins contained a large number of small secretion bubbles. Interstitial edema was observed, stromal cells were enlarged, and the nuclei clearly showed a typical decidual-like stromal change. (F) 31d group (hormones were provided for 28 days and then no hormone support for the remaining 3 days). A large number of leukocytes were infiltrated, and the endometrial tissue structure was disintegrated with erythrocyte leakage. Original magnification: 400× (H&E).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3040756&req=5

pone-0016840-g002: Histological examination of xenotransplanted human endometrial tissues.(A) Human endometrial tissues before transplantation. Endometrial tissues showed simple columnar epithelium and dense stroma, which characterized a typical human early proliferative phase endometrium. (B) Control group without hormone treatment. The tissue fragments were small in size and increased in lumen diameter. (C) 14d group (E2 provided alone). Glandular epithelium was in high columnar form with a significant pseudostratification of the nuclei. (D) 21d group (E2 provided for 21 days of which P4 provided for last 7 days). Glandular epithelial cells were changed into low columnar. Subnuclear vacuolation was clearly visible in the glandular epithelial cells with nuclei close to the basilar membrane, whereas stromal cell density was decreased. (E) 28d group (E2 provided for 28 days of which P4 provided for last 14 days). The cell-cavity surface with irregular margins contained a large number of small secretion bubbles. Interstitial edema was observed, stromal cells were enlarged, and the nuclei clearly showed a typical decidual-like stromal change. (F) 31d group (hormones were provided for 28 days and then no hormone support for the remaining 3 days). A large number of leukocytes were infiltrated, and the endometrial tissue structure was disintegrated with erythrocyte leakage. Original magnification: 400× (H&E).
Mentions: Before transplantation, endometrial tissues showed simple columnar epithelium, small glandular lumen, and dense stromal cells with most of them being spindle-like, which characterized a typical human early proliferative phase endometrium (Fig. 2A). After transplantation and hormone treatment, the endometrial tissue fragments increased in volume and were surrounded by a connective tissue capsule with a clear boundary. In the absence of hormones, the tissue fragments of the control group did not grow, and were significantly smaller than those of the hormone-treated groups, although the lumen was enlarged (Fig. 2B). After 14 days of 17β-estradiol (17β-E2) treatment (14d group), the following features were shown: tissue volume increased significantly; glandular epithelium was in high columnar form with a significant pseudostratification of the nuclei; glandular lumen was expanded, stromal cells were mostly spindle or round in shape; the cell cytoplasm was scarce (Fig. 2C). In the 21d group, the glandular lumen was expanded more, with cavities contained secretions and exfoliated epithelial cells in the cavity. Glandular epithelial cells were changed into low columnar in appearance. Subnuclear vacuolation was clearly visible in the glandular epithelial cells with nuclei close to the basilar membrane, whereas stromal cell density was decreased (Fig. 2D). In the 28d group, the cell-cavity surface with irregular margins contained a large number of small secretion bubbles. The interstitial edema was very observed, and stromal cells were enlarged with nuclei clearly showing a typical decidual-like stromal change (Fig. 2E). In the 31d group, a large number of leukocytes were infiltrated, and the endometrial tissue structure was disintegrated with erythrocyte leakage (Fig. 2F).

Bottom Line: Human CD45+ cells showed a peak of increase 28 days post-transplantation.Three days after progesterone withdrawal, mouse CD45+ cells increased rapidly in number and were significantly greater than human CD45+ cell counts.After progesterone withdrawal, the expression levels of matrix metalloproteinases (MMP) 1, 2, and 9 were increased.

View Article: PubMed Central - PubMed

Affiliation: Graduate School, Peking Union Medical College, Beijing, People's Republic of China.

ABSTRACT
In our previous study, menstrual-like changes in mouse were provoked through the pharmacologic withdrawal of progesterone with mifepristone following induction of decidualization. However, mouse is not a natural menstruation animal, and the menstruation model using external stimuli may not truly reflect the occurrence and development of the human menstrual process. Therefore, we established a model of menstruation based on human endometrial xenotransplantation. In this model, human endometrial tissues were transplanted subcutaneously into SCID mice that were ovarectomized and supplemented with estrogen and progestogen by silastic implants with a scheme imitating the endocrinological milieu of human menstrual cycle. Morphology, hormone levels, and expression of vimentin and cytokeratin markers were evaluated to confirm the menstrual-like changes in this model. With 28 days of hormone treatment, transplanted human endometrium survived and underwent proliferation, differentiation and disintegration, similar to human endometrium in vivo. Human CD45+ cells showed a peak of increase 28 days post-transplantation. Three days after progesterone withdrawal, mouse CD45+ cells increased rapidly in number and were significantly greater than human CD45+ cell counts. Mouse CD31+ blood vascular-like structures were detected in both transplanted and host tissues. After progesterone withdrawal, the expression levels of matrix metalloproteinases (MMP) 1, 2, and 9 were increased. In summary, we successfully established a human endometrial xenotransplantation model in SCID mice, based on the results of menstrual-like changes in which MMP-1, 2 and 9 are involved. We showed that leukocytes are originated from in situ proliferation in human xenografts and involved in the occurrence of menstruation. This model will help to further understand the occurrence, growth, and differentiation of the endometrium and the underlying mechanisms of menstruation.

Show MeSH
Related in: MedlinePlus