Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 376
Filtrar
1.
Ceska Gynekol ; 89(4): 269-277, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-39242201

RESUMEN

OBJECTIVE: Endometrial polyp (EP) is a type of pathology that is quite common in clinical practice. Although its exact etiology is not fully known, there is evidence to support that it is sensitive to hormonal stimuli. We aimed to investigate the relationship between kisspeptin (KP) and EP by comparing the genetic (tissue-blood) and immunohistochemical (IHC) expression of KP in EP lesions in patients with normal endometrial findings. MATERIALS AND METHODS: A prospective case-control study of 50 patients with EP (N = 25) and normal endometrial findings (N = 25) on biopsy and/or excision material was performed. Blood and biopsy samples obtained from all patients were stored at -80 °C. KP gene expression levels were determined from paraffin blocks, and peripheral venous blood samples obtained from biopsy specimens and IHC-H-score analysis were performed from paraffin blocks. EP and matched controls were compared for KP. RESULTS: After IHC, the KP H-score of the control group was higher than the EP group, and this difference was statistically significant; H-score: control: 5 (++; 1-15); polyp: 1 (+; 0-12) (P < 0.05). Although KP expression in both tissue and blood was higher in the control group than in the EP group, this difference was not statistically significant (P > 0.05). No significant correlation was found between IHC H-score and KP expression levels in tissue and blood. According to the ROC analysis, the tissue and blood KP expression cut-off value and area under the curve (AUC) predicting the likelihood of developing EP were not significant (tissue KP: 1.04, AUC: 0.570, P = 0.388, sensitivity 56%, specificity 60%, Blood KP: 1.06, AUC: 0.569, P = 0.401, sensitivity 80%, specificity 40%). CONCLUSIONS: Decreased KP expression level in EP lesions may predict the diagnosis of EP, and in the future, KP may have therapeutic potential for benign gynecological pathologies such as polyps.


Asunto(s)
Inmunohistoquímica , Kisspeptinas , Pólipos , Humanos , Femenino , Pólipos/genética , Pólipos/metabolismo , Pólipos/patología , Kisspeptinas/genética , Kisspeptinas/metabolismo , Estudios de Casos y Controles , Enfermedades Uterinas/genética , Enfermedades Uterinas/metabolismo , Enfermedades Uterinas/patología , Enfermedades Uterinas/sangre , Estudios Prospectivos , Adulto , Endometrio/metabolismo , Endometrio/patología , Persona de Mediana Edad
2.
Reprod Biol Endocrinol ; 22(1): 118, 2024 Sep 13.
Artículo en Inglés | MEDLINE | ID: mdl-39272165

RESUMEN

Zearalenone (ZEA) is a mycotoxin produced by Fusarium fungi that has been shown to have adverse effects on human and animal health, particularly on the fertility of females. As a saponin derived from the medicinal plant Centella asiatica, asiaticoside (AS) has multiple bioactivities. This study aimed to investigate the protective effects of AS on ZEA-induced uterine injury and the underlying mechanism. In the present study, we demonstrated that AS could rescue ZEA-induced uterine histopathological damage and modulate the secretion of sex hormones, including progesterone (P4), luteinizing hormone (LH), and estradiol (E2), in ZEA-treated mice. Moreover, AS alleviated ZEA-induced damage to endometrial barrier function by upregulating the expression of tight junction proteins (ZO-1, occludin, and claudin-3). Further mechanistic investigations indicated that ZEA reduces the antioxidant capacity of uterine tissues, whereas AS improves the antioxidant capacity through activating the Nrf2 signaling pathway. Most notably, the protective effect of AS was blocked in Nrf2 gene knockout (Nrf2-/-) mice. Moreover, the p38/ERK MAPK pathway has been implicated in regulating ZEA toxicity and the beneficial effect of AS. Additionally, an Nrf2 inhibitor (ML385) weaken the suppressive effect of AS on the oxidative stress and MAPK pathway. AS also inhibits ZEA-induced apoptosis in uterine tissues via the PI3K/Akt signaling pathway. However, when the PI3K small molecule inhibitor LY294002 was co-administered, the ability of AS to suppress the expression of apoptosis-related proteins and inhibit ZEA-induced apoptosis decreased. Collectively, these findings reveal the involvement of multiple pathways and targets in the protective effect of AS against ZEA-induced uterine injury, providing a new perspective for the application of AS and the development of a ZEA antidote.


Asunto(s)
Apoptosis , Endometrio , Estrés Oxidativo , Triterpenos , Útero , Zearalenona , Animales , Femenino , Estrés Oxidativo/efectos de los fármacos , Triterpenos/farmacología , Zearalenona/toxicidad , Apoptosis/efectos de los fármacos , Ratones , Endometrio/efectos de los fármacos , Endometrio/metabolismo , Endometrio/patología , Útero/efectos de los fármacos , Útero/metabolismo , Útero/patología , Transducción de Señal/efectos de los fármacos , Enfermedades Uterinas/patología , Enfermedades Uterinas/metabolismo , Enfermedades Uterinas/inducido químicamente , Enfermedades Uterinas/prevención & control , Enfermedades Uterinas/genética
3.
Commun Biol ; 7(1): 1022, 2024 Aug 20.
Artículo en Inglés | MEDLINE | ID: mdl-39164588

RESUMEN

IL-33 belongs to the inflammatory factor family and is closely associated with the inflammatory response. However, its role in the development of intrauterine adhesions (IUAs) remains unclear. In this study, the role of IL-33 in the formation of IUAs after endometrial injury was identified via RNA sequencing after mouse endometrial organoids were transplanted into an IUA mouse model. Major pathological changes in the mouse uterus, consistent with the expression of fibrotic markers, such as TGF-ß, were observed in response to treatment with IL-33. This finding may be attributed to activation of the phosphorylation of downstream MAPK signaling pathway components, which are activated by the release of IL-33 in macrophages. Our study provides a novel mechanism for elucidating IUA formation, suggesting a new therapeutic strategy for the prevention and clinical treatment of IUAs.


Asunto(s)
Interleucina-33 , Sistema de Señalización de MAP Quinasas , Animales , Interleucina-33/metabolismo , Interleucina-33/genética , Femenino , Ratones , Adherencias Tisulares/metabolismo , Adherencias Tisulares/patología , Enfermedades Uterinas/patología , Enfermedades Uterinas/metabolismo , Enfermedades Uterinas/genética , Ratones Endogámicos C57BL , Modelos Animales de Enfermedad , Transducción de Señal , Útero/metabolismo , Útero/patología , Endometrio/metabolismo , Endometrio/patología , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Proteínas Quinasas Activadas por Mitógenos/genética
4.
Biol Reprod ; 111(2): 322-331, 2024 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-38984926

RESUMEN

Intrauterine adhesion (IUA) is manifestations of endometrial fibrosis and excessive extracellular matrix deposition. C1q/tumor necrosis factor-related protein-6 (CTRP6) is a newly identified adiponectin paralog which has been reported to modulate the fibrosis process of several diseases; however, the endometrial fibrosis function of CTRP6 remains unknown. Our study aimed to assess the role of CTRP6 in endometrial fibrosis and further explore the underlying mechanism. Here, we found that the expression of CTRP6 was downregulated in the endometrial tissues of IUA. In vitro experiments demonstrated the reduced level of CTRP6 in facilitated transforming growth factor-ß1 (TGF-ß1)-induced human endometrial stromal cells (HESCs). In addition, CTRP6 inhibited the expression of α-smooth muscle actin (α-SMA) and collagen I in TGF-ß1-treated HESCs. Mechanistically, CTRP6 activated the AMP-activated protein kinase (AMPK) and protein kinase B (AKT) pathway in HESCs, and AMPK inhibitor (AraA) or PI3K inhibitor (LY294002) pretreatment abolished the protective effect of CTRP6 on TGF-ß1-induced fibrosis. CTRP6 markedly decreased TGF-ß1-induced Smad3 phosphorylation and nuclear translocation, and AMPK or AKT inhibition reversed these effects. Notably, CTRP6-overexpressing treatment alleviated the fibrosis of endometrium in vivo. Therefore, CTRP6 ameliorates endometrial fibrosis, among which AMPK and AKT are essential for the anti-fibrotic effect of CTRP6 via the Smad3 pathway. Taken together, CTRP6 may be a potential therapeutic target for the treatment of intrauterine adhesion.


Asunto(s)
Endometrio , Fibrosis , Transducción de Señal , Proteína smad3 , Animales , Femenino , Humanos , Ratones , Adipoquinas/metabolismo , Colágeno , Endometrio/metabolismo , Endometrio/efectos de los fármacos , Endometrio/patología , Transducción de Señal/efectos de los fármacos , Proteína smad3/metabolismo , Proteína smad3/genética , Adherencias Tisulares/metabolismo , Factor de Crecimiento Transformador beta1/metabolismo , Factores de Necrosis Tumoral/metabolismo , Factores de Necrosis Tumoral/genética , Enfermedades Uterinas/metabolismo , Enfermedades Uterinas/patología
5.
Zhen Ci Yan Jiu ; 49(6): 566-576, 2024 Jun 25.
Artículo en Inglés, Chino | MEDLINE | ID: mdl-38897800

RESUMEN

OBJECTIVES: To observe the effect of electroacupuncture (EA) on the Wnt/ß-catenin signaling pathway and epithelial-mesenchymal transition (EMT)-related proteins in rats with intrauterine adhesions (IUA), so as to explore the possible mechanisms of EA in repairing endometrial damage in IUA. METHODS: Female SD rats were randomly divided into blank, model, EA, and ICG-001 groups, with 10 rats in each group. The IUA model was established by using mechanical scraping combined with lipopolysaccharide infection for double injury. In the EA group, "Guanyuan" (CV4) was needled and EA (2 Hz/15 Hz, 1-2 mA) was applied to "Zusanli" (ST36) and "Sanyinjiao"(SP6) on both sides. In the ICG-001 group, ICG-001 (5 mg/kg), the inhibitor of ß-catenin was intraperitoneally injected. After intervention, samples were taken from 5 rats in each group, and uterine endometrium morphology, endometrial thickness, and gland counts were observed using HE staining. Masson staining was used to assess the degree of fibrosis in the endometrial tissue. Immunohistochemistry was used to detect the positive expression of transforming growth factor ß1 (TGF-ß1), α-smooth muscle actin (α-SMA), fibronectin (FN), connective tissue growth factor (CTGF), type I collagen (Col- Ⅰ), glycogen synthase kinase-3ß (GSK-3ß), ß-catenin, E-cadherin, N-cadherin, and Vimentin in the endometrial tissue. Western blot was used to detect the relative expression of GSK-3ß, ß-catenin, E-cadherin, N-cadherin, and Vimentin proteins in the endometrial tissue. Another 5 rats from each group were placed in cages with male rats after intervention to record the number of embryo implantations. RESULTS: Necrosis and loss of endometrial tissue in the model group observed after HE staining were alleviated in the EA group, better than those in the ICG-001 group. Compared with the blank group, the numbers of glands and endometrial thickness in the uterine endometrial tissue, relative expression and positive expression of E-cadherin and GSK-3ß proteins in the uterine endometrial tissue, and embryo implantation numbers were reduced(P<0.000 1, P<0.001, P<0.01) in the model group, while fibrosis area ratio in the uterine endometrial tissue, TGF- ß 1, α -SMA, FN, CTGF, Col- Ⅰ positive expressions, N-cadherin, Vimentin, and ß-catenin proteins expression and positive expression were increased(P<0.000 1, P<0.001, P<0.01). Compared with the model group, the number of glands and endometrial thickness, E-cadherin and GSK-3ß proteins expression and positive expression, and embryo implantation numbers were increased (P<0.001, P<0.05, P<0.01) in the EA and ICG-001 groups, while the fibrosis area ratio in the uterine endometrial tissue, TGF-ß1, α-SMA, FN, CTGF, Col- Ⅰ positive expression, and N-cadherin, Vimentin, and ß-catenin proteins expression and positive expression were decreased(P<0.001, P<0.01, P<0.05). Compared with the EA group, the differences of the above-mentioned indicators in the ICG-001 group were not statistically significant. CONCLUSIONS: EA may reverse the EMT process and reduce the degree of fibrosis in endometrial tissue by inhibiting the Wnt/ß-catenin signaling pathway, thereby promoting the repair of endometrial damage in IUA.


Asunto(s)
Electroacupuntura , Endometrio , Transición Epitelial-Mesenquimal , Fibrosis , Ratas Sprague-Dawley , Vía de Señalización Wnt , beta Catenina , Animales , Femenino , Ratas , Humanos , beta Catenina/metabolismo , beta Catenina/genética , Endometrio/metabolismo , Fibrosis/terapia , Fibrosis/genética , Adherencias Tisulares/terapia , Adherencias Tisulares/metabolismo , Adherencias Tisulares/genética , Enfermedades Uterinas/terapia , Enfermedades Uterinas/metabolismo , Enfermedades Uterinas/genética , Cadherinas/metabolismo , Cadherinas/genética , Puntos de Acupuntura , Útero/metabolismo
6.
BMC Womens Health ; 24(1): 366, 2024 Jun 22.
Artículo en Inglés | MEDLINE | ID: mdl-38909214

RESUMEN

BACKGROUND: Insulin resistance (IR) induces hyperinsulinemia, which activates downstream signaling pathways such as the phosphatidylinositol-3-kinase/protein kinase B (PI3K/AKT) pathway, ultimately leading to abnormal proliferation and apoptosis of endometrial cells. This is thought to be a key pathogenic mechanism underlying the development of endometrial polyps (EP). This study aims to investigate the relationship between IR and the development of EP, the expression levels of downstream signaling molecules, including PI3K and AKT, and related laboratory parameters were examined. METHODS: A total of 100 patients who visited the gynecology outpatient clinic of Zhongda Hospital affiliated with Southeast University from May 2021 to March 2023 and were diagnosed with abnormal endometrial echoes by vaginal ultrasound and underwent hysteroscopic diagnostic curettage were enrolled in this study. General data and relevant hematological indicators were compared, and intraoperative specimens were obtained for pathological examination. Possible factors influencing the development of endometrial polyps were analyzed using Pearson correlation analysis and logistic regression analysis. RESULTS: In terms of body mass index, waist circumference, fasting insulin, insulin resistance index, serum total testosterone, and free testosterone index, women of childbearing age in the endometrial polyp group had higher values than those in the non-polyp group, while sex hormone-binding globulin in the endometrial polyp group was lower than that in the non-polyp group, and the differences were statistically significant (P < 0.05). The expression scores and mRNA expression levels of PI3K and AKT proteins were higher in the EP group than in the non-EP group (p < 0.05). Pearson correlation analysis showed a positive correlation between HOMA-IR and the expression scores of PI3K and AKT proteins (p < 0.01). CONCLUSIONS: Insulin resistance and abnormal activation of the phosphatidylinositol 3-kinase/protein kinase B signaling pathway may be potential pathogenic mechanisms for the development of endometrial polyps.


Asunto(s)
Resistencia a la Insulina , Fosfatidilinositol 3-Quinasas , Pólipos , Proteínas Proto-Oncogénicas c-akt , Humanos , Femenino , Proteínas Proto-Oncogénicas c-akt/metabolismo , Adulto , Fosfatidilinositol 3-Quinasas/metabolismo , Persona de Mediana Edad , Enfermedades Uterinas/metabolismo , Enfermedades Uterinas/patología , Índice de Masa Corporal , Transducción de Señal , Endometrio/metabolismo , Endometrio/patología , Globulina de Unión a Hormona Sexual/metabolismo , Globulina de Unión a Hormona Sexual/análisis , Testosterona/sangre , Insulina/metabolismo , Insulina/sangre
7.
Zhen Ci Yan Jiu ; 49(5): 487-498, 2024 May 25.
Artículo en Inglés, Chino | MEDLINE | ID: mdl-38764120

RESUMEN

OBJECTIVES: To observe the effect of electroacupuncture(EA) on endometrial fibrosis and M1-type macrophages in rats with intrauterine adhesions(IUA), so as to explore the possible mechanism of EA in the treatment of IUA. METHODS: Fifteen female SD rats were randomly divided into blank group, model group and EA group, with 5 rats in each group. The IUA rat model was established by double damage method using mechanical scraping combined with lipopolysaccharide infection. Rats in the EA group were treated with acupuncture at "Guanyuan"(CV4), and EA at bilateral "Zusanli"(ST36) and "Sanyinjiao"(SP6)for 20 minutes each time, once a day, for 3 consecutive cycles of estrus. Five rats in each group were sampled during the estrous period, and the endometrial morphology, endometrial thickness and the number of blood vessels and glands were observed after HE staining. The fibrotic area of the uterus was observed after Masson staining. The positive expressions of Runt-related transcription factor(RUNX1), transforming growth factor-ß1(TGF-ß1), connective tissue growth factor(CTGF), α-smooth muscle actin(α-SMA), collagen type I(Col-Ⅰ), cluster of differentiation 86(CD86), interleukin-1ß(IL-1ß), and tumor necrosis factor-α(TNF-α) in endometrial tissue were detected by immunohistochemistry. Western blot was used to detect relative protein expressions of RUNX1, TGF-ß1, α-SMA, CD86, and TNF receptor 2 (TNFR2), and real-time fluorescence quantitative PCR was used to detect mRNA expressions of RUNX1, TGF-ß1, α-SMA, CD86, and TNF-α in the endometrium. RESULTS: During the estrous phase, the endometrial layer in the model group was damaged, with reduced folds, disordered arrangement of epithelial cells, loose fibrous connective tissue, significant narrowing and adhesions in the uterine cavity, interstitial congestion, edema, and a significant infiltration of inflammatory cells with sparse glands. While uterine tissue structure of the EA group was basically intact, resembling a normal uterus, with more newly formed glands and a small amount of inflammatory cell infiltration. In comparison with the blank group, the endometrial thickness, the number of blood vessels, and the number of glands were significantly decreased(P<0.001) in the model group, while the ratio of uterine fibrosis area, the positive expressions of RUNX1, TGF-ß1, CTGF, α-SMA, Col-Ⅰ, CD86, IL-1ß, and TNF-α, the protein relative expressions of RUNX1, TGF-ß1, α-SMA, CD86 and TNFR2, and the mRNA relative expression levels of RUNX1, TGF-ß1, α-SMA, CD86 and TNF-α in the endometrium were significantly increased (P<0.001, P<0.01). Compared to the model group, the endometrial thickness, the number of blood vessels, and the number of glands were significantly increased(P<0.01, P<0.05) in the EA group, while the ratio of uterine fibrosis area, the positive expressions of RUNX1, TGF-ß1, CTGF, α-SMA, Col-Ⅰ, CD86, IL-1ß and TNF-α in the endometrial tissue, the protein expressions of RUNX1, TGF-ß1, α-SMA, CD86 and TNFR2, and the mRNA relative expressions of RUNX1, TGF-ß1, α-SMA, CD86 and TNF-α in the endometrium were significantly decreased (P<0.001, P<0.01, P<0.05). CONCLUSIONS: EA can improve endometrial fibrosis in IUA rats, which may be related to its function in decreasing the level of endometrial M1-type macrophages and the secretion of related inflammatory factors.


Asunto(s)
Electroacupuntura , Endometrio , Macrófagos , Ratas Sprague-Dawley , Animales , Femenino , Ratas , Endometrio/metabolismo , Adherencias Tisulares/terapia , Adherencias Tisulares/metabolismo , Adherencias Tisulares/genética , Humanos , Macrófagos/metabolismo , Factor de Crecimiento Transformador beta1/metabolismo , Factor de Crecimiento Transformador beta1/genética , Puntos de Acupuntura , Enfermedades Uterinas/terapia , Enfermedades Uterinas/metabolismo , Factor de Crecimiento del Tejido Conjuntivo/metabolismo , Factor de Crecimiento del Tejido Conjuntivo/genética
8.
Reprod Biol ; 24(2): 100882, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38604016

RESUMEN

This study aims to elucidate the effects of Platelet-rich plasma (PRP) in fibrosis development in intrauterine adhesion (IUA), and the associated underlying mechanisms are also explored, which are expected to be a potential therapeutic scheme for IUA. In this research, PRP was obtained and prepared from the peripheral venous blood of rats. A rat model was induced by mechanical injury. Further, PRP was directly injected into the uterus for treatment. The appearance and shape of the uterus were assessed based on the tissues harvested. The fibrosis biomarker levels were analyzed. The transforming growth factor beta 1 (TGF-ß1) and Mothers against decapentaplegic homolog 7 (Smad7) levels, the phosphorylation of Smad2 (p-Smad2), and the phosphorylation of Smad3 (p-Smad3) were analyzed, and the molecular mechanism was investigated by rescue experiments. It was found that PRP improved the appearance and shape of the uterus in IUA and increased endometrial thickness and gland numbers. The administration of PRP resulted in a decrease in the expressions of fibrosis markers including collagen I, α-SMA, and fibronectin. Furthermore, PRP increased Smad7 levels and decreased TGF-ß1 levels, p-Smad2, and p-Smad3. Meanwhile, administration of TGF-ß1 activator reversed the therapeutic effects of PRP in IUA. Collectively, the intrauterine infusion of PRP can promote endometrial damage recovery and improve endometrial fibrosis via the TGF-ß1/Smad pathway. Hence, PRP can be a potential therapeutic strategy for IUA.


Asunto(s)
Fibrosis , Plasma Rico en Plaquetas , Ratas Sprague-Dawley , Transducción de Señal , Factor de Crecimiento Transformador beta1 , Enfermedades Uterinas , Útero , Animales , Femenino , Factor de Crecimiento Transformador beta1/metabolismo , Ratas , Adherencias Tisulares/metabolismo , Enfermedades Uterinas/terapia , Enfermedades Uterinas/metabolismo , Transducción de Señal/efectos de los fármacos , Útero/metabolismo , Modelos Animales de Enfermedad , Proteínas Smad/metabolismo , Proteína Smad2/metabolismo , Proteína smad3/metabolismo
9.
Reproduction ; 167(5)2024 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-38451875

RESUMEN

In brief: The impact of adenomyosis on reproductive health needs to be fully understood. By using a murine model, this study provides novel insights into the nuanced mechanisms associated with fertility challenges and offers a foundation for targeted interventions. Abstract: This study investigates the intricate relationship between adenomyosis and reproductive health using a murine model, offering novel insights into this prevalent gynecological disorder. Adenomyosis, characterized by the invasive growth of endometrial tissue into the myometrium, is believed to negatively impact fertility. However, the challenge lies in disentangling this influence, as adenomyosis often coexists with other gynecological diseases. A tamoxifen-induced mice model presents a significant advantage by enabling the specific study of adenomyosis, devoid of confounding influences of concurrent gynecological diseases such as endometriosis. Focusing exclusively on adenomyosis, our study aims to elucidate pathogenic mechanisms underlying fertility issues, focusing on estrous cyclicity, ovarian follicle development, and overall fertility. Our findings uncover disruptions in estrous cyclicity, characterized by an increased duration of time spent in the estrus phase in adenomyosis-induced mice. These disturbances are potentially linked to observed compromised folliculogenesis and the remarkable reduction in litter number and size in mice affected by adenomyosis. Moreover, this study unveils potential drivers of subfertility such as progesterone resistance and altered endometrial receptivity. Within the uteri of mice with adenomyosis, reduced expression of the progesterone receptor and a decreased expression of two implantation-related markers (HoxA10 and integrin ß3) were observed. This comprehensive examination sheds light on the nuanced complexities of adenomyosis-associated reproductive challenges, providing a foundation for targeted interventions in addressing fertility issues related to this disease.


Asunto(s)
Adenomiosis , Endometriosis , Endometrio/anomalías , Enfermedades Uterinas , Femenino , Humanos , Animales , Ratones , Modelos Animales de Enfermedad , Enfermedades Uterinas/metabolismo , Endometrio/metabolismo , Endometriosis/patología , Fertilidad
10.
J Mater Chem B ; 12(14): 3543-3555, 2024 Apr 03.
Artículo en Inglés | MEDLINE | ID: mdl-38529560

RESUMEN

Intrauterine adhesions (IUAs) are common sequelae of cervical mucosa damage caused by uterine curettage. Establishing an anti-adhesion barrier between the damaged endometrium with a sustained-release drug capability and hence promoting endogenous regeneration of the endometrium is an available treatment for IUA. However, current therapy lacks long-term intracavitary residence, drug-delivery permeability, and tissue anti-adhesion to the endometrium. Here, we report the design of a Janus microneedle patch consisting of two layers: an adhesive inner layer with an exosomes-loaded microneedle, which endows the patch with a tissue adhesive capability as well as transdermal drug-delivery capability; and an anti-adhesion outer layer, which prevents the intrauterine membrane from postoperative adhesion. This Janus adhesive microneedle patch firmly adhered to uterine tissue, and sustainedly released ∼80% of the total loaded exosomes in 7 days, hence promoting the expression of vascular- and endothelial-related cell signals. Furthermore, the anti-adhesive layer of the microneedle patch exhibited low cell and protein adhesion performance. In rats, the microneedle patch successfully prevented uterine adhesions, improved endometrial angiogenesis, proliferation, and hormone response levels. This study provides a stable anti-adhesion barrier as well as efficient drug-release capability treatment for intrauterine adhesion treatment.


Asunto(s)
Exosomas , Enfermedades Uterinas , Humanos , Femenino , Ratas , Animales , Adhesivos/farmacología , Adhesivos/metabolismo , Enfermedades Uterinas/metabolismo , Enfermedades Uterinas/terapia , Endometrio/metabolismo , Proteínas/metabolismo
11.
Acta Biomater ; 177: 77-90, 2024 03 15.
Artículo en Inglés | MEDLINE | ID: mdl-38331133

RESUMEN

Intrauterine adhesions (IUA) are the most common cause of uterine infertility, and conventional treatments have not consistently achieved satisfactory pregnancy rates. Stem cell therapy shows promising potential for the clinical treatment of IUA. Although various advanced biomaterials have been designed for delivering stem cells to the uterine cavity, there remain significant challenges, particularly in devising therapeutic strategies for clinical application that minimize surgical incisions and conform to the intricate structure of uterine cavity. Herein, an injectable hydrogel loaded with human umbilical cord-derived mesenchymal stem cells (UCMSCs) was synthesized via the Diels-Alder click reaction for endometrial regeneration and fertility restoration, exhibiting suitable mechanical properties, good biocompatibility, and desirable degradation properties. Notably, this hydrogel permitted minimally invasive administration and integrated seamlessly with surrounding tissue. Our study revealed that the UCMSCs-laden injectable hydrogel enhanced cell proliferation, migration, angiogenesis, and exhibited anti-fibrotic effects in vitro. The implantation of this hydrogel significantly facilitated endometrium regeneration and restored fertility in a rat endometrial damage model. Mechanistically, in vivo results indicated that the UCMSCs-laden injectable hydrogel effectively promoted macrophage recruitment and facilitated M2 phenotype polarization. Collectively, this hydrogel demonstrated efficacy in regenerating damaged endometrium, leading to the restoration of fertility. Consequently, it holds promise as a potential therapeutic strategy for endometrial damage and fertility decline arising from intrauterine adhesions. STATEMENT OF SIGNIFICANCE: Severe endometrial traumas frequently lead to intrauterine adhesions and subsequent infertility. Stem cell therapy shows promising potential for the clinical treatment of IUA; however, challenges remain, including low delivery efficiency and compromised stem cell activity during the delivery process. In this study, we fabricated an injectable hydrogel loaded with UCMSCs via the Diels-Alder click reaction, which exhibited unique bioorthogonality. The in situ-gelling hydrogels could be introduced through a minimally invasive procedure and adapt to the intricate anatomy of the uterus. The UCMSCs-laden injectable hydrogel promoted endometrial regeneration and fertility restoration in a rat endometrial damage model, efficaciously augmenting macrophage recruitment and promoting their polarization to the M2 phenotype. The administration of UCMSCs-laden injectable hydrogel presents a promising therapeutic strategy for patients with severe intrauterine adhesion.


Asunto(s)
Infertilidad , Células Madre Mesenquimatosas , Enfermedades Uterinas , Embarazo , Femenino , Humanos , Ratas , Animales , Hidrogeles/química , Enfermedades Uterinas/terapia , Enfermedades Uterinas/metabolismo , Enfermedades Uterinas/patología , Endometrio/patología , Infertilidad/metabolismo , Infertilidad/patología , Adherencias Tisulares/terapia , Adherencias Tisulares/metabolismo , Cordón Umbilical/metabolismo
12.
Biol Res ; 57(1): 6, 2024 Feb 13.
Artículo en Inglés | MEDLINE | ID: mdl-38347646

RESUMEN

BACKGROUND: The monthly regeneration of human endometrial tissue is maintained by the presence of human endometrial mesenchymal stromal/stem cells (eMSC), a cell population co-expressing the perivascular markers CD140b and CD146. Endometrial regeneration is impaired in the presence of intrauterine adhesions, leading to infertility, recurrent pregnancy loss and placental abnormalities. Several types of somatic stem cells have been used to repair the damaged endometrium in animal models, reporting successful pregnancy. However, the ability of endometrial stem cells to repair the damaged endometrium remains unknown. METHODS: Electrocoagulation was applied to the left uterine horn of NOD/SCID mice causing endometrial injury. Human eMSC or PBS was then injected into the left injured horn while the right normal horn served as controls. Mice were sacrificed at different timepoints (Day 3, 7 and 14) and the endometrial morphological changes as well as the degree of endometrial injury and repair were observed by histological staining. Gene expression of various inflammatory markers was assessed using qPCR. The functionality of the repaired endometrium was evaluated by fertility test. RESULTS: Human eMSC successfully incorporated into the injured uterine horn, which displayed significant morphological restoration. Also, endometrium in the eMSC group showed better cell proliferation and glands formation than the PBS group. Although the number of blood vessels were similar between the two groups, gene expression of VEGF-α significantly increased in the eMSC group. Moreover, eMSC had a positive impact on the regeneration of both stromal and epithelial components of the mouse endometrium, indicated by significantly higher vimentin and CK19 protein expression. Reduced endometrial fibrosis and down-regulation of fibrosis markers were also observed in the eMSC group. The eMSC group had a significantly higher gene expression of anti-inflammatory factor Il-10 and lower mRNA level of pro-inflammatory factors Ifng and Il-2, indicating the role of eMSC in regulation of inflammatory reactions. The eMSC group showed higher implantation sites than the PBS group, suggesting better endometrial receptivity with the presence of newly emerged endometrial lining. CONCLUSIONS: Our findings suggest eMSC improves regeneration of injured endometrium in mice.


Asunto(s)
Células Madre Mesenquimatosas , Enfermedades Uterinas , Ratones , Femenino , Humanos , Embarazo , Animales , Ratones Endogámicos NOD , Ratones SCID , Placenta/patología , Endometrio/metabolismo , Endometrio/patología , Enfermedades Uterinas/terapia , Enfermedades Uterinas/metabolismo , Enfermedades Uterinas/patología , Fibrosis
13.
Cell Biol Int ; 48(5): 647-664, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38353345

RESUMEN

Intrauterine adhesions (IUA), the main cause of secondary infertility in women, result from irreversible fibrotic repair of the endometrium due to inflammation or human factors, accompanied by disruptions in the repair function of endometrial stem cells. This significantly impacts the physical and mental health of women in their childbearing years. Telocytes (TCs), a distinctive type of interstitial cells found in various tissues and organs, play diverse repair functions due to their unique spatial structure. In this study, we conduct the inaugural exploration of the changes in TCs in IUA disease and their potential impact on the function of stem cells. Our results show that in vivo, through double immunofluorescence staining (CD34+/Vimentin+; CD34+/CD31-), as endometrial fibrosis deepens, the number of TCs gradually decreases, telopodes shorten, and the three-dimensional structure becomes disrupted in the mouse IUA mode. In vitro, TCs can promote the proliferation and cycle of bone mesenchymal stem cells (BMSCs) by promoting the Wnt/ß-catenin signaling pathway, which were inhibited using XAV939. TCs can promote the migrated ability of BMSCs and contribute to the repair of stem cells during endometrial injury. In addition, TCs can inhibit the apoptosis of BMSCs through the Bcl-2/Bax pathway. In conclusion, our study demonstrates, for the first time, the resistance role of TCs in IUA disease, shedding light on their potential involvement in endometrial repair through the modulation of stem cell function.


Asunto(s)
Células Madre Mesenquimatosas , Telocitos , Enfermedades Uterinas , Humanos , Ratones , Femenino , Animales , Enfermedades Uterinas/metabolismo , Enfermedades Uterinas/patología , Endometrio/patología , Células Madre Mesenquimatosas/metabolismo , Telocitos/metabolismo , Vía de Señalización Wnt , Modelos Animales de Enfermedad
14.
PeerJ ; 12: e16953, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38406291

RESUMEN

Background: Currently, bone marrow mesenchymal stem cells (BMSCs) have been reported to promote endometrial regeneration in rat models of mechanically injury-induced uterine adhesions (IUAs), but the therapeutic effects and mechanisms of hypoxic BMSC-derived exosomes on IUAs have not been elucidated. Objective: To investigate the potential mechanism by which the BMSCS-derived exosomal miR-424-5p regulates IUA angiogenesis through the DLL4/Notch signaling pathway under hypoxic conditions and promotes endometrial injury repair. Methods: The morphology of the exosomes was observed via transmission electron microscopy, and the expression of exosome markers (CD9, CD63, CD81, and HSP70) was detected via flow cytometry and Western blotting. The expression of angiogenesis-related genes (Ang1, Flk1, Vash1, and TSP1) was detected via RT‒qPCR, and the expression of DLL4/Notch signaling pathway-related proteins (DLL4, Notch1, and Notch2) was detected via Western blotting. Cell proliferation was detected by a CCK-8 assay, and angiogenesis was assessed via an angiogenesis assay. The expression of CD3 was detected by immunofluorescence. The endometrial lesions of IUA rats were observed via HE staining, and the expression of CD3 and VEGFA was detected via immunohistochemistry. Results: Compared with those in exosomes from normoxic conditions, miR-424-5p was more highly expressed in the exosomes from hypoxic BMSCs. Compared with those in normoxic BMSC-derived exosomes, the proliferation and angiogenesis of HUVECs were significantly enhanced after treatment with hypoxic BMSC-derived exosomes, and these effects were weakened after inhibition of miR-424-5p. miR-424-5p can target and negatively regulate the expression of DLL4, promote the expression of the proangiogenic genes Ang1 and Flk1, and inhibit the expression of the antiangiogenic genes Vash1 and TSP1. The effect of miR-424-5p can be reversed by overexpression of DLL4. In IUA rats, treatment with hypoxic BMSC exosomes and the miR-424-5p mimic promoted angiogenesis and improved endometrial damage. Conclusion: The hypoxic BMSC-derived exosomal miR-424-5p promoted angiogenesis and improved endometrial injury repair by regulating the DLL4/Notch signaling pathway, which provides a new idea for the treatment of IUAs.


Asunto(s)
Exosomas , Células Madre Mesenquimatosas , MicroARNs , Enfermedades Uterinas , Animales , Femenino , Ratas , Proteínas Adaptadoras Transductoras de Señales/genética , Angiogénesis , Proteínas de Unión al Calcio/genética , Exosomas/genética , MicroARNs/genética , Transducción de Señal/genética , Enfermedades Uterinas/metabolismo
15.
Biol Open ; 13(2)2024 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-38224009

RESUMEN

Mesenchymal stem cells play important roles in repairing injured endometrium. However, the molecular targets and potential mechanism of the endometrial recipient cells for stem cell therapy in intrauterine adhesion (IUA) are poorly understood. In this study, umbilical cord mesenchymal stem-cell-conditioned medium (UCMSCs-CM) produced positive effects on a Transforming growth factor beta (TGF-ß) induced IUA cell model. RNA-sequencing was performed on clinical IUA tissues, and the top 40 upregulated and top 20 downregulated mRNAs were selected and verified using high-throughput (HT) qPCR in both tissues and cell models. Based on a bioinformatic analysis of RNA-sequencing and HT-qPCR results, 11 mRNAs were uncovered to be the intervention targets of UCMSCs-CM on IUA endometrium cell models. Among them, IGFBP3 was striking as a key pathogenic gene and a potential diagnostic marker of IUA, which exhibited the area under the curve (AUC), sensitivity, specificity were 0.924, 93.1% and 80.6%, respectively in 60 endometrial tissues. The silencing of IGFBP3 exerted positive effects on the IUA cell model through partially upregulating MMP1 and KLF2. In conclusion, RNA-sequencing combined with HT qPCR based on clinical tissues and IUA cell models were used in IUA research and our results may provide some scientific ideas for the diagnosis and treatment of IUA.


Asunto(s)
Proteína 3 de Unión a Factor de Crecimiento Similar a la Insulina , Células Madre Mesenquimatosas , Enfermedades Uterinas , Femenino , Humanos , Medios de Cultivo Condicionados/farmacología , Proteína 3 de Unión a Factor de Crecimiento Similar a la Insulina/genética , Proteína 3 de Unión a Factor de Crecimiento Similar a la Insulina/metabolismo , ARN/metabolismo , Adherencias Tisulares/metabolismo , Adherencias Tisulares/patología , Adherencias Tisulares/terapia , Cordón Umbilical/metabolismo , Cordón Umbilical/patología , Enfermedades Uterinas/metabolismo , Enfermedades Uterinas/patología , Enfermedades Uterinas/terapia
16.
Photochem Photobiol ; 100(1): 214-224, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-37212452

RESUMEN

Intrauterine adhesion (IUA), a major cause of uterine infertility, is pathologically characterized by endometrial fibrosis. Current treatments for IUA have poor efficacy with high recurrence rate, and restoring uterine functions is difficult. We aimed to determine the therapeutic efficacy of photobiomodulation (PBM) therapy on IUA and elucidate its underlying mechanisms. A rat IUA model was established via mechanical injury, and PBM was applied intrauterinely. The uterine structure and function were evaluated using ultrasonography, histology, and fertility tests. PBM therapy induced a thicker, more intact, and less fibrotic endometrium. PBM also partly recovered endometrial receptivity and fertility in IUA rats. A cellular fibrosis model was then established with human endometrial stromal cells (ESCs) cultured in the presence of TGF-ß1. PBM alleviated TGF-ß1-induced fibrosis and triggered cAMP/PKA/CREB signaling in ESCs. Pretreatment with the inhibitors targeting this pathway weakened PBM's protective efficacy in the IUA rats and ESCs. Therefore, we conclude that PBM improved endometrial fibrosis and fertility via activating cAMP/PKA/CREB signaling in IUA uterus. This study sheds more lights on the efficacy of PBM as a potential treatment for IUA.


Asunto(s)
Terapia por Luz de Baja Intensidad , Enfermedades Uterinas , Femenino , Ratas , Animales , Humanos , Factor de Crecimiento Transformador beta1/metabolismo , Enfermedades Uterinas/terapia , Enfermedades Uterinas/metabolismo , Enfermedades Uterinas/patología , Endometrio/metabolismo , Endometrio/patología , Adherencias Tisulares/tratamiento farmacológico , Adherencias Tisulares/patología
17.
Biol. Res ; 57: 6-6, 2024. ilus, graf
Artículo en Inglés | LILACS | ID: biblio-1550061

RESUMEN

BACKGROUND: The monthly regeneration of human endometrial tissue is maintained by the presence of human endometrial mesenchymal stromal/stem cells (eMSC), a cell population co-expressing the perivascular markers CD140b and CD146. Endometrial regeneration is impaired in the presence of intrauterine adhesions, leading to infertility, recurrent pregnancy loss and placental abnormalities. Several types of somatic stem cells have been used to repair the damaged endometrium in animal models, reporting successful pregnancy. However, the ability of endometrial stem cells to repair the damaged endometrium remains unknown. METHODS: Electrocoagulation was applied to the left uterine horn of NOD/SCID mice causing endometrial injury. Human eMSC or PBS was then injected into the left injured horn while the right normal horn served as controls. Mice were sacrificed at different timepoints (Day 3, 7 and 14) and the endometrial morphological changes as well as the degree of endometrial injury and repair were observed by histological staining. Gene expression of various inflammatory markers was assessed using qPCR. The functionality of the repaired endometrium was evaluated by fertility test. RESULTS: Human eMSC successfully incorporated into the injured uterine horn, which displayed significant morphological restoration. Also, endometrium in the eMSC group showed better cell proliferation and glands formation than the PBS group. Although the number of blood vessels were similar between the two groups, gene expression of VEGF-α significantly increased in the eMSC group. Moreover, eMSC had a positive impact on the regeneration of both stromal and epithelial components of the mouse endometrium, indicated by significantly higher vimentin and CK19 protein expression. Reduced endometrial fibrosis and down-regulation of fibrosis markers were also observed in the eMSC group. The eMSC group had a significantly higher gene expression of anti-inflammatory factor Il-10 and lower mRNA level of pro-inflammatory factors Ifng and Il-2, indicating the role of eMSC in regulation of inflammatory reactions. The eMSC group showed higher implantation sites than the PBS group, suggesting better endometrial receptivity with the presence of newly emerged endometrial lining. CONCLUSIONS: Our findings suggest eMSC improves regeneration of injured endometrium in mice.


Asunto(s)
Humanos , Animales , Femenino , Embarazo , Ratones , Enfermedades Uterinas/metabolismo , Enfermedades Uterinas/patología , Enfermedades Uterinas/terapia , Células Madre Mesenquimatosas , Placenta/patología , Fibrosis , Ratones SCID , Ratones Endogámicos NOD , Endometrio/metabolismo , Endometrio/patología
18.
Stem Cell Res Ther ; 14(1): 379, 2023 12 20.
Artículo en Inglés | MEDLINE | ID: mdl-38124100

RESUMEN

The endometrium is a dynamic tissue that undergoes cyclic changes in response to ovarian hormones during the menstrual cycle. These changes are crucial for pregnancy establishment and maintenance. Endometrial stem cells play a pivotal role in endometrial regeneration and repair by differentiating into various cell types within the endometrium. However, their involvement in endometrial disorders such as endometriosis, infertility, and endometrial cancer is still not fully understood yet. Traditional bulk sequencing methods have limitations in capturing heterogeneity and complexity of endometrial stem cell populations. To overcome these limitations, recent single-cell analysis techniques, including single-cell RNA sequencing (scRNA-Seq), single-cell ATAC sequencing (scATAC-Seq), and spatial transcriptomics, have emerged as valuable tools for studying endometrial stem cells. In this review, although there are still many technical limitations that require improvement, we will summarize the current state-of-the-art single-cell analysis techniques for endometrial stem cells and explore their relevance to related diseases. We will discuss studies utilizing various single-cell analysis platforms to identify and characterize distinct endometrial stem cell populations and investigate their dynamic changes in gene expression and epigenetic patterns during menstrual cycle and differentiation processes. These techniques enable the identification of rare cell populations, capture heterogeneity of cell populations within the endometrium, and provide potential targets for more effective therapies.


Asunto(s)
Endometrio , Enfermedades Uterinas , Femenino , Embarazo , Humanos , Células Madre , Enfermedades Uterinas/metabolismo , Ciclo Menstrual , Análisis de la Célula Individual
19.
Zhen Ci Yan Jiu ; 48(12): 1209-1217, 2023 Dec 25.
Artículo en Inglés, Chino | MEDLINE | ID: mdl-38146243

RESUMEN

OBJECTIVES: To investigate the effects of electroacupuncture(EA) combined with bone marrow mesen-chymal stem cells(BMSCs) transplantation on the endometrium of rats with intrauterine adhesions(IUA), so as to explore the possible mechanisms underlying their combined therapeutic effects. METHODS: Forty adult female SD rats were randomly divided into control, model, cell, and combined groups. The IUA rat model was established using a dual injury method of mechanical scratching and lipopolysaccharide infection. After successful modeling, on days 1, 3, and 7, rats in the model group received tail vein injection of phosphate buffered solution, while rats in the cell group received tail vein injection of BMSCs suspension for BMSCs transplantation;and rats in the combined group received BMSCs transplantation combined with EA treatment (2 Hz/15 Hz, 1-2 mA), targeting the "Guanyuan"(CV4), bilateral "Zusanli"(ST36) and "Sanyinjiao"(SP6) for 20 min daily for 3 consecutive estrous cycles. After intervention, uterine tissue was collected from 5 rats in each group. Histological analysis was performed using hematoxylin and eosin staining to evaluate endometrial thickness and glandular number. Masson staining was used to assess endometrial fibrosis area. Immunohistochemistry was performed to detect the positive expressions of vascular endothelial growth factor(VEGF), proliferating cell nuclear antigen(PCNA), and estrogen receptor(ER). Western blot analysis was conducted to determine the protein expressions of homeobox A10(HoxA10) and leukemia inhibitory factor(LIF), both key regulators of endometrial receptivity. The remaining 5 rats in each group were co-housed with male rats, and the uterine function recovery was evaluated by assessing the number of embryo implantations. RESULTS: Compared with the control group, the model group showed thinning endometrium(P<0.001), decreased glandular number(P<0.001), increased endometrial fibrosis area(P<0.001), reduced positive expressions of VEGF, PCNA, ER, expressions of HoxA10 and LIF, and decreased embryo implantation number (P<0.001) on the injured side of the uterus. Compared with the model group, the combined group showed a reversal of the aforementioned indicators(P<0.001, P<0.01);the cell group exhibited thicker endometrium(P<0.001) and reduced endometrial fibrosis area(P<0.001). Compared with the cell group, the combined group showed increased endometrial thickness(P<0.01), elevated glandular number(P<0.05), significantly decreased endometrial fibrosis area(P<0.05), enhanced positive expressions of VEGF, PCNA and ER, expressions of HoxA10 and LIF in the endometrium, and a significant increase in embryo implantation number (P<0.001, P<0.05, P<0.01) on the injured side of the uterus, indicating better results than the cell group. CONCLUSIONS: The combination of EA and BMSCs synergistically promotes the repair of damaged endometrium, improves endometrial morphology, reduces fibrosis levels, enhances vascular regeneration and matrix cell proliferation, improves endometrial receptivity, which ultimately facilitates embryo implantation.


Asunto(s)
Electroacupuntura , Trasplante de Células Madre Mesenquimatosas , Enfermedades Uterinas , Humanos , Ratas , Masculino , Femenino , Animales , Factor A de Crecimiento Endotelial Vascular/genética , Antígeno Nuclear de Célula en Proliferación/metabolismo , Antígeno Nuclear de Célula en Proliferación/farmacología , Ratas Sprague-Dawley , Trasplante de Células Madre Mesenquimatosas/métodos , Médula Ósea/patología , Enfermedades Uterinas/genética , Enfermedades Uterinas/terapia , Enfermedades Uterinas/metabolismo , Endometrio/metabolismo , Fibrosis
20.
Cell Transplant ; 32: 9636897231212746, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-38006220

RESUMEN

Intrauterine adhesions (IUAs) often occurred after common obstetrical and gynecological procedures or infections in women of reproductive age. It was characterized by the formation of endometrial fibrosis and prevention of endometrial regeneration, usually with devastating fertility consequences and poor treatment outcomes so far. Telocytes (TCs), as a novel interstitial cell type, present in female uterus with in vitro therapeutic potential in decidualization-defective gynecologic diseases. This study aims to further investigate the role of TC-derived Wnt ligands carried by exosomes (Exo) in reversal of fibrosis and enhancement of regeneration repair in endometrium. IUA cellular and animal models were established from endometrial stromal cells (ESCs) and mice, followed with treatment of TC-conditioned medium (TCM) or TC-derived Exo. In cellular model, fibrosis markers (collagen type 1 alpha 1 [COL1A1], fibronectin [FN], and α-smooth muscle actin [α-SMA]), angiogenesis (vascular endothelial growth factor [VEGF]), and pathway protein (ß-catenin) were determined by quantitative reverse transcription polymerase chain reaction (qRT-PCR), Western blotting (WB), and immunofluorescence. Results showed that, TCs (either TCM or TC-derived Exo) provide a source of Wnts that inhibit cellular fibrosis, as evidenced by significantly elevated VEGF and ß-catenin with decreased fibrotic markers, whereas TCs lost salvage on fibrosis after being blocked with Wnt/ß-catenin inhibitors (XAV939 or ETC-159). Further in mouse model, regeneration repair (endometrial thickness, number of glands, and fibrosis area ratio), fibrosis markers (fibronectin [FN]), mesenchymal-epithelial transition (MET) (E-cadherin, N-cadherin), and angiogenesis (VEGF, microvessel density [MVD]) were studied by hematoxylin-eosin (HE), Masson staining, and immunohistochemistry. Results demonstrated that TC-Exo treatment effectively promotes regeneration repair of endometrium by relieving fibrosis, enhancing MET, and angiogenesis. These results confirmed new evidence for therapeutic perspective of TC-derived Exo in IUAs.


Asunto(s)
Exosomas , Telocitos , Enfermedades Uterinas , Humanos , Femenino , Ratones , Animales , beta Catenina/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo , Fibronectinas/metabolismo , Exosomas/metabolismo , Endometrio/metabolismo , Enfermedades Uterinas/metabolismo , Enfermedades Uterinas/patología , Enfermedades Uterinas/terapia , Fibrosis , Telocitos/metabolismo
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA