Application of histone lactation in bidirectional dynamic regulation of stromal cell decidualization

Abstract

This invention discloses the application of histone lactation in bidirectional dynamic regulation of stromal cell decidualization, relating to the field of biology. This application reveals for the first time that histone lactation modification exhibits a dose-dependent bidirectional regulatory characteristic during decidualization—moderate lactation promotes decidualization, while abnormally elevated lactation inhibits it. Based on the decidualization regulatory mechanism, this invention provides two types of regulatory tools: histone lactation promoters and inhibitors. These tools can bidirectionally regulate the decidualization process of endometrial stromal cells according to clinical needs, providing a novel epigenetic intervention strategy and drug target for pregnancy maintenance disorders in older women and women with recurrent miscarriages.

Description

Technical Field

[0001] This invention relates to biotechnology, specifically to the application of histone lactation in bidirectional dynamic regulation of stromal cell decidualization. Background Technology

[0002] Lactic acid, as a major nutrient, is maintained at high levels both in vivo and in vitro in the embryonic microenvironment, participating in the interactive regulation of the embryo and endometrium. During embryonic invasion, embryonic-derived trophoblast cells and uterine-derived decidual cells work closely together, with key metabolic characteristics including increased glycolysis and lactate levels in decidual cells near the implantation site. This increased "local" lactate flux near the implantation site can promote endometrial tissue breakdown, induce angiogenesis, increase vascular permeability, and promote immune tolerance. However, recent studies have found that excessive accumulation of lactate in decidual cells may be an important risk factor for recurrent miscarriage. Literature reports that lactate dehydrogenase A (LDHA) expression in the decidual tissue of women with recurrent miscarriage is significantly higher than in normal women. Under persistent hypoxia, high levels of lactate can induce trophoblast cells to drive M1 macrophage polarization, disrupting immune tolerance and promoting miscarriage. Previous literature has found that progesterone promotes metabolic reprogramming of endometrial stromal cells and enhances glycolytic activity by promoting glycogen synthesis and breakdown, inducing the expression of glucose transporter 1 (GLUT1) and glycolysis-related enzymes. Lactic acid, as the end product of glycolysis, can provide a substrate source for histone lactation modification and regulate gene transcription. Based on the above research, histone lactation can be used to bidirectionally and dynamically regulate stromal cell decidualization, thereby improving pregnancy maintenance difficulties in older women and those with recurrent miscarriages. Summary of the Invention

[0003] The purpose of this invention is to provide an application of histone lactation in bidirectional dynamic regulation of stromal cell decidualization, so as to improve pregnancy maintenance disorders in older women and women with recurrent miscarriages.

[0004] To achieve the above objectives, the present invention provides the following technical solution: the application of histone lactation bidirectionally and dynamically regulating stromal cell decidualization, and the application of a substance that regulates the level of histone lactation in a product that bidirectionally and dynamically regulates stromal cell decidualization, wherein the substance can regulate the level of histone lactation in endometrial stromal cells.

[0005] Preferably, the substance regulating histone lactation levels is one or more of the following:

[0006] A histone lactation promoter targeting endometrial stromal cells, compared to endometrial stromal cells not regulated by the substance, the histone lactation promoter increases the level of histone lactation in endometrial stromal cells and inhibits decidualization of endometrial stromal cells.

[0007] The histone lactation inhibitor for endometrial stromal cells reduces histone lactation levels in endometrial stromal cells and promotes decidualization of endometrial stromal cells compared to endometrial stromal cells not regulated by the substance.

[0008] Preferably, the lactated histones in the endometrial stromal cells include Pan-Kla, H3K9la, H3K14la, and H3K18la.

[0009] Preferably, when the histone lactation promoter increases the histone lactation level in endometrial stromal cells, the expression of prolactin PRL and forkhead box protein O1 FoxO1 in the endometrial stromal cells shows a decreasing trend; when the histone lactation inhibitor reduces the histone lactation level in endometrial stromal cells, the expression of prolactin PRL and forkhead box protein O1 FoxO1 in the endometrial stromal cells shows an increasing trend.

[0010] Preferably, the promoter is a histone lactation promoter targeting endometrial stromal cells, contained in a medicament or pharmaceutical composition for improving decidualization disorders in older women with recurrent miscarriages.

[0011] The inhibitor is a histone lactation inhibitor targeting endometrial stromal cells, and is included in a drug or pharmaceutical composition for improving decidualization disorders in older women with recurrent miscarriages.

[0012] Compared with existing technologies, the application of histone lactation in bidirectional dynamic regulation of stromal cell decidualization provided by this invention reveals for the first time that histone lactation modification exhibits a dose-dependent bidirectional regulatory characteristic during decidualization—moderate lactation can promote decidualization, while abnormally elevated lactation inhibits decidualization. Based on the decidualization regulation mechanism, this invention provides two types of regulatory tools: histone lactation promoters and inhibitors. These tools can bidirectionally regulate the decidualization process of endometrial stromal cells according to clinical needs, providing a novel epigenetic intervention strategy and drug target for pregnancy maintenance disorders in older women and women with recurrent miscarriages. Attached Figure Description

[0013] To more clearly illustrate the technical solutions in the embodiments of this application or the prior art, the drawings used in the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments recorded in this invention. For those skilled in the art, other drawings can be obtained based on these drawings.

[0014] Figure 1This is a series of images illustrating the dynamic bidirectional regulatory effect of histone lactation modification on stromal cell decidualization provided in embodiments of the present invention. In the images:

[0015] A. Pan-Kla immunohistochemical staining of mouse uterine tissues at D1, D4, D5, D6, and D8 of pregnancy to observe the spatiotemporal distribution characteristics of histone lactation modification during decidual development. PDZ: primary decidual zone; SDZ: secondary decidual zone;

[0016] B. After HESCs induced decidualization in vitro, cells were collected at different time points, and Western blot was used to detect the expression changes of HDAC1, Pan-Kla, H3K9la, H3K14la, H3K18la and FoxO1.

[0017] C. After treating decidualized HESCs with different concentrations of sodium lactate (Na-lactate), the expression levels of FoxO1 and H3K9la proteins were detected by Western blot.

[0018] DE and qRT-PCR were used to detect the expression levels of PRL (D) and FoxO1 (E) mRNA. Detailed Implementation

[0019] To enable those skilled in the art to better understand the technical solution of the present invention, the present invention will be further described in detail below with reference to the accompanying drawings.

[0020] Histone lactation modification plays a dynamic, bidirectional regulatory role in decidualization of stromal cells. The applicant team discovered that in the early pregnancy uterus of mice, histone lactation modification in decidual cells exhibits a spatially non-uniform distribution: lactation signaling is significantly enhanced in the primary decidual zone near the implantation site, while lactation levels are decreased in the peripheral decidual region. After in vitro induction of decidualization of human endometrial stromal cells, the levels of Pan-Kla, H3K9la, H3K14la, and H3K18la significantly decreased as decidualization progressed. Treatment of decidualized cells with exogenous sodium lactate (Na-lactate) significantly increased H3K9la levels; low concentrations (1 mM) of sodium lactate treatment showed an increasing trend in PRL and FoxO1 expression, while high concentrations (5–20 mM) led to a gradual decrease in PRL and FoxO1 expression. These results indicate that histone lactation exhibits spatiotemporal dynamic changes during decidualization and demonstrates a dose-dependent, bidirectional regulatory characteristic. Moderate lactation promotes decidualization, while abnormally elevated lactation inhibits it.

[0021] As attached Figure 1 As shown:

[0022] The dynamic bidirectional regulatory effect of histone lactation on decidualization of stromal cells. A. Immunohistochemical staining of Pan-Kla in mouse uterine tissues at D1, D4, D5, D6, and D8 of pregnancy to observe the spatiotemporal distribution characteristics of histone lactation during decidual development. PDZ: primary decidual zone; SDZ: secondary decidual zone. B. After HESCs were induced to decidualize in vitro, cells were collected at different time points, and Western blot was used to detect the expression changes of HDAC1, Pan-Kla, H3K9la, H3K14la, H3K18la, and FoxO1. C. After treating decidualized HESCs with different concentrations of sodium lactate (Na-lactate), Western blot was used to detect the protein expression levels of FoxO1 and H3K9la. D. qRT-PCR was used to detect the mRNA expression levels of PRL (D) and FoxO1 (E). The results showed that low concentrations of sodium lactate (1 mM) slightly promoted the expression of decidualization marker genes, while high concentrations of sodium lactate (5–20 mM) inhibited their expression, suggesting that histone lactation modification has a dynamic and dose-dependent bidirectional regulatory role in decidualization. Data are expressed as mean ± SEM. *P < 0.001.

[0023] Example:

[0024] This invention provides the application of histone lactation in bidirectional dynamic regulation of stromal cell decidualization, and the application of substances that regulate histone lactation levels in products that bidirectionally and dynamically regulate stromal cell decidualization, wherein the substances can regulate the histone lactation level of endometrial stromal cells.

[0025] The substances that regulate histone lactation levels are one or more of the following:

[0026] A histone lactation promoter targeting endometrial stromal cells, compared to endometrial stromal cells not regulated by the substance, the histone lactation promoter increases the level of histone lactation in endometrial stromal cells and inhibits decidualization of endometrial stromal cells.

[0027] The histone lactation inhibitor for endometrial stromal cells reduces histone lactation levels in endometrial stromal cells and promotes decidualization of endometrial stromal cells compared to endometrial stromal cells not regulated by the substance.

[0028] The lactated histones in the endometrial stromal cells include Pan-Kla, H3K9la, H3K14la, and H3K18la.

[0029] When the histone lactation promoter increases the histone lactation level in endometrial stromal cells, the expression of prolactin PRL and forkhead box protein O1 FoxO1 in the endometrial stromal cells shows a decreasing trend. When the histone lactation inhibitor reduces the histone lactation level in endometrial stromal cells, the expression of prolactin PRL and forkhead box protein O1 FoxO1 in the endometrial stromal cells shows an increasing trend.

[0030] The promoter is a histone lactation promoter targeting endometrial stromal cells, and is included in a drug or pharmaceutical composition for improving decidualization disorders in older women with recurrent miscarriages.

[0031] The inhibitor is a histone lactation inhibitor targeting endometrial stromal cells, and is included in a drug or pharmaceutical composition for improving decidualization disorders in older women with recurrent miscarriages.

[0032] As shown above, this study reveals for the first time that histone lactation modification exhibits a dose-dependent bidirectional regulatory characteristic during decidualization—moderate lactation promotes decidualization, while abnormally elevated lactation inhibits it. Based on the decidualization regulatory mechanism, this invention provides two types of regulatory tools: histone lactation promoters and inhibitors. These tools can bidirectionally regulate the decidualization process of endometrial stromal cells according to clinical needs, providing a novel epigenetic intervention strategy and drug target for pregnancy maintenance disorders in older women and women with recurrent miscarriages.

[0033] The foregoing has only described certain exemplary embodiments of the present invention by way of illustration. Undoubtedly, those skilled in the art can modify the described embodiments in various ways without departing from the spirit and scope of the present invention. Therefore, the foregoing drawings and descriptions are illustrative in nature and should not be construed as limiting the scope of protection of the claims of the present invention.

Claims

1. The application of histone lactation in bidirectional dynamic regulation of stromal cell decidualization, characterized in that, Application of substances that regulate histone lactation levels in products that bidirectionally and dynamically regulate the decidualization of stromal cells, wherein the substances can regulate histone lactation levels in endometrial stromal cells.

2. The application according to claim 1, characterized in that, The substances that regulate histone lactation levels are one or more of the following: A histone lactation promoter targeting endometrial stromal cells, compared to endometrial stromal cells not regulated by the substance, the histone lactation promoter increases the level of histone lactation in endometrial stromal cells and inhibits decidualization of endometrial stromal cells. The histone lactation inhibitor for endometrial stromal cells reduces histone lactation levels in endometrial stromal cells and promotes decidualization of endometrial stromal cells compared to endometrial stromal cells not regulated by the substance.

3. The application according to claim 2, characterized in that, The lactated histones in the endometrial stromal cells include Pan-Kla, H3K9la, H3K14la, and H3K18la.

4. The application according to claim 2, characterized in that, When the histone lactation promoter increases the histone lactation level in endometrial stromal cells, the expression of prolactin PRL and forkhead box protein O1 FoxO1 in the endometrial stromal cells shows a decreasing trend. When the histone lactation inhibitor reduces the histone lactation level in endometrial stromal cells, the expression of prolactin PRL and forkhead box protein O1 FoxO1 in the endometrial stromal cells shows an increasing trend.

5. The application according to claim 2, characterized in that: The promoter is a histone lactation promoter targeting endometrial stromal cells, and is included in a drug or pharmaceutical composition for improving decidualization disorders in older women with recurrent miscarriages. The inhibitor is a histone lactation inhibitor targeting endometrial stromal cells, and is included in a drug or pharmaceutical composition for improving decidualization disorders in older women with recurrent miscarriages.

Images