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CD147 deficiency is associated with impairedsperm motility/acrosome reaction and offersa therapeutic target for asthenozoospermia.

ABSTRACT: Patients with asthenozoospermia often present multiple defects in sperm functions apart from a decrease in sperm motility. However, the etiological factors underlying these multifaceted defects remain mostly unexplored, which may lead to unnecessary treatment and unsatisfactory assisted reproductive technologies (ART) outcome. Here, we show that the protein levels of CD147 were lowered in sperm obtained from asthenozoospermic infertile patients exhibiting defects in both sperm motility and the acrosome reaction. Whereas CD147 maintained sperm motility before capacitation, female tract-derived soluble CD147 interacted with sperm-bound CD147 to induce an acrosome reaction in capacitated sperm. Soluble CD147 treatment restored the acrosome reaction and improved the fertility of sperm from patients with asthenozoospermia. Mechanistically, CD147 promotes sperm motility and acrosome reaction (AR) by eliciting Ca2+ influx through soluble CD147 binding to sperm-bound CD147. Notably, the level of soluble CD147 in seminal plasma was positively correlated with the fertilization rate and pregnancy outcome in infertile couples undergoing in vitro fertilization. Our study has identified a marker for the diagnosis and a therapeutic target for the defective AR capability in asthenozoospermia and a candidate for the prediction of in vitro fertilization outcomes for male infertile patients that facilitates the development of precision medicine in ART.

SUBMITTER: Chen H

PROVIDER: S-EPMC8626663 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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CD147 deficiency is associated with impairedsperm motility/acrosome reaction and offersa therapeutic target for asthenozoospermia.

Chen Hao H Shi Xiao X Li Xiaofeng X Diao Ruiying R Ma Qian Q Jin Jing J Qiu Zhuolin Z Li Cailing C Yu Mei Kuen MK Wang Chaoqun C Li Xianxin X Li Fanghong F Chan David Yiu Leung DYL Zhao Allan Zijian AZ Cai Zhiming Z Sun Fei F Fok Kin Lam KL

Molecular therapy. Nucleic acids 20211110

Patients with asthenozoospermia often present multiple defects in sperm functions apart from a decrease in sperm motility. However, the etiological factors underlying these multifaceted defects remain mostly unexplored, which may lead to unnecessary treatment and unsatisfactory assisted reproductive technologies (ART) outcome. Here, we show that the protein levels of CD147 were lowered in sperm obtained from asthenozoospermic infertile patients exhibiting defects in both sperm motility and the a ...[more]

PMID: 34900396

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Project description:BackgroundDiabetes is known to be a main risk factor of post-stroke hemorrhagic transformation following recombinant tissue plasminogen activator (rt-PA) therapy. However, the mechanism through which diabetes exacerbates hemorrhagic transformation is insufficiently understood. We aimed to verify that CD147, the extracellular matrix metalloproteinase (MMP) inducer, played a vital role in the progress.MethodsWe performed middle cerebral artery occlusion on diabetic and non-diabetic rats, with or without rt-PA treatment, and then compared the glycosylation level of CD147, caveolin-1, MMPs activities, and blood-brain barrier (BBB) permeability. In vitro, tunicamycin treatment and genetic tools were used to produce non-glycosylated and lowly glycosylated CD147. An endogenous glucagon-like peptide-1 receptor (GLP-1R) agonist was used to downregulate the glycosylation of CD147 in vivo.ResultsCompared with non-diabetic rats, diabetic rats expressed higher levels of highly glycosylated CD147 in endothelium and astrocytes following rt-PA treatment accompanied by higher activity of MMPs and BBB permeability, in the middle cerebral artery occlusion model. Caveolin-1 was also overexpressed and co-localized with CD147 in astrocytes and endothelium in diabetic rats. In vitro, advanced glycation end products increased the expression of highly glycosylated CD147 in astrocytes and endothelial cells. Downregulating the glycosylation of CD147 lowered the activity of MMPs and promoted the expression of tight junction proteins. The expression of caveolin-1 in endothelial cells and astrocytes was not inhibited by tunicamycin, which revealed that caveolin-1 was an upstream of CD147. In vivo, GLP-1R agonist downregulated the glycosylation of CD147 and further reduced the activity of MMPs and protected the BBB in diabetic rats.ConclusionCD147 is essential for diabetes-associated rt-PA-induced hemorrhagic transformation, and downregulation of CD147 glycosylation is a promising therapy for neurovascular-unit repair after rt-PA treatment of patients with diabetes.

Project description:Rationale: Idiopathic asthenozoospermia (iAZS) is one of the major causes of male infertility and has no effective therapeutic treatment. Understanding the potential mechanisms that cause it may be helpful in seeking novel targets and treatment strategies for overcoming the problem of low sperm motility in iAZS individuals. Methods: Computer-assisted semen analysis (CASA) was utilized to assess the sperm motility. RT-qPCR, Western blot, immunofluorescence staining, and calcium imaging analysis were performed to examine the expression and function of CatSper channels. Hyperactivation and acrosome reaction were used to evaluate the functional characteristics of epididymal sperm. In vivo fertility assay was applied to determine the fertility of rats. CatSper1 knockdown and overexpression experiments were performed to confirm the roles of CatSper channels in the pathogenesis of iAZS and the therapeutic effects of electroacupuncture (EA) treatment on AZS model rats. Results: Here, we reported a functional down-regulation of CatSper channel from CatSper1 to CatSper 4 in the sperm of both iAZS patients and ornidazole (ORN)-induced AZS model rats, and an impaired sperm function characterized by a reduction of protein tyrosine phosphorylation, hyperactivation, and acrosome reaction in the epididymal sperm of AZS rats. Knockdown of CatSper1 in the testis tissues is sufficient to induce AZS in normal rats, and this action was validated by the reversal effects of CatSper1 overexpression. Transcutaneous electrical acupoint stimulation (TEAS) and electroacupuncture (EA) at 2 Hz frequency improve the sperm motility via enhancing the functional expression of CatSper channels in the sperm. Gene silencing CatSper1 in the sperm abolishes the therapeutic effects of 2 Hz-EA treatment on AZS rats. Conclusions: We conclude that a functional down-regulation of CatSper channel in the sperm may be a contributor or a downstream indicator for a portion of AZS, especially iAZS, while 2 Hz-TEAS or EA treatment has a therapeutic effect on iAZS through inducing the functional up-regulation of CatSper channels in the sperm. This study provides a novel mechanism for the pathogenesis of some AZS especially iAZS, and presents a potential therapeutic target of CatSper for iAZS treatment. Acupuncture treatment like TEAS may be used as a promising complementary and alternative medicine (CAM) therapy for male infertility caused by iAZS in clinical practice.

Dataset Information

CD147 deficiency is associated with impairedsperm motility/acrosome reaction and offersa therapeutic target for asthenozoospermia.

Publications

CD147 deficiency is associated with impairedsperm motility/acrosome reaction and offersa therapeutic target for asthenozoospermia.

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