Low Expression of Mfn2 Is Associated with Mitochondrial Damage and Apoptosis of Ovarian Tissues in the Premature Ovarian Failure Model

Chen, Wenqi; Xu, Xiaoyan; Wang, Lingjuan; Bai, Ge; Xiang, Wenpei

doi:10.1371/journal.pone.0136421

Cited by 25 publications

(26 citation statements)

References 37 publications

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“…We developed a POF mouse model using cisplatin-induced ovarian injury, which has been shown to cause ovarian failure in humans [1, 43]. Moreover, cisplatin induces apoptosis in GCs [44], which are required for oocyte survival and follicle development [40, 45].…”

Section: Discussionmentioning

confidence: 99%

Study of the reparative effects of menstrual-derived stem cells on premature ovarian failure in mice

et al. 2017

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BackgroundYoung female patients who receive chemotherapy frequently face premature ovarian failure (POF). The therapeutic potential of stem cells in these patients has been explored in stem cells derived from different sources. However, many of these types of stem cells are either difficult to obtain or obtaining them involves invasive procedures. Here, we show that menstrual-derived stem cells (MenSCs) are easy to access and exhibit mesenchymal stem cell-like properties. MenSCs are therefore a novel source of stem cells that can be used for tissue repair. The aim of this study was to explore the reparative capacity and the mechanism underlying the activities of MenSCs.MethodsPOF mouse models were established by 7 consecutive days of intraperitoneal injection of cisplatin, and then MenSCs or MenSC-derived conditioned media (CM) were infused via the tail vein. The ovaries were excised after either 7 or 21 days of treatment and the follicles were counted and categorized. Apoptosis of granulosa cells was observed by terminal deoxynucleotidyl transferase mediated dUTP nick end labelling staining. Ovarian function was evaluated by monitoring serum sex hormone levels. Furthermore, MenSC tracking, Q-PCR, and small interfering RNA transfection were used to reveal the inner mechanism of repair.ResultsMenSC transplantation could improve the ovarian microenvironment by reducing apoptosis in granulosa cells and the fibrosis of ovarian interstitium, which contributes to increase the follicular numbers and return sex hormone levels to normal values. Meanwhile, the transplanted MenSCs directively migrate to ovarian interstitium to play a role in repair rather than differentiate to oocytes directly. Additionally, MenSCs and CM derived from these cells exerted protective effects on damaged ovaries partially by secreting FGF2.ConclusionMenSCs repair ovarian injury, improve ovarian function, and stimulate regeneration, suggesting that transplantation of MenSCs may provide an effective and novel method for treating POF.

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Section: Discussionmentioning

confidence: 99%

Study of the reparative effects of menstrual-derived stem cells on premature ovarian failure in mice

et al. 2017

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“…Particularly interesting candidates are GATA2, TAL1, and ETS1, which are known to regulate megakaryocytopoiesis and expression of many platelet-specific genes. We further hypothesize that variation in MFN2 expression alters platelet production given that low Mfn2 expression has been linked to mitochondrial damage in mice, 62 and mitochondrial number and function are critical for platelet production by megakaryocytes. Nevertheless, addressing these testable hypotheses will require much more work and the development of new reagents.…”

Section: Mfn2 and Platelet Countmentioning

confidence: 94%

Integrative Multi-omic Analysis of Human Platelet eQTLs Reveals Alternative Start Site in Mitofusin 2

Simon

Chen

Edelstein

et al. 2016

The American Journal of Human Genetics

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Platelets play a central role in ischemic cardiovascular events. Cardiovascular disease (CVD) is a major cause of death worldwide. Numerous genome-wide association studies (GWASs) have identified loci associated with CVD risk. However, our understanding of how these variants contribute to disease is limited. Using data from the platelet RNA and expression 1 (PRAX1) study, we analyzed cis expression quantitative trait loci (eQTLs) in platelets from 154 normal human subjects. We confirmed these results in silico by performing allele-specific expression (ASE) analysis, which demonstrated that the allelic directionality of eQTLs and ASE patterns correlate significantly. Comparison of platelet eQTLs with data from the Genotype-Tissue Expression (GTEx) project revealed that a number of platelet eQTLs are platelet specific and that platelet eQTL peaks localize to the gene body at a higher rate than eQTLs from other tissues. Upon integration with data from previously published GWASs, we found that the trait-associated variant rs1474868 coincides with the eQTL peak for mitofusin 2 (MFN2). Additional experimental and computational analyses revealed that this eQTL is linked to an unannotated alternate MFN2 start site preferentially expressed in platelets. Integration of phenotype data from the PRAX1 study showed that MFN2 expression levels were significantly associated with platelet count. This study links the variant rs1474868 to a platelet-specific regulatory role for MFN2 and demonstrates the utility of integrating multi-omic data with eQTL analysis in disease-relevant tissues for interpreting GWAS results.

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“…However, when co-cultured with MSCs, Mfn2 levels appeared higher when compared to trophoblasts cultured alone. Mfn2, a conserved dynamin-like GTPases, is mainly involved in the process of mitochondrial fusion and regulates the structure and function of mitochondrial [ 37 , 38 ]. Mfn2 is located on the mitochondrial outer membrane and the abnormal expression may have an effect on the generation of ATP and activate the apoptosis cascade.…”

Section: Discussionmentioning

confidence: 99%

Bone Marrow Mesenchymal Stem Cells Attenuate Mitochondria Damage Induced by Hypoxia in Mouse Trophoblasts

Wang

Kang

et al. 2016

PLoS ONE

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ObjectiveWe aimed to observe the change of mitochondrial function and structure as well as the cell function induced by hypoxia in mouse trophoblasts, and moreover, to validate the restoration of these changes after co-culture with bone marrow mesenchymal stem cells (hereinafter referred to as “MSCs”). Further, we explored the mechanism of MSCs attenuating the functional damage of trophoblasts caused by hypoxia.MethodsCells were divided into two groups, trophoblasts and MSCs+trophoblasts respectively, and the two groups of cells were incubated with normoxia or hypoxia. Chemiluminescence was used to assay the β-HCG and progesterone in cell culture supernatants quantitatively. Western blotting and PCR were applied to detect the expression of Mfn2, MMP-2, MMP-9 and integrin β1 in the two groups. The mitochondrial membrane potential of each group of cells was detected with JC-1 dye and the ATP content was measured by the phosphomolybdic acid colorimetric method. We utilized transmission electron microscopy for observing the ultrastructure of mitochondria in trophoblasts. Finally, we assessed the cell apoptosis with flow cytometry (FCM) and analyzed the expression of the apoptosis related genes—Bcl-2, Bax, Caspase3 and Caspase9 by western blotting.ResultsThe results showed that the Mfn2 expression was reduced after 4 h in hypoxia compared with that in normoxia, but increased in the co-culture group when compared with that in the separated-culture group (p<0.05). In addition, compared with the separated-culture group, theβ-HCG and progesterone levels in the co-culture group were significantly enhanced (p<0.05), and so were the expressions of MMP-2, MMP-9 and integrin β1 (p<0.05). Moreover, it exhibited significantly higher in ATP levels and intensified about the mitochondrial membrane potential in the co-culture group. TEM revealed disorders of the mitochondrial cristae and presented short rod-like structure and spheroids in hypoxia, however, in the co-culture group, the mitochondrial cristae had a relatively regular arrangement and the mitochondrial ultrastructure showed hyperfusion. The expression of Bax, Caspase3 and Caspase9 was decreased in the co-culture group when compared with that in trophoblast cells cultured alone (p<0.05), while the Bcl-2 levels and the Apoptosis Index (AI) were markedly increased in the co-culture group (p<0.05).ConclusionBone marrow mesenchymal stem cells can attenuate mitochondria damage and cell apoptosis induced by hypoxia; the mechanism could be upregulating the expression of Mfn2 in mouse trophoblasts and changing mitochondrial structure.

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Low Expression of Mfn2 Is Associated with Mitochondrial Damage and Apoptosis of Ovarian Tissues in the Premature Ovarian Failure Model

Cited by 25 publications

References 37 publications

Study of the reparative effects of menstrual-derived stem cells on premature ovarian failure in mice

Study of the reparative effects of menstrual-derived stem cells on premature ovarian failure in mice

Integrative Multi-omic Analysis of Human Platelet eQTLs Reveals Alternative Start Site in Mitofusin 2

Bone Marrow Mesenchymal Stem Cells Attenuate Mitochondria Damage Induced by Hypoxia in Mouse Trophoblasts

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