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(1) Effects of hPMSCs on granulosa cell apoptosis and AMH expression and their role in the restoration of ovary function in premature ovarian failure mice.[TOP]

Pubmed ID :29386068
Publication Date : //
This study was performed to determine the effects of human placenta mesenchymal stem cell (hPMSC) transplantation on granulosa cell apoptosis and anti-Müllerian hormone (AMH) and follicle-stimulating hormone receptor (FSHR) expression in autoimmune drug-induced premature ovarian failure (POF) mice. The aim of this research is to investigate the mechanisms of hPMSCs on ovarian reserve capacity.

Authors : Zhang Hongqin, Luo Qianqian, Lu Xueyan, Yin Na, Zhou Dongli, Zhang Lianshuang, Zhao Wei, Wang Dong, Du Pengchao, Hou Yun, Zhang Yan, Yuan Wendan,

(2) Regulatory T cells and TLR9 activation shape antibody formation to a secreted transgene product in AAV muscle gene transfer.[TOP]

Pubmed ID :28888664
Publication Date : //
Adeno-associated viral (AAV) gene delivery to skeletal muscle is being explored for systemic delivery of therapeutic proteins. To better understand the signals that govern antibody formation against secreted transgene products in this approach, we administered an intramuscular dose of AAV1 vector expressing human coagulation factor IX (hFIX), which does not cause antibody formation against hFIX in C57BL/6 mice. Interestingly, co-administration of a TLR9 agonist (CpG-deoxyoligonucleotide, ODN) but not of lipopolysaccharide, caused a transient anti-hFIX response. ODN activated monocyte-derived dendritic cells and enhanced T follicular helper cell responses. While depletion of regulatory T cells (Tregs) also caused an antibody response, TLR9 activation combined with Treg depletion instead resulted in prolonged CD8 T cell infiltration of transduced muscle. Thus, Tregs modulate the response to the TLR9 agonist. Further, Treg re-population eventually resolved humoral and cellular immune responses. Therefore, specific modes of TLR9 activation and Tregs orchestrate antibody formation in muscle gene transfer.

Authors : Herzog Roland W, Cooper Mario, Perrin George Q, Biswas Moanaro, Martino Ashley T, Morel Laurence, Terhorst Cox, Hoffman Brad E,

(3) The Ox40/Ox40 Ligand Pathway Promotes Pathogenic Th Cell Responses, Plasmablast Accumulation, and Lupus Nephritis in NZB/W F1 Mice.[TOP]

Pubmed ID :28696253
Publication Date : //
Ox40 ligand (Ox40L) locus genetic variants are associated with the risk for systemic lupus erythematosus (SLE); however, it is unclear how Ox40L contributes to SLE pathogenesis. In this study, we evaluated the contribution of Ox40L and its cognate receptor, Ox40, using in vivo agonist and antagonist approaches in the NZB × NZW (NZB/W) F1 mouse model of SLE. Ox40 was highly expressed on several CD4 Th cell subsets in the spleen and kidney of diseased mice, and expression correlated with disease severity. Treatment of aged NZB/W F1 mice with agonist anti-Ox40 mAbs potently exacerbated renal disease, which was accompanied by activation of kidney-infiltrating T cells and cytokine production. The agonist mAbs also induced activation and inflammatory gene expression in splenic CD4 T cells, including IFN-regulated genes, increased the number of follicular helper T cells and plasmablasts in the spleen, and led to elevated levels of serum IgM and enhanced renal glomerular IgM deposition. In a type I IFN-accelerated lupus model, treatment with an antagonist Ox40:Fc fusion protein significantly delayed the onset of severe proteinuria and improved survival. These data support the hypothesis that the Ox40/Ox40L pathway drives cellular and humoral autoimmune responses during lupus nephritis in NZB/W F1 mice and emphasize the potential clinical value of targeting this pathway in human lupus.

Authors : Sitrin Jonathan, Suto Eric, Wuster Arthur, Eastham-Anderson Jeffrey, Kim Jeong M, Austin Cary D, Lee Wyne P, Behrens Timothy W,

(4) IL-23 Limits the Production of IL-2 and Promotes Autoimmunity in Lupus.[TOP]

Pubmed ID :28646040
Publication Date : //
The IL-23/IL-17 pathway is important in multiple autoimmune diseases, but its effect on lupus pathology remains unclear, with opposing trials in murine models of the disease. In this study, we show a disease activity-related upregulation of serum IL-23 and IL-23 receptor in patients with systemic lupus erythematosus (SLE) as compared with healthy controls. When added in SLE T cell in vitro cultures, IL-23 induced IL-17 and limited IL-2 production, whereas T follicular helper and double negative (DN) T cells significantly expanded. To further dissect the role of IL-23 in the expression of autoimmunity and related pathology, we generated IL-23 receptor-deficient MRL. mice. These IL-23RMRL. mice displayed attenuated lupus nephritis with a striking decrease in the accumulation of DN T cells in the kidneys and secondary lymphoid organs. Moreover, T cells from IL-23RMRL. mice produced increased amounts of IL-2 and reduced amounts of IL-17 compared with T cells from wild type animals. In vitro IL-23 treatment promoted IL-17 production and downregulated IL-2 production. The IL-23RMRL. had fewer T follicular helper cells, B cells, and plasma cells, leading to decreased production of anti-dsDNA Abs. Our results show that IL-23 accounts for the main aspects of human and murine lupus including the expansion of DN T cells, decreased IL-2, and increased IL-17 production. We propose that blockade of IL-23 should have a therapeutic value in patients with SLE.

Authors : Dai Hong, He Fan, Tsokos George C, Kyttaris Vasileios C,

(5) Ovary-specific depletion of the nuclear receptor Nr5a2 compromises expansion of the cumulus oophorus but not fertilization by intracytoplasmic sperm injection.[TOP]

Pubmed ID :28520915
Publication Date : //
The orphan nuclear receptor, liver receptor homolog-1 (aka Nuclear receptor subfamily 5, Group A, Member 2 (Nr5a2)), is widely expressed in mammalian tissues, and its ovarian expression is restricted to granulosa cells of activated follicles. We employed the floxed Nr5a2 (Nr5a2f/f) mutant mouse line and two granulosa-specific Cre lines, Anti-Müllerian hormone receptor- 2 (Amhr2Cre) and transgenic cytochrome P450 family 19 subfamily A polypeptide 1 (tgCyp19Cre), to develop two tissue- and time-specific Nr5a2 depletion models: Nr5a2Amhr2-/- and Nr5a2Cyp19-/-. In the Nr5a2Cyp19-/- ovaries, Nr5a2 was depleted in mural granulosa, but not cumulus cells. We induced follicular development in mutant and wild-type (control, CON) mice with equine chorionic gonadotropin followed 44 h later treatment with human chorionic gonadotropin (hCG) to induce ovulation. Both Nr5a2Amhr2-/- and Nr5a2Cyp19-/- cumulus-oocyte complexes underwent a reduced degree of expansion in vitro relative to wild-type mice. We found downregulation of epiregulin (Ereg), amphiregulin (Areg), betacellulin (Btc) and tumor necrosis factor stimulated gene-6 (Tnfaip6) transcripts in Nr5a2Amhr2-/- and Nr5a2Cyp19-/- ovaries. Tnfaip6 protein abundance, by quantitative immunofluorescence, was likewise substantially reduced in the Nr5a2-depleted model. Transcript abundance for connexin 43 (Gja1) in granulosa cells was lower at 0 h and maximum at 8 h post-hCG in both Nr5a2Amhr2-/- and Nr5a2Cyp19-/- follicles, while Gja1 protein was not different prior to the ovulatory signal, but elevated at 8 h in Nr5a2Amhr2-/- and Nr5a2Cyp19-/- follicles. In both mutant genotypes, oocytes can mature in vivo and resulting embryos were capable of proceeding to blastocyst stagein vitro. We conclude that Nr5a2 is essential for cumulus expansion in granulosa cells throughout follicular development. The disruption of Nr5a2 in follicular somatic cells does not affect the capacity of the oocyte to be fertilized by intracytoplasmic sperm injection.

Authors : Bertolin Kalyne, Meinsohn Marie-Charlotte, Suzuki João, Gossen Jan, Schoonjans Kristina, Duggavathi Rajesha, Murphy Bruce D,

(6) Oxidative stress-induced apoptosis in granulosa cells involves JNK, p53 and Puma.[TOP]

Pubmed ID :28445976
Publication Date : //
Reactive oxygen species (ROS) play important roles in follicular development and survival. Granulosa cell death is associated with increased ROS, but the mechanism of granulosa cell death induced by ROS is not clear. In order to define the molecular link between ROS and granulosa cell death, COV434, human granulosa tumor cells, were treated with H2O2. Compared to control cells, H2O2 induced granulosa cell death in a dose- and time-dependent manner. H2O2 induced an increase in Bax, Bak and Puma, and a decrease in anti-apoptotic molecules such as Bcl-2, Bcl-xL and Mcl-1. Both knockdown of Puma and overexpression of Bcl-xL could inhibit H2O2-induced granulosa cell death. These results suggest that suppression of Puma and overexpression of anti-apoptotic Bcl-2 family members could improve granulosa cell survival. To explore the mechanisms responsible for these findings, ROS in granulosa cells treatment with H2O2 were measured. The results showed that ROS was increased in a H2O2 dose- and time-dependent manner at the earlier time point. In addition, H2O2 induced an increase in Nrf2 and phosphorylation of JNK and p53. SP600125, an inhibitor of JNK, inhibits H2O2-induced phosphorylation of JNK and p53, and granulosa cell death. Antioxidant N-acetylcysteine (NAC) dose-dependently prevents H2O2-induced granulosa cell death. Furthermore, NAC also prevents phosphorylation of JNK and p53 induced by H2O2. Taken together, these data suggest that H2O2 regulates cell death in granulosa cells via the ROS-JNK-p53 pathway. These findings provide an improved understanding of the mechanisms underlying granulosa cell apoptosis, which could potentially be useful for future clinical applications.

Authors : Yang Hongyan, Xie Yan, Yang Dongyu, Ren Decheng,

(7) Defects in the first wave of folliculogenesis in mouse XO ovaries.[TOP]

Pubmed ID :28392504
Publication Date : //
In mouse ovaries, the first wave of folliculogenesis perinatally starts near the medullary region, which directs the initial round of follicular growth soon after birth. At the same time, cortical primordial follicles start forming in the ovarian surface region, and then some are cyclically recruited for the second and subsequent rounds of follicular growth. Recent studies suggest different dynamics between the first and subsequent waves of follicular growth in postnatal ovaries. However, the phenotypic differences between these phases remain unclear. Here, we show direct evidence that XO female mice, a murine model for Turner Syndrome, lack the first wave of folliculogenesis. Our histopathological analyses of XX and XO littermates revealed a lack of anti-Müllerian hormone (AMH)-positive primary follicles in the XO ovaries by 4 days post partum (dpp). This loss of first follicles was also confirmed by histological bioassay for SRY-dependent SOX9 inducibility, a specific marker for the first follicular granulosa cells. In contrast, cortical primordial follicles formed properly in XO ovaries, and some of them formed primary and secondary follicles in the subcortical region by 7 dpp. They rapidly developed into late antral follicles, showing similarities to XX littermate ovaries by 21 dpp. These results suggest distinct X-monosomy effects between the first and subsequent waves of follicular growth, highlighting the high susceptibility to elimination of XO oocytes in the first wave of mammalian folliculogenesis.

Authors : Miura Kento, Murata Chiharu, Harikae Kyoko, Suzuki Hitomi, Kanai-Azuma Masami, Kurohmaru Masamichi, Tsunekawa Naoki, Kanai Yoshiakira,

(8) Anti-Müllerian hormone inhibits activation and growth of bovine ovarian follicles in vitro and is localized to growing follicles.[TOP]

Pubmed ID :28333275
Publication Date : //
Does anti-Müllerian hormone (AMH) inhibit activation (initiation of growth) of primordial follicles and attenuate the growth of primary follicles in cattle, an excellent animal model for human ovarian follicular development?

Authors : Yang M Y, Cushman R A, Fortune J E,

(9) Ovarian hormones and obesity.[TOP]

Pubmed ID :28333235
Publication Date : //
Obesity is caused by an imbalance between energy intake, i.e. eating and energy expenditure (EE). Severe obesity is more prevalent in women than men worldwide, and obesity pathophysiology and the resultant obesity-related disease risks differ in women and men. The underlying mechanisms are largely unknown. Pre-clinical and clinical research indicate that ovarian hormones may play a major role.

Authors : Leeners Brigitte, Geary Nori, Tobler Philippe N, Asarian Lori,

(10) Human Umbilical Cord Mesenchymal Stem Cells Inhibit T Follicular Helper Cell Expansion Through the Activation of iNOS in Lupus-Prone B6.MRL- Mice.[TOP]

Pubmed ID :28105982
Publication Date : //
The aberrant generation or activation of T follicular helper (Tfh) cells contributes to the pathogenesis of systemic lupus erythematosus (SLE), yet little is known about how these cells are regulated. In this study, we demonstrated that the frequency of Tfh cells was increased in lupus-prone B6.MRL-Faslpr (B6.lpr) mice and positively correlated to plasma cell proportions and serum total IgG as well as anti-dsDNA antibody levels. Transplantation of mesenchymal stem cells derived from Wharton's jelly of human umbilical cords (hUC-MSCs) ameliorated lupus symptoms in B6.lpr mice, along with decreased percentages of Tfh cells. In vitro studies showed that the differentiation and proliferation of Tfh cells were markedly suppressed by hUC-MSCs. The production of inducible nitric oxide synthase (iNOS) was dramatically upregulated in hUC-MSCs when cocultured with CD4+ T cells directly, while adding the specific inhibitor of iNOS into the coculture system significantly reversed the inhibitory effect of hUC-MSCs on Tfh cell generation. Interestingly, the efficacy of hUC-MSCs in inhibiting Tfh cells was impaired in the Transwell system, with the reduction of iNOS in both mRNA and protein levels. Taken together, our findings suggest that hUC-MSCs could effectively inhibit Tfh cell expansion through the activation of iNOS in lupus-prone B6.lpr mice, which is highly dependent on cell-to-cell contacts.

Authors : Zhang Zhuoya, Feng Ruihai, Niu Lingying, Huang Saisai, Deng Wei, Shi Bingyu, Yao Genhong, Chen Weiwei, Tang Xiaojun, Gao Xiang, Feng Xuebing, Sun Lingyun,