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Li S, Zhao B, Yang H, Dai K, Cai Y, Xu H, Chen P, Wang F, Zhang Y. Comprehensive transcriptomic analysis revealing the regulatory dynamics and networks of the pituitary-testis axis in sheep across developmental stages. Front Vet Sci 2024; 11:1367730. [PMID: 38440388 PMCID: PMC10909840 DOI: 10.3389/fvets.2024.1367730] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2024] [Accepted: 02/05/2024] [Indexed: 03/06/2024] Open
Abstract
Spermatogenesis is a complex process intricately regulated by the hypothalamic-pituitary-testis (HPT) axis. However, research on the regulatory factors governing the HPT axis remains limited. This study addresses this gap by conducting a comprehensive analysis of transcriptomes from the pituitary and testis tissues across various developmental stages, encompassing embryonic day (E120), neonatal period (P0), pre-puberty (P90), and post-puberty day (P270). Utilizing edgeR and WGCNA, we identified stage-specific genes in both the pituitary and testis throughout the four developmental stages. Notably, 380, 242, 34, and 479 stage-specific genes were identified in the pituitary, while 886, 297, 201, and 3,678 genes were identified in the testis. Subsequent analyses unveiled associations between these stage-specific genes and crucial pathways such as the cAMP signaling pathway, GnRH secretion, and male gamete generation. Furthermore, leveraging single-cell data from the pituitary and testis, we identified some signaling pathways involving BMP, HGF, IGF, and TGF-β, highlighting mutual regulation between the pituitary and testis at different developmental stages. This study sheds light on the pivotal role of the pituitary-testis axis in the reproductive process of sheep across four distinct developmental stages. Additionally, it delves into the intricate regulatory networks governing reproduction, offering novel insights into the dynamics of the pituitary-testis axis within the reproductive system.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Yanli Zhang
- Jiangsu Livestock Embryo Engineering Laboratory, Nanjing Agricultural University, Nanjing, China
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Mi X, Chen C, Feng C, Qin Y, Chen ZJ, Yang Y, Zhao S. The Functions and Application Prospects of Hepatocyte Growth Factor in Reproduction. Curr Gene Ther 2024; 24:347-355. [PMID: 39005061 DOI: 10.2174/0115665232291010240221104445] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2023] [Revised: 02/01/2024] [Accepted: 02/13/2024] [Indexed: 07/16/2024]
Abstract
Hepatocyte growth factor (HGF) is expressed in multiple systems and mediates a variety of biological activities, such as mitosis, motility, and morphogenesis. A growing number of studies have revealed the expression patterns and functions of HGF in ovarian and testicular physiology from the prenatal to the adult stage. HGF regulates folliculogenesis and steroidogenesis by modulating the functions of theca cells and granulosa cells in the ovary. It also mediates somatic cell proliferation and steroidogenesis, thereby affecting spermatogenesis in males. In addition to its physiological effects on the reproductive system, HGF has shown advantages in preclinical studies over recent years for the treatment of male and female infertility, particularly in women with premature ovarian insufficiency. This review aims to summarize the pleiotropic functions of HGF in the reproductive system and to provide prospects for its clinical application.
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Affiliation(s)
- Xin Mi
- Institute of Women, Children and Reproductive Health, Shandong University, Jinan, Shandong, 250012, China
- State Key Laboratory of Reproductive Medicine and Offspring Health, Shandong University, Jinan, Shandong, 250012, China
- Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, Jinan, Shandong, 250012, China
- Shandong Key Laboratory of Reproductive Medicine, Jinan, Shandong, 250012, China
- Shandong Provincial Clinical Research Center for Reproductive Health, Jinan, Shandong, 250012, China
- Shandong Technology Innovation Center for Reproductive Health, Jinan, Shandong, China
- National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, Shandong, China
| | - Caiyi Chen
- Institute of Women, Children and Reproductive Health, Shandong University, Jinan, Shandong, 250012, China
- State Key Laboratory of Reproductive Medicine and Offspring Health, Shandong University, Jinan, Shandong, 250012, China
- Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, Jinan, Shandong, 250012, China
- Shandong Key Laboratory of Reproductive Medicine, Jinan, Shandong, 250012, China
- Shandong Provincial Clinical Research Center for Reproductive Health, Jinan, Shandong, 250012, China
- Shandong Technology Innovation Center for Reproductive Health, Jinan, Shandong, China
- National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, Shandong, China
| | - Chen Feng
- Institute of Women, Children and Reproductive Health, Shandong University, Jinan, Shandong, 250012, China
- State Key Laboratory of Reproductive Medicine and Offspring Health, Shandong University, Jinan, Shandong, 250012, China
- Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, Jinan, Shandong, 250012, China
- Shandong Key Laboratory of Reproductive Medicine, Jinan, Shandong, 250012, China
- Shandong Provincial Clinical Research Center for Reproductive Health, Jinan, Shandong, 250012, China
- Shandong Technology Innovation Center for Reproductive Health, Jinan, Shandong, China
- National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, Shandong, China
| | - Yingying Qin
- Institute of Women, Children and Reproductive Health, Shandong University, Jinan, Shandong, 250012, China
- State Key Laboratory of Reproductive Medicine and Offspring Health, Shandong University, Jinan, Shandong, 250012, China
- Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, Jinan, Shandong, 250012, China
- Shandong Key Laboratory of Reproductive Medicine, Jinan, Shandong, 250012, China
- Shandong Provincial Clinical Research Center for Reproductive Health, Jinan, Shandong, 250012, China
- Shandong Technology Innovation Center for Reproductive Health, Jinan, Shandong, China
- National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, Shandong, China
| | - Zi-Jiang Chen
- Institute of Women, Children and Reproductive Health, Shandong University, Jinan, Shandong, 250012, China
- State Key Laboratory of Reproductive Medicine and Offspring Health, Shandong University, Jinan, Shandong, 250012, China
- Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, Jinan, Shandong, 250012, China
- Shandong Key Laboratory of Reproductive Medicine, Jinan, Shandong, 250012, China
- Shandong Provincial Clinical Research Center for Reproductive Health, Jinan, Shandong, 250012, China
- Shandong Technology Innovation Center for Reproductive Health, Jinan, Shandong, China
- National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, Shandong, China
- Research Unit of Gametogenesis and Health of ART-Offspring (No.2021RU001), Chinese Academy of Medical Sciences, Jinan, China
- Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai, China
- Center for Reproductive Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yajuan Yang
- Institute of Women, Children and Reproductive Health, Shandong University, Jinan, Shandong, 250012, China
- State Key Laboratory of Reproductive Medicine and Offspring Health, Shandong University, Jinan, Shandong, 250012, China
- Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, Jinan, Shandong, 250012, China
- Shandong Key Laboratory of Reproductive Medicine, Jinan, Shandong, 250012, China
- Shandong Provincial Clinical Research Center for Reproductive Health, Jinan, Shandong, 250012, China
- Shandong Technology Innovation Center for Reproductive Health, Jinan, Shandong, China
- National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, Shandong, China
| | - Shidou Zhao
- Institute of Women, Children and Reproductive Health, Shandong University, Jinan, Shandong, 250012, China
- State Key Laboratory of Reproductive Medicine and Offspring Health, Shandong University, Jinan, Shandong, 250012, China
- Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, Jinan, Shandong, 250012, China
- Shandong Key Laboratory of Reproductive Medicine, Jinan, Shandong, 250012, China
- Shandong Provincial Clinical Research Center for Reproductive Health, Jinan, Shandong, 250012, China
- Shandong Technology Innovation Center for Reproductive Health, Jinan, Shandong, China
- National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, Shandong, China
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Mi X, Jiao W, Yang Y, Qin Y, Chen ZJ, Zhao S. HGF Secreted by Mesenchymal Stromal Cells Promotes Primordial Follicle Activation by Increasing the Activity of the PI3K-AKT Signaling Pathway. Stem Cell Rev Rep 2022; 18:1834-1850. [PMID: 35089464 PMCID: PMC9209380 DOI: 10.1007/s12015-022-10335-x] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/14/2022] [Indexed: 01/08/2023]
Abstract
Primordial follicle activation is fundamental for folliculogenesis and for the maintenance of fertility. An effective therapeutic strategy for patients with premature ovarian insufficiency (POI) is to promote the activation of residual primordial follicles. The secretome of human umbilical cord mesenchymal stromal cells (hUC-MSC-sec) contains several components that might promote the activation of primordial follicles. In the present study, we revealed that treatment with the hUC-MSC-sec significantly increased the proportion of activated primordial follicles in mouse ovaries both in vitro and in vivo. The activating effects of hUC-MSC-sec on primordial follicles were attributed to the activation of the PI3K-AKT signaling pathway by hepatocyte growth factor (HGF). While the effect of the hUC-MSC-sec was attenuated by the neutralizing antibodies against HGF, application of exogenous HGF alone also promoted the activation of primordial follicles. Furthermore, we demonstrated that HGF promoted the expression of KITL in granulosa cells by binding with the HGF receptor c-Met, thereby increasing the activity of the PI3K-AKT signaling pathway to activate primordial follicles. Taken together, our findings demonstrate that hUC-MSC-sec promotes primordial follicle activation through the functional component HGF to increase the PI3K-AKT signaling activity, highlighting the application of the hUC-MSC-sec or HGF for the treatment of POI patients.
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Affiliation(s)
- Xin Mi
- Center for Reproductive Medicine, Cheeloo College of Medicine, Shandong University, 44 Wenhua Xi Road, Jinan, 250012, Shandong, China.,Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, Jinan, 250012, Shandong, China.,Shandong Key Laboratory of Reproductive Medicine, Jinan, 250012, Shandong, China.,Shandong Provincial Clinical Research Center for Reproductive Health, Jinan, 250012, Shandong, China.,National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, 250012, Shandong, China
| | - Wenlin Jiao
- Center for Reproductive Medicine, Cheeloo College of Medicine, Shandong University, 44 Wenhua Xi Road, Jinan, 250012, Shandong, China.,Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, Jinan, 250012, Shandong, China.,Shandong Key Laboratory of Reproductive Medicine, Jinan, 250012, Shandong, China.,Shandong Provincial Clinical Research Center for Reproductive Health, Jinan, 250012, Shandong, China.,National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, 250012, Shandong, China
| | - Yajuan Yang
- Center for Reproductive Medicine, Cheeloo College of Medicine, Shandong University, 44 Wenhua Xi Road, Jinan, 250012, Shandong, China.,Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, Jinan, 250012, Shandong, China.,Shandong Key Laboratory of Reproductive Medicine, Jinan, 250012, Shandong, China.,Shandong Provincial Clinical Research Center for Reproductive Health, Jinan, 250012, Shandong, China.,National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, 250012, Shandong, China
| | - Yingying Qin
- Center for Reproductive Medicine, Cheeloo College of Medicine, Shandong University, 44 Wenhua Xi Road, Jinan, 250012, Shandong, China.,Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, Jinan, 250012, Shandong, China.,Shandong Key Laboratory of Reproductive Medicine, Jinan, 250012, Shandong, China.,Shandong Provincial Clinical Research Center for Reproductive Health, Jinan, 250012, Shandong, China.,National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, 250012, Shandong, China
| | - Zi-Jiang Chen
- Center for Reproductive Medicine, Cheeloo College of Medicine, Shandong University, 44 Wenhua Xi Road, Jinan, 250012, Shandong, China.,Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, Jinan, 250012, Shandong, China.,Shandong Key Laboratory of Reproductive Medicine, Jinan, 250012, Shandong, China.,Shandong Provincial Clinical Research Center for Reproductive Health, Jinan, 250012, Shandong, China.,National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, 250012, Shandong, China.,Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai, 200135, China.,Center for Reproductive Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200135, China
| | - Shidou Zhao
- Center for Reproductive Medicine, Cheeloo College of Medicine, Shandong University, 44 Wenhua Xi Road, Jinan, 250012, Shandong, China. .,Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, Jinan, 250012, Shandong, China. .,Shandong Key Laboratory of Reproductive Medicine, Jinan, 250012, Shandong, China. .,Shandong Provincial Clinical Research Center for Reproductive Health, Jinan, 250012, Shandong, China. .,National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, 250012, Shandong, China.
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Bahrehbar K, Rezazadeh Valojerdi M, Esfandiari F, Fathi R, Hassani SN, Baharvand H. Human embryonic stem cell-derived mesenchymal stem cells improved premature ovarian failure. World J Stem Cells 2020; 12:857-878. [PMID: 32952863 PMCID: PMC7477659 DOI: 10.4252/wjsc.v12.i8.857] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2020] [Revised: 06/01/2020] [Accepted: 07/18/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Premature ovarian failure (POF) affects many adult women less than 40 years of age and leads to infertility. According to previous reports, various tissue-specific stem cells can restore ovarian function and folliculogenesis in mice with chemotherapy-induced POF. Human embryonic stem cells (ES) provide an alternative source for mesenchymal stem cells (MSCs) because of their similarities in phenotype and immunomodulatory and anti-inflammatory characteristics. Embryonic stem cell-derived mesenchymal stem cells (ES-MSCs) are attractive candidates for regenerative medicine because of their high proliferation and lack of barriers for harvesting tissue-specific MSCs. However, possible therapeutic effects and underlying mechanisms of transplanted ES-MSCs on cyclophosphamide and busulfan-induced mouse ovarian damage have not been evaluated. AIM To evaluate ES-MSCs vs bone marrow-derived mesenchymal stem cells (BM-MSCs) in restoring ovarian function in a mouse model of chemotherapy-induced premature ovarian failure. METHODS Female mice received intraperitoneal injections of different doses of cyclophosphamide and busulfan to induce POF. Either human ES-MSCs or BM-MSCs were transplanted into these mice. Ten days after the mice were injected with cyclophosphamide and busulfan and 4 wk after transplantation of the ES-MSCs and/or BM-MSCs, we evaluated body weight, estrous cyclicity, follicle-stimulating hormone and estradiol hormone concentrations and follicle count were used to evaluate the POF model and cell transplantation. Moreover, terminal deoxynucleotidyl transferase mediated 2-deoxyuridine 5-triphosphate nick end labeling, real-time PCR, Western blot analysis and immunohistochemistry and mating was used to evaluate cell transplantation. Enzyme-linked immunosorbent assay was used to analyze vascular endothelial growth factor, insulin-like growth factor 2 and hepatocyte growth factor levels in ES-MSC condition medium in order to investigate the mechanisms that underlie their function. RESULTS The human ES-MSCs significantly restored hormone secretion, survival rate and reproductive function in POF mice, which was similar to the results obtained with BM-MSCs. Gene expression analysis and the terminal deoxynucleotidyl transferase mediated 2-deoxyuridine 5-triphosphate nick end labeling assay results indicated that the ES-MSCs and/or BM-MSCs reduced apoptosis in the follicles. Notably, the transplanted mice generated new offspring. The results of different analyses showed increases in antiapoptotic and trophic proteins and genes. CONCLUSION These results suggested that transplantation of human ES-MSCs were similar to BM-MSCs in that they could restore the structure of the injured ovarian tissue and its function in chemotherapy-induced damaged POF mice and rescue fertility. The possible mechanisms of human ES-MSC were related to promotion of follicular development, ovarian secretion, fertility via a paracrine effect and ovarian cell survival.
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Affiliation(s)
- Khadijeh Bahrehbar
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, Tehran 1665659911, Iran
- Department of Developmental Biology, University of Science and Culture, Tehran 1665659911, Iran
| | - Mojtaba Rezazadeh Valojerdi
- Department of Embryology, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, Tehran 1665659911, Iran
- Department of Anatomy, Faculty of Medical Science, Tarbiat Modares University, Tehran 1665659911, Iran
| | - Fereshteh Esfandiari
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, Tehran 1665659911, Iran
| | - Rouhollah Fathi
- Department of Embryology, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, Tehran 1665659911, Iran
| | - Seyedeh-Nafiseh Hassani
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, Tehran 1665659911, Iran
| | - Hossein Baharvand
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, Tehran 1665659911, Iran
- Department of Developmental Biology, University of Science and Culture, Tehran 1665659911, Iran.
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Bongrani A, Elfassy Y, Brun JS, Ramé C, Mellouk N, Fellahi S, Bastard JP, Levy R, Vasseur C, Froment P, Dupont J. Expression of adipokines in seminal fluid of men of normal weight. Asian J Androl 2020; 21:528-530. [PMID: 31115360 PMCID: PMC6732888 DOI: 10.4103/aja.aja_25_19] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Affiliation(s)
- Alice Bongrani
- UMR 85 Unit of Reproductive Physiology and Behaviors, INRA Val de Loire Center, Nouzilly 37380, France
| | - Yaelle Elfassy
- Unit of Biology of Reproduction and Inflammatory and Metabolic Biomarkers, Hôpital Tenon, Research Center Saint Antoine, IHU ICAN, Inserm UMRS 938, AP-HP, UPMC University of Paris 06, Paris 75005, France
| | - Jean Sebastien Brun
- Assisted Medical Procreation Pôle Santé Léonard de Vinci, Chambray-lès-Tours 37170, France
| | - Christelle Ramé
- UMR 85 Unit of Reproductive Physiology and Behaviors, INRA Val de Loire Center, Nouzilly 37380, France
| | - Namya Mellouk
- UMR 85 Unit of Reproductive Physiology and Behaviors, INRA Val de Loire Center, Nouzilly 37380, France
| | - Soraya Fellahi
- Unit of Biology of Reproduction and Inflammatory and Metabolic Biomarkers, Hôpital Tenon, Research Center Saint Antoine, IHU ICAN, Inserm UMRS 938, AP-HP, UPMC University of Paris 06, Paris 75005, France
| | - Jean Philippe Bastard
- Unit of Biology of Reproduction and Inflammatory and Metabolic Biomarkers, Hôpital Tenon, Research Center Saint Antoine, IHU ICAN, Inserm UMRS 938, AP-HP, UPMC University of Paris 06, Paris 75005, France
| | - Rachel Levy
- Unit of Biology of Reproduction and Inflammatory and Metabolic Biomarkers, Hôpital Tenon, Research Center Saint Antoine, IHU ICAN, Inserm UMRS 938, AP-HP, UPMC University of Paris 06, Paris 75005, France
| | - Claudine Vasseur
- Assisted Medical Procreation Pôle Santé Léonard de Vinci, Chambray-lès-Tours 37170, France
| | - Pascal Froment
- UMR 85 Unit of Reproductive Physiology and Behaviors, INRA Val de Loire Center, Nouzilly 37380, France
| | - Joëlle Dupont
- UMR 85 Unit of Reproductive Physiology and Behaviors, INRA Val de Loire Center, Nouzilly 37380, France
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Human amnion-derived mesenchymal stem cell (hAD-MSC) transplantation improves ovarian function in rats with premature ovarian insufficiency (POI) at least partly through a paracrine mechanism. Stem Cell Res Ther 2019; 10:46. [PMID: 30683144 PMCID: PMC6347748 DOI: 10.1186/s13287-019-1136-x] [Citation(s) in RCA: 139] [Impact Index Per Article: 23.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2018] [Revised: 01/03/2019] [Accepted: 01/06/2019] [Indexed: 12/21/2022] Open
Abstract
Background Chemotherapy can induce premature ovarian insufficiency (POI) and reduce fertility in young female patients. Currently, there is no effective therapy for POI. Human amnion-derived mesenchymal stem cells (hAD-MSCs) may be a promising seed cell for regenerative medicine. This study investigated the effects and mechanisms of hAD-MSC transplantation on chemotherapy-induced POI in rats. Methods Chemotherapy-induced POI rat models were established by intraperitoneal injection of cyclophosphamide. Seventy-two female SD rats were randomly divided into control, POI, and hAD-MSC-treated groups. hAD-MSCs were labeled with PKH26 and injected into the tail veins of POI rats. To examine the underlying mechanisms, the differentiation of transplanted hAD-MSCs in the POI ovaries was analyzed by immunofluorescent staining. The in vitro expression of growth factors secreted by hAD-MSCs in hAD-MSC-conditioned media (hAD-MSC-CM) was analyzed by ELISA. Sixty female SD rats were divided into control, POI, and hAD-MSC-CM-treated groups, and hAD-MSC-CM was injected into the bilateral ovaries of POI rats. After hAD-MSC transplantation or hAD-MSC-CM injection, serum sex hormone levels, estrous cycles, ovarian pathological changes, follicle counts, granulosa cell (GC) apoptosis, and Bcl-2, Bax, and VEGF expression in ovaries were examined. Results PKH26-labeled hAD-MSCs mainly homed to ovaries after transplantation. hAD-MSC transplantation reduced ovarian injury and improved ovarian function in rats with POI. Transplanted hAD-MSCs were only located in the interstitium of ovaries, rather than in follicles, and did not express the typical markers of oocytes and GCs, which are ZP3 and FSHR, respectively. hAD-MSCs secreted FGF2, IGF-1, HGF, and VEGF, and those growth factors were detected in the hAD-MSC-CM. hAD-MSC-CM injection improved the local microenvironment of POI ovaries, leading to a decrease in Bax expression and an increase in Bcl-2 and endogenous VEGF expression in ovarian cells, which inhibited chemotherapy-induced GC apoptosis, promoted angiogenesis and regulated follicular development, thus partly reducing ovarian injury and improving ovarian function in rats with POI. Conclusions hAD-MSC transplantation can improve ovarian function in rats with chemotherapy-induced POI at least partly through a paracrine mechanism. The presence of a paracrine mechanism accounting for hAD-MSC-mediated recovery of ovarian function might be attributed to the growth factors secreted by hAD-MSCs.
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7
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Yerushalmi GM, Salmon-Divon M, Ophir L, Yung Y, Baum M, Coticchio G, Fadini R, Mignini-Renzini M, Dal Canto M, Machtinger R, Maman E, Hourvitz A. Characterization of the miRNA regulators of the human ovulatory cascade. Sci Rep 2018; 8:15605. [PMID: 30353018 PMCID: PMC6199329 DOI: 10.1038/s41598-018-33807-y] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2018] [Accepted: 09/21/2018] [Indexed: 11/16/2022] Open
Abstract
Ovarian follicular development and ovulation are complex and tightly regulated processes that involve regulation by microRNAs (miRNAs). We previously identified differentially expressed mRNAs between human cumulus granulosa cells (CGCs) from immature early antral follicles (germinal vesicle - GV) and mature preovulatory follicles (metaphase II - M2). In this study, we performed an integrated analysis of the transcriptome and miRNome in CGCs obtained from the GV cumulus-oocyte complex (COC) obtained from IVM and M2 COC obtained from IVF. A total of 43 differentially expressed miRNAs were identified. Using Ingenuity IPA analysis, we identified 7288 potential miRNA-regulated target genes. Two hundred thirty-four of these target genes were also found in our previously generated ovulatory gene library while exhibiting anti-correlated expression to the identified miRNAs. IPA pathway analysis suggested that miR-21 and FOXM1 cooperatively inhibit CDC25A, TOP2A and PRC1. We identified a mechanism for the temporary inhibition of VEGF during ovulation by TGFB1, miR-16-5p and miR-34a-5p. The linkage bioinformatics analysis between the libraries of the coding genes from our preliminary study with the newly generated library of regulatory miRNAs provides us a comprehensive, integrated overview of the miRNA-mRNA co-regulatory networks that may play a key role in controlling post-transcriptomic regulation of the ovulatory process.
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Affiliation(s)
- G M Yerushalmi
- Reproduction Lab and IVF Unit, Department of Obstetrics and Gynecology, Sheba Medical Center, 52662, Tel Hashomer, Affiliated with the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
| | - M Salmon-Divon
- Department of Molecular Biology, Ariel University, Ariel, Israel
| | - L Ophir
- Reproduction Lab and IVF Unit, Department of Obstetrics and Gynecology, Sheba Medical Center, 52662, Tel Hashomer, Affiliated with the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Y Yung
- Reproduction Lab and IVF Unit, Department of Obstetrics and Gynecology, Sheba Medical Center, 52662, Tel Hashomer, Affiliated with the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - M Baum
- Reproduction Lab and IVF Unit, Department of Obstetrics and Gynecology, Sheba Medical Center, 52662, Tel Hashomer, Affiliated with the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - G Coticchio
- Biogenesi, Reproductive Medicine Centre, Istituti Clinici Zucchi, Via Zucchi 24, 20052, Monza, Italy
| | - R Fadini
- Biogenesi, Reproductive Medicine Centre, Istituti Clinici Zucchi, Via Zucchi 24, 20052, Monza, Italy
| | - M Mignini-Renzini
- Biogenesi, Reproductive Medicine Centre, Istituti Clinici Zucchi, Via Zucchi 24, 20052, Monza, Italy
| | - M Dal Canto
- Biogenesi, Reproductive Medicine Centre, Istituti Clinici Zucchi, Via Zucchi 24, 20052, Monza, Italy
| | - R Machtinger
- Reproduction Lab and IVF Unit, Department of Obstetrics and Gynecology, Sheba Medical Center, 52662, Tel Hashomer, Affiliated with the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - E Maman
- Reproduction Lab and IVF Unit, Department of Obstetrics and Gynecology, Sheba Medical Center, 52662, Tel Hashomer, Affiliated with the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - A Hourvitz
- Reproduction Lab and IVF Unit, Department of Obstetrics and Gynecology, Sheba Medical Center, 52662, Tel Hashomer, Affiliated with the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
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Ling L, Feng X, Wei T, Wang Y, Wang Y, Zhang W, He L, Wang Z, Zeng Q, Xiong Z. Effects of low-intensity pulsed ultrasound (LIPUS)-pretreated human amnion-derived mesenchymal stem cell (hAD-MSC) transplantation on primary ovarian insufficiency in rats. Stem Cell Res Ther 2017; 8:283. [PMID: 29258619 PMCID: PMC5735876 DOI: 10.1186/s13287-017-0739-3] [Citation(s) in RCA: 61] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2017] [Revised: 11/26/2017] [Accepted: 11/29/2017] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Human amnion-derived mesenchymal stem cells (hAD-MSCs) have the features of mesenchymal stem cells (MSCs). Low-intensity pulsed ultrasound (LIPUS) can promote the expression of various growth factors and anti-inflammatory molecules that are necessary to keep the follicle growing and to reduce granulosa cell (GC) apoptosis in the ovary. This study aims to explore the effects of LIPUS-pretreated hAD-MSC transplantation on chemotherapy-induced primary ovarian insufficiency (POI) in rats. METHODS The animals were divided into control, POI, hAD-MSC treatment, and LIPUS-pretreated hAD-MSC treatment groups. POI rat models were established by intraperitoneal injection of cyclophosphamide (CTX). The hAD-MSCs isolated from the amnion were exposed to LIPUS or sham irradiation for 5 consecutive days and injected into the tail vein of POI rats. Expression and secretion of growth factors promoted by LIPUS in hAD-MSCs were detected by real-time quantitative polymerase chain reaction (RT-qPCR) and enzyme-linked immunosorbent assay (ELISA) in vitro. Estrous cycle, serum sex hormone levels, follicle counts, ovarian pathological changes, GC apoptosis, Bcl2 and Bax expression, and pro-inflammatory cytokine levels in ovaries were examined. RESULTS Primary hAD-MSCs were successfully isolated from the amnion. LIPUS promoted the expression and secretion of growth factors in hAD-MSCs in vitro. Both hAD-MSC and LIPUS-pretreated hAD-MSC transplantation increased the body and reproductive organ weights, improved ovarian function, and reduced reproductive organ injuries in POI rats. Transplantation of hAD-MSCs increased the Bcl-2/Bax ratio and reduced GC apoptosis and ovarian inflammation induced by chemotherapy in ovaries. These effects could be improved by pretreatment with LIPUS on hAD-MSCs. CONCLUSION Both hAD-MSC transplantation and LIPUS-pretreated hAD-MSC transplantation can repair ovarian injury and improve ovarian function in rats with chemotherapy-induced POI. LIPUS-pretreated hAD-MSC transplantation is more advantageous for reducing inflammation, improving the local microenvironment, and inhibiting GC apoptosis induced by chemotherapy in ovarian tissue of POI rats.
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Affiliation(s)
- Li Ling
- Department of Obstetrics and Gynecology, the Second Affiliated Hospital of Chongqing Medical University, No. 76, Linjiang Road, Chongqing, 400010 China
| | - Xiushan Feng
- Department of Obstetrics and Gynecology, the Second Affiliated Hospital of Chongqing Medical University, No. 76, Linjiang Road, Chongqing, 400010 China
| | - Tianqin Wei
- Department of Obstetrics and Gynecology, the Second Affiliated Hospital of Chongqing Medical University, No. 76, Linjiang Road, Chongqing, 400010 China
| | - Yan Wang
- State Key Laboratory of Ultrasound Engineering in Medicine Co-Founded by Chongqing and the Ministry of Science and Technology, Chongqing Key Laboratory of Biomedical Engineering, College of Biomedical Engineering, Chongqing Medical University, Chongqing, 400010 China
| | - Yaping Wang
- Department of Histology and Embryology, Laboratory of Stem Cell and Tissue Engineering, Chongqing Medical University, Chongqing, 400010 China
| | - Wenqian Zhang
- Department of Obstetrics and Gynecology, the Second Affiliated Hospital of Chongqing Medical University, No. 76, Linjiang Road, Chongqing, 400010 China
| | - Lianli He
- Department of Obstetrics and Gynecology, the Third Affiliated Hospital, Zunyi Medical College, Zunyi, 563000 Guizhou China
| | - Ziling Wang
- Department of Obstetrics and Gynecology, the Second Affiliated Hospital of Chongqing Medical University, No. 76, Linjiang Road, Chongqing, 400010 China
| | - Qianru Zeng
- Department of Obstetrics and Gynecology, the Second Affiliated Hospital of Chongqing Medical University, No. 76, Linjiang Road, Chongqing, 400010 China
| | - Zhengai Xiong
- Department of Obstetrics and Gynecology, the Second Affiliated Hospital of Chongqing Medical University, No. 76, Linjiang Road, Chongqing, 400010 China
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9
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Bahrami A, Shahidsales S, Khazaei M, Ghayour-Mobarhan M, Maftouh M, Hassanian SM, Avan A. C-Met as a potential target for the treatment of gastrointestinal cancer: Current status and future perspectives. J Cell Physiol 2017; 232:2657-2673. [PMID: 28075018 DOI: 10.1002/jcp.25794] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2017] [Accepted: 01/10/2017] [Indexed: 01/05/2025]
Abstract
Aberrant activation of the HGF/c-Met signalling pathways is shown to be related with cell proliferation, progression, metastasis, and worse prognosis in several tumor types, including gastrointestinal cancers, suggesting its value as a stimulating-target for cancer-therapy. Several approaches have been developed for targeting HGF and/or c-Met, and one of them, crizotinib (dual c-Met/ALK inhibitor), is recently been approved by FDA for lung-cancers with ALK-rearrangement. The main aim of current review is to give an overview on the role of c-Met/HGF pathway in gastrointestinal cancer, in preclinical and clinical trials. Although several important matters is still remained to be elucidated on the molecular pathways underlying the antitumor effects of this therapy in gastrointestinal-cancers. Further investigations are warranted to recognize the main determinants of the activity of c-Met inhibitors, for parallel targeting signalling pathway associated/activated via MET/HGF pathway or in response to the cell resistance to anti-c-Met agents. Additionally, identification of patients that might benefit from therapy could help to increase the selectivity and efficacy of the therapy.
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Affiliation(s)
- Afsane Bahrami
- Molecular Medicine Group, Department of Modern Sciences and Technology, Mashhad University of Medical Sciences, Mashhad, Iran
- Student Research Center, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Soodabeh Shahidsales
- Cancer Research Center, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Majid Khazaei
- Neurogenic Inflammatory Research Center and Department of Physiology, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Majid Ghayour-Mobarhan
- Metabolic syndrome Research Center, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mina Maftouh
- Metabolic syndrome Research Center, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Seyed Mahdi Hassanian
- Metabolic syndrome Research Center, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Medical Biochemistry, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amir Avan
- Metabolic syndrome Research Center, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
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Chapin RE, Winton T, Nowland W, Danis N, Kumpf S, Johnson K, Coburn A, Stukenborg JB. Lost in translation: The search for an in vitro screen for spermatogenic toxicity. ACTA ACUST UNITED AC 2016; 107:225-242. [DOI: 10.1002/bdrb.21188] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2016] [Revised: 11/18/2016] [Accepted: 11/18/2016] [Indexed: 11/07/2022]
Affiliation(s)
- Robert E. Chapin
- Developmental and Reproductive Toxicology Center of Expertise; Pfizer Worldwide R&D (WRD); Groton CT USA
| | - Timothy Winton
- Developmental and Reproductive Toxicology Center of Expertise; Pfizer Worldwide R&D (WRD); Groton CT USA
| | - William Nowland
- Developmental and Reproductive Toxicology Center of Expertise; Pfizer Worldwide R&D (WRD); Groton CT USA
| | - Nichole Danis
- Developmental and Reproductive Toxicology Center of Expertise; Pfizer Worldwide R&D (WRD); Groton CT USA
- Histopathology Laboratory; WRD; Groton CT USA
| | - Steven Kumpf
- Developmental and Reproductive Toxicology Center of Expertise; Pfizer Worldwide R&D (WRD); Groton CT USA
| | - Kjell Johnson
- Developmental and Reproductive Toxicology Center of Expertise; Pfizer Worldwide R&D (WRD); Groton CT USA
- Arbor Analytics; Ann Arbor MI USA
| | - Aleasha Coburn
- Developmental and Reproductive Toxicology Center of Expertise; Pfizer Worldwide R&D (WRD); Groton CT USA
| | - Jan-Bernd Stukenborg
- Department of Women's and Children's Health; Karolinska Institutet; Stockholm Sweden
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11
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Wen Q, Cheng CY, Liu YX. Development, function and fate of fetal Leydig cells. Semin Cell Dev Biol 2016; 59:89-98. [PMID: 26968934 PMCID: PMC5016207 DOI: 10.1016/j.semcdb.2016.03.003] [Citation(s) in RCA: 88] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2016] [Accepted: 03/01/2016] [Indexed: 12/21/2022]
Abstract
During fetal testis development, fetal Leydig cells (FLCs) are found to be originated from multiple progenitor cells. FLC specification and function are under tight regulation of specific genes and signaling proteins. Furthermore, Sertoli cells play a crucial role to regulate FLC differentiation during fetal testis development. FLC progenitor- and FLC-produced biomolecules are also involved in the differentiation and activity of rodent FLCs. The main function of FLCs is to produce androgens to masculinize XY embryos. However, FLCs are capable of producing androstenedione but not testosterone due to the lack of 17β-HSD (17β-hydroxysteroid dehydrogenase), but fetal Sertoli cells express 17β-HSD which thus transforms androstenedione to testosterone in the fetal testis. On the other hand, FLCs produce activin A to regulate Sertoli cell proliferation, and Sertoli cells in turn modulate testis cord expansion. It is now generally accepted that adult Leydig cells (ALCs) gradually replace FLCs during postnatal development to produce testosterone to support spermatogenesis as FLCs undergo degeneration in neonatal and pre-pubertal testes. However, based on studies using genetic tracing mouse models, FLCs are found to persist in adult testes, making up ∼20% of total Leydig cells. In this review, we evaluate the latest findings regarding the development, function and fate of FLCs during fetal and adult testis development.
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Affiliation(s)
- Qing Wen
- State Key Laboratory of Stem Cells and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing, 100049, China
| | - C Yan Cheng
- The Mary M. Wohlford Laboratory for Male Contraceptive Research, Center for Biomedical Research, Population Council, New York, New York 10065, United States.
| | - Yi-Xun Liu
- State Key Laboratory of Stem Cells and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing, 100049, China.
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12
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Kwon Y, Godwin AK. Regulation of HGF and c-MET Interaction in Normal Ovary and Ovarian Cancer. Reprod Sci 2016; 24:494-501. [PMID: 27170665 DOI: 10.1177/1933719116648212] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Binding of hepatocyte growth factor (HGF) to the c-MET receptor has mitogenic, motogenic, and morphogenic effects on cells. The versatile biological effects of HGF and c-MET interactions make them important contributors to the development of malignant tumors. We and others have demonstrated a therapeutic value in targeting the interaction of c-MET and HGF in epithelial ovarian cancer (EOC). However, both HGF and c-MET are expressed in the normal ovary as well. Therefore, it is important to understand the differences in mechanisms that control HGF signaling activation and its functional role in the normal ovary and EOC. In the normal ovary, HGF signaling may be under hormonal regulation. During ovulation, HGF-converting proteases are secreted and the subsequent activation of HGF signaling enhances the proliferation of ovarian surface epithelium in order to replenish the area damaged due to expulsion of the ovum. In contrast, EOC cells that exhibit epithelial characteristics constitutively express both c-MET and HGF-converting proteases such as urokinase-type plasminogen activator. In EOC, mechanisms to control the activation of HGF signaling are absent since HGF is provided locally from the tissue microenvironment as well as remotely throughout the body. Potential incessant HGF signaling in EOC may lead to an increase in proliferation, invasion through the stroma, and migration to other tissues of cancer cells. Therefore, targeting the interaction of c-MET and HGF would be beneficial in treating EOC.
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Affiliation(s)
- Youngjoo Kwon
- 1 Department of Food Science and Engineering, Ewha Womans University, Seoul, Korea
| | - Andrew K Godwin
- 2 Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, USA.,3 University of Kansas Cancer Center, Kansas City, KS, USA
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13
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Sargis RM, Salgia R. Multiple Endocrine Disruption by the MET/ALK Inhibitor Crizotinib in Patients With Non-small Cell Lung Cancer. Am J Clin Oncol 2016; 38:442-7. [PMID: 23934135 DOI: 10.1097/coc.0b013e3182a46896] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
OBJECTIVES Non-small cell lung cancer (NSCLC) is a heterogenous group of disorders that can be subclassified based upon molecular characterization. Anaplastic lymphoma kinase translocation and MET aberrations occur in a subset of NSCLC. Anaplastic lymphoma kinase/MET have been shown to be inhibited by the small molecule tyrosine kinase inhibitor crizotinib. Recently, crizotinib was shown to decrease testosterone in males. Herein, we describe the effects of crizotinib on multiple hormonal axes. MATERIALS AND METHODS Seven consecutive patients with NSCLC who were receiving crizotinib as part of their standard care were evaluated for hormonal disruptions. RESULTS Primary hypogonadism was detected in 4/5 of males, whereas mildly elevated prolactin was observed in 4/7 patients. Hypocalcemia was observed in 3/7 patients. Interestingly, 5/7 patients had elevated levels of insulin-like growth factor-1 (IGF-1) levels, and the remaining 2 individuals had levels that were near the upper limits of the normal range. CONCLUSIONS Because of cellular cross-talk between MET and IGF-1 signaling, elevated IGF-1 levels induced by crizotinib treatment may have implications for long-term drug efficacy. Furthermore, this finding suggests a potential avenue of therapeutic synergy, namely coordinate inhibition of the MET and IGF-1 signaling pathways. Finally, as crizotinib has been recently approved, it is prudent to check hormone and calcium biomarkers and correct noted deficiencies for improved outcomes and quality of life.
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Affiliation(s)
- Robert M Sargis
- *Section of Endocrinology, Diabetes, and Metabolism †Section of Hematology and Oncology, Department of Medicine, University of Chicago, Chicago, IL
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14
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Zama AM, Bhurke A, Uzumcu M. Effects of Endocrine-disrupting Chemicals on Female Reproductive Health. ACTA ACUST UNITED AC 2016. [DOI: 10.2174/1874070701610010054] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Endocrine-disrupting chemicals (EDCs) are increasingly prevalent in the environment and the evidence demonstrates that they affect reproductive health, has been accumulating for the last few decades. In this review of recent literature, we present evidence of the effects of estrogen-mimicking EDCs on female reproductive health especially the ovaries and uteri. As representative EDCs, data from studies with a pharmaceutical estrogen, diethylstilbestrol (DES), an organochlorine pesticide methoxychlor (MXC), a phytoestrogen (genistein), and a chemical used in plastics, bisphenol a (BPA) have been presented. We also discuss the effects of a commonly found plasticizer in the environment, a phthalate (DEHP), even though it is not a typical estrogenic EDC. Collectively, these studies show that exposures during fetal and neonatal periods cause developmental reprogramming leading to adult reproductive disease. Puberty, estrous cyclicity, ovarian follicular development, and uterine functions are all affected by exposure to these EDCs. Evidence that epigenetic modifications are involved in the progression to adult disease is also presented.
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15
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Hepatocyte growth factor activator is a potential target proteinase for Kazal-type inhibitor in turkey ( Meleagris gallopavo ) seminal plasma. Theriogenology 2015; 84:425-436.e3. [DOI: 10.1016/j.theriogenology.2015.03.026] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2014] [Revised: 03/24/2015] [Accepted: 03/26/2015] [Indexed: 11/22/2022]
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16
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Girard A, Dufort I, Douville G, Sirard MA. Global gene expression in granulosa cells of growing, plateau and atretic dominant follicles in cattle. Reprod Biol Endocrinol 2015; 13:17. [PMID: 25879740 PMCID: PMC4355352 DOI: 10.1186/s12958-015-0010-7] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2014] [Accepted: 02/13/2015] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND The physiological state of the dominant follicle is important as it may be linked to the competence of the oocyte within. The objective of this study was to analyze, by transcriptomic analysis, the changes occurring in granulosa cells from dominant follicles at different phases of follicular growth. METHODS Granulosa cells were collected from slaughterhouse dairy cattle follicles with a diameter greater than 9 mm, and were classified at different phases of follicle growth based on flow cytometry profiles of DNA content after staining with propidium iodide. Three phases were identified based on the proportion of cells in -G1 (less than 2n DNA), G0-G1 (2n DNA) or S-M (more than 2n DNA) and follicles were thus allocated to the growing, plateau or atresia group. Between group analysis (BGA) showed clear segregation of the three groups, and the groups were contrasted against each other in a loop design to identify differently expressed genes. Ingenuity Pathway Analysis (IPA) was used to identify the functions and upstream regulators associated with the observed differently expressed genes. RESULTS Major differences were observed between the growth phases. Granulosa cells from follicles in the plateau phase had increased expression of TYRO3 and downregulation of JAM2 compared to growing follicles, supporting the idea of a shift from proliferation to differentiation. On the other hand, genes regulating the response to oxidative stress (VNN1) and angiogenesis (ANGPT2) were upregulated in granulosa cells from atretic follicles. While the predicted activated functions in cells at the plateau stage compared to cells at the growing stage included synthesis and transport of molecules, the predictions for atretic follicles relative to plateau ones included an increase in apoptosis and cell death. CONCLUSION Consistent with previous studies, these observations allowed us to match the presence of specific gene transcripts to a particular physiological status and consequently to classify follicles. The results also demonstrated that the plateau phase is not a simple 'in between' status between growth and atresia, as several characteristics are unique to this stage.
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Affiliation(s)
- Annie Girard
- Département des Sciences Animales, Pavillon INAF, Faculté des Sciences de l'Agriculture et de l'Alimentation, Centre de Recherche en Biologie de la Reproduction (CRBR), Université Laval, Québec, Québec, G1V 0A6, Canada.
| | - Isabelle Dufort
- Département des Sciences Animales, Pavillon INAF, Faculté des Sciences de l'Agriculture et de l'Alimentation, Centre de Recherche en Biologie de la Reproduction (CRBR), Université Laval, Québec, Québec, G1V 0A6, Canada.
| | - Gabriel Douville
- Département des Sciences Animales, Pavillon INAF, Faculté des Sciences de l'Agriculture et de l'Alimentation, Centre de Recherche en Biologie de la Reproduction (CRBR), Université Laval, Québec, Québec, G1V 0A6, Canada.
| | - Marc-André Sirard
- Département des Sciences Animales, Pavillon INAF, Faculté des Sciences de l'Agriculture et de l'Alimentation, Centre de Recherche en Biologie de la Reproduction (CRBR), Université Laval, Québec, Québec, G1V 0A6, Canada.
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17
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Mungunsukh O, McCart EA, Day RM. Hepatocyte Growth Factor Isoforms in Tissue Repair, Cancer, and Fibrotic Remodeling. Biomedicines 2014; 2:301-326. [PMID: 28548073 PMCID: PMC5344272 DOI: 10.3390/biomedicines2040301] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2014] [Revised: 10/21/2014] [Accepted: 10/27/2014] [Indexed: 01/18/2023] Open
Abstract
Hepatocyte growth factor (HGF), also known as scatter factor (SF), is a pleotropic factor required for normal organ development during embryogenesis. In the adult, basal expression of HGF maintains tissue homeostasis and is up-regulated in response to tissue injury. HGF expression is necessary for the proliferation, migration, and survival of epithelial and endothelial cells involved in tissue repair in a variety of organs, including heart, lung, kidney, liver, brain, and skin. The administration of full length HGF, either as a protein or using exogenous expression methodologies, increases tissue repair in animal models of tissue injury and increases angiogenesis. Full length HGF is comprised of an N-terminal hairpin turn, four kringle domains, and a serine protease-like domain. Several naturally occurring alternatively spliced isoforms of HGF were also identified. The NK1 variant contains the N-terminal hairpin and the first kringle domain, and the NK2 variant extends through the second kringle domain. These alternatively spliced forms of HGF activate the same receptor, MET, but they differ from the full length protein in their cellular activities and their biological functions. Here, we review the species-specific expression of the HGF isoforms, their regulation, the signal transduction pathways they activate, and their biological activities.
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Affiliation(s)
- Ognoon Mungunsukh
- Department of Pharmacology, Uniformed Services University of the Health Sciences, Bethesda, MD 20814-4799, USA.
| | - Elizabeth A McCart
- Department of Pharmacology, Uniformed Services University of the Health Sciences, Bethesda, MD 20814-4799, USA.
| | - Regina M Day
- Department of Pharmacology, Uniformed Services University of the Health Sciences, Bethesda, MD 20814-4799, USA.
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18
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Ricci G, Catizone A. Pleiotropic Activities of HGF/c-Met System in Testicular Physiology: Paracrine and Endocrine Implications. Front Endocrinol (Lausanne) 2014; 5:38. [PMID: 24772104 PMCID: PMC3982073 DOI: 10.3389/fendo.2014.00038] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2013] [Accepted: 03/14/2014] [Indexed: 01/28/2023] Open
Abstract
In the last decades, a growing body of evidence has been reported concerning the expression and functional role of hepatocyte growth factor (HGF) on different aspects of testicular physiology. This review has the aim to summarize what is currently known regarding this topic. From early embryonic development to adult age, HGF and its receptor c-Met appeared to be clearly detectable in the testis. These molecules acquire different distribution patterns and roles depending on the developmental stage or the post-natal age considered. HGF acts as a paracrine modulator of testicular functions promoting the epithelium-mesenchyme cross-talk as described even in other organs. Interestingly, it has been reported that testicular HGF acts even as an autocrine factor and that its receptor might be modulated by endocrine signals that change at puberty: HGF receptor expressed by Sertoli cells, in fact, is up-regulated by FSH administration. HGF is in turn able to modify endocrine state of the organism being able to increase testosterone secretion of both fetal and adult Leydig cells. Moreover, c-Met is expressed in mitotic and meiotic male germ cells as well as in spermatozoa. The distribution pattern of c-Met on sperm cell membrane changes in the caput and cauda epididymal sperms and HGF is able to maintain epididymal sperm motility in vitro suggesting a physiological role of this growth factor in the acquisition of sperm motility. Noteworthy changes in HGF concentration in seminal plasma have been reported in different andrological diseases. All together these data indicate that HGF has a role in the control of spermatogenesis and sperm quality either directly, acting on male germ cells, or indirectly acting on tubular and interstitial somatic cells of the testis.
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Affiliation(s)
- Giulia Ricci
- Department of Experimental Medicine, School of Medicine, Second University of Naples, Naples, Italy
| | - Angela Catizone
- Department of Anatomy Histology, Forensic Medicine and Orthopedics, School of Medicine, “Sapienza” University of Rome, Rome, Italy
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Sambroni E, Lareyre JJ, Le Gac F. Fsh controls gene expression in fish both independently of and through steroid mediation. PLoS One 2013; 8:e76684. [PMID: 24194844 PMCID: PMC3806798 DOI: 10.1371/journal.pone.0076684] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2013] [Accepted: 08/29/2013] [Indexed: 01/07/2023] Open
Abstract
The mechanisms and the mediators relaying Fsh action on testicular functions are poorly understood. Unlike in mammals, in fish both gonadotropins (Fsh and Lh) are able to efficiently stimulate steroidogenesis, likely through a direct interaction with their cognate receptors present on the Leydig cells. In this context, it is crucial to understand if Fsh effects are mediated through the production of steroids. To address this issue we performed transcriptome studies after in vitro incubations of rainbow trout testis explants in the presence of Fsh alone or in combination with trilostane, an inhibitor of Δ4- steroidogenesis. Trilostane significantly reduced or suppressed the response of many genes to Fsh (like wisp1, testis gapdhs, cldn11, inha, vt1 or dmrt1) showing that, in fish, important aspects of Fsh action follow indirect pathways and require the production of Δ4-steroids. What is more, most of the genes regulated by Fsh through steroid mediation were similarly regulated by Lh (and/or androgens). In contrast, the response to Fsh of other genes was not suppressed in the presence of trilostane. These latter included genes encoding for anti-mullerian hormone, midkine a (pleiotrophin related), angiopoietine-related protein, cyclins E1 and G1, hepatocyte growth factor activator, insulin-like growth factor 1b/3. A majority of those genes were preferentially regulated by Fsh, when compared to Lh, suggesting that specific regulatory effects of Fsh did not depend on steroid production. Finally, antagonistic effects between Fsh and steroids were found, in particular for genes encoding key factors of steroidogenesis (star, hsd3b1, cyp11b2-2) or for genes of the Igf system (igf1b/3). Our study provides the first clear evidence that, in fish, Fsh exerts Δ4-steroid-independent regulatory functions on many genes which are highly relevant for the onset of spermatogenesis.
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Affiliation(s)
- Elisabeth Sambroni
- INRA, UR1037 LPGP, Testicular Physiology and Puberty, SFR BIOSIT, Biogenouest, Campus de Beaulieu, Rennes, France
| | - Jean-Jacques Lareyre
- INRA, UR1037 LPGP, Testicular Physiology and Puberty, SFR BIOSIT, Biogenouest, Campus de Beaulieu, Rennes, France
| | - Florence Le Gac
- INRA, UR1037 LPGP, Testicular Physiology and Puberty, SFR BIOSIT, Biogenouest, Campus de Beaulieu, Rennes, France
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Guvendag Guven ES, Dilbaz S, Duraker R, Mentese A, Cinar O, Ozdegirmenci O. The effect of cabergoline on folicular microenviroment profile in patients with high risk of OHSS. Gynecol Endocrinol 2013; 29:749-53. [PMID: 23741965 DOI: 10.3109/09513590.2013.801440] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
The aim of this study to evaluate the effect of cabergoline on follicular microenvironment by measuring follicular fluid (FF) insulin like growth hormone -I (IGF-I), antimullerian hormone (AMH), inhibin B and hepatocyte growth factor (HGF) levels in women with PCOS and high risk of ovarian hyperstimulation syndrome (OHSS). In this prospective cohort study, 41 women with PCOS undergoing controlled ovarian hyperstimulation for assisted reproduction and having the high risk factors for OHSS are included. The women in the study group (n = 15) received cabergoline for OHSS prevention while the women in the control did not received any medications for OHSS prevention. FF samples were collected during oocyte pick-up procedure for all women were determined using commercially available ELISA kits. Concentrations of FF IGF-I, AMH, inhibin B and HGF were assessed. In the study group FF AMH (2.96 ± 1.27 versus 1.91 ± 0.64 ng/mL), Inhibin B (1339.47 ± 198.56 versus 1200.09 ± 133.64 pg/mL), HGF (5623.21 ± 2411.09 versus 3787.42 ± 2269.89 pg/mL) and IGF-I (298.60 ± 37.80 versus 219.90 ± 71.40 pg/mL) concentrations were significantly decreased compared with control group. Cabergolin prevents OHSS in high risk patients by disrupting FF hormone microenvironment.
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Affiliation(s)
- Emine Seda Guvendag Guven
- Department of Obstetrics and Gynecology, Recep Tayyip Erdogan University, Faculty of Medicine, Rize, Turkey.
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Ricci G, Guglielmo MC, Caruso M, Ferranti F, Canipari R, Galdieri M, Catizone A. Hepatocyte Growth Factor Is a Mouse Fetal Leydig Cell Terminal Differentiation Factor1. Biol Reprod 2012; 87:146. [DOI: 10.1095/biolreprod.112.104638] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/01/2022] Open
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Wright JW, Harding JW. Importance of the brain Angiotensin system in Parkinson's disease. PARKINSON'S DISEASE 2012; 2012:860923. [PMID: 23213621 PMCID: PMC3503402 DOI: 10.1155/2012/860923] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/09/2012] [Revised: 10/01/2012] [Accepted: 10/02/2012] [Indexed: 11/17/2022]
Abstract
Parkinson's disease (PD) has become a major health problem affecting 1.5% of the world's population over 65 years of age. As life expectancy has increased so has the occurrence of PD. The primary direct consequence of this disease is the loss of dopaminergic (DA) neurons in the substantia nigra and striatum. As the intensity of motor dysfunction increases, the symptomatic triad of bradykinesia, tremors-at-rest, and rigidity occur. Progressive neurodegeneration may also impact non-DA neurotransmitter systems including cholinergic, noradrenergic, and serotonergic, often leading to the development of depression, sleep disturbances, dementia, and autonomic nervous system failure. L-DOPA is the most efficacious oral delivery treatment for controlling motor symptoms; however, this approach is ineffective regarding nonmotor symptoms. New treatment strategies are needed designed to provide neuroprotection and encourage neurogenesis and synaptogenesis to slow or reverse this disease process. The hepatocyte growth factor (HGF)/c-Met receptor system is a member of the growth factor family and has been shown to protect against degeneration of DA neurons in animal models. Recently, small angiotensin-based blood-brain barrier penetrant mimetics have been developed that activate this HGF/c-Met system. These compounds may offer a new and novel approach to the treatment of Parkinson's disease.
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Affiliation(s)
- John W. Wright
- Departments of Psychology, Veterinary and Comparative Anatomy, Pharmacology, and Physiology and Programs in Neuroscience and Biotechnology, Washington State University, P.O. Box 644820, Pullman, WA 99164-4820, USA
| | - Joseph W. Harding
- Departments of Psychology, Veterinary and Comparative Anatomy, Pharmacology, and Physiology and Programs in Neuroscience and Biotechnology, Washington State University, P.O. Box 644820, Pullman, WA 99164-4820, USA
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Zama AM, Uzumcu M. Epigenetic effects of endocrine-disrupting chemicals on female reproduction: an ovarian perspective. Front Neuroendocrinol 2010; 31:420-39. [PMID: 20609371 PMCID: PMC3009556 DOI: 10.1016/j.yfrne.2010.06.003] [Citation(s) in RCA: 103] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2010] [Revised: 06/16/2010] [Accepted: 06/25/2010] [Indexed: 01/16/2023]
Abstract
The link between in utero and neonatal exposure to environmental toxicants, such as endocrine-disrupting chemicals (EDCs) and adult female reproductive disorders is well established in both epidemiological and animal studies. Recent studies examining the epigenetic mechanisms involved in mediating the effects of EDCs on female reproduction are gathering momentum. In this review, we describe the developmental processes that are susceptible to EDC exposures in female reproductive system, with a special emphasis on the ovary. We discuss studies with select EDCs that have been shown to have physiological and correlated epigenetic effects in the ovary, neuroendocrine system, and uterus. Importantly, EDCs that can directly target the ovary can alter epigenetic mechanisms in the oocyte, leading to transgenerational epigenetic effects. The potential mechanisms involved in such effects are also discussed.
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Affiliation(s)
- Aparna Mahakali Zama
- Department of Animal Sciences, School of Environmental and Biological Sciences, Rutgers, The State University of New Jersey, New Brunswick, NJ 08901-8525, USA
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Knudsen BS, Vande Woude G. Showering c-MET-dependent cancers with drugs. Curr Opin Genet Dev 2008; 18:87-96. [PMID: 18406132 DOI: 10.1016/j.gde.2008.02.001] [Citation(s) in RCA: 121] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2008] [Accepted: 02/05/2008] [Indexed: 11/18/2022]
Abstract
The receptor tyrosine kinase, c-MET and its ligand hepatocyte growth factor/scatter factor (HGF/SF) have become leading candidates for targeted cancer therapies. Inappropriate c-MET signaling through autocrine, paracrine, amplification, and mutational activation occurs in virtually all types of solid tumors (http://www.vai.org/met), contributing to one or a combination of proliferative, invasive, survival, or angiogenic cancer phenotypes. c-MET and HGF/SF participate in all stages of malignant progression and represent promising drug targets in a variety of cancer types, including carcinomas, sarcomas, and brain tumors. While many are in pre-clinical testing, a few inhibitors have entered clinical trials. With hundreds of thousands of potential responding cancers that express c-MET, the interest in this molecule as a drug target is not surprising. However, the cognate c-MET diagnostic tests lag behind. In addition, despite the great enthusiasm based on response rates in phase I trials, there is a need for caution. It is almost without question that combination therapies with c-MET-HGF/SF inhibitors will be required for most cancers to achieve a cytotoxic tumor response.
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Affiliation(s)
- Beatrice S Knudsen
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue, Seattle, WA 98109, United States
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