Role of the Hedgehog Signaling Pathway in Regulating the Behavior of Germline Stem Cells

Li, Shiqin; Wang, Meng; Chen, Yanghui; Wang, Wei; Wu, Junying; Yu, Chengpeng; Zheng, Yuehui; Pan, Zezheng

doi:10.1155/2017/5714608

Cited by 16 publications

(9 citation statements)

References 77 publications

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“…15 This also provides a novel strategy for preserving fertility. While several studies recently revealed the regulatory mechanisms underlying FGSC differentiation, 3,[16][17][18][19][20] proliferation, 4,[21][22][23][24] and apoptosis, 21,25 which are considered crucial for female fertility, other biological processes such as autophagy and its mechanism in FGSCs are largely unknown, and the use of small compounds may help us to understand them further.…”

Section: Introductionmentioning

confidence: 99%

GAS5/miR-21 Axis as a Potential Target to Rescue ZCL-082-Induced Autophagy of Female Germline Stem Cells In Vitro

Yang

et al. 2019

Molecular Therapy - Nucleic Acids

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Several studies have recently revealed the regulatory mechanisms underlying female germline stem cell (FGSC) differentiation, proliferation, and apoptosis, but other biological processes such as autophagy and its mechanism in FGSCs are largely unclear. The use of small chemical compounds may be a good approach to further investigate the process and mechanism of autophagy in FGSC development. In this study, we used ZCL-082, a derivative of benzoxaboroles, to treat FGSCs. Using a cell counting kit-8 (CCK8) and 5-ethynyl-2′-deoxyuridine (EdU) assays, we found that ZCL-082 could significantly reduce the viability, proliferation, and number of FGSCs in vitro . Moreover, western blotting revealed that the expression of light chain 3 beta 2 (LC3B-II) in FGSCs was significantly increased after treatment with ZCL-082 for 3 and 6 h. Meanwhile, the expression of sequestosome-1 (SQSTM1) was significantly decreased. These results suggested that ZCL-082 can induce autophagy of FGSCs in vitro . Regarding the molecular mechanism, ZCL-082 could significantly reduce the expression of growth arrest-specific 5 ( GAS5 ) long non-coding RNA, which could directly bind to microRNA-21a ( miR-21a ) and negatively regulate each other in FGSCs. Knockdown of GAS5 induced the autophagy of FGSCs, while GAS5 overexpression inhibited the autophagy of FGSCs in vitro and rescued FGSC autophagy induced by ZCL-082. Additionally, overexpression of miR-21a significantly enhanced LC3B-II protein expression while significantly reducing the expression of programmed cell death protein 4 (PDCD4) and SQSTM1 protein in FGSCs compared with control cells. The inhibition of miR-21a significantly reduced the basal or ZCL-082-induced upregulated expression of LC3B-II, and it significantly enhanced the expression of PDCD4 while downregulating the basal or ZCL-082-induced expression of SQSTM1 in FGSCs. Furthermore, the overexpression of GAS5 enhanced the protein expression of PDCD4, but knockdown of GAS5 reduced the protein expression of PDCD4. Taken together, these results suggested that ZCL-082 induced autophagy through GAS5 functioning as a competing endogenous RNA (ceRNA) sponge for miR-21a in FGSCs. It also suggested that the GAS5 / miR-21a axis may be a potential therapeutic target for premature ovarian failure in the clinic.

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Section: Introductionmentioning

confidence: 99%

GAS5/miR-21 Axis as a Potential Target to Rescue ZCL-082-Induced Autophagy of Female Germline Stem Cells In Vitro

Yang

et al. 2019

Molecular Therapy - Nucleic Acids

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“…Previous studies showed that there are multiple signaling pathways involved in the proliferation and differentiation of OGSCs, and the occurrence of the decline of ovarian function maybe associated with the loss of OGSCs. Supplementation of OGSCs may have a role in remodeling ovarian function [ 41 – 43 ]. These findings have important implications for the reproductive capacity of female mammals and the treatment of germ cell-related diseases, and provide new directions for the treatment of ovarian function decline after chemotherapy for scientists.…”

Section: Discussionmentioning

confidence: 99%

The role of Chito-oligosaccharide in regulating ovarian germ stem cells function and restoring ovarian function in chemotherapy mice

Huang

Zhu

et al. 2021

Reprod Biol Endocrinol

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In recent years, the discovery of ovarian germ stem cells (OGSCs) has provided a new research direction for the treatment of female infertility. The ovarian microenvironment affects the proliferation and differentiation of OGSCs, and immune cells and related cytokines are important components of the microenvironment. However, whether improving the ovarian microenvironment can regulate the proliferation of OGSCs and remodel ovarian function has not been reported. In this study, we chelated chito-oligosaccharide (COS) with fluorescein isothiocyanate (FITC) to track the distribution of COS in the body. COS was given to mice through the best route of administration, and the changes in ovarian and immune function were detected using assays of organ index, follicle counting, serum estrogen (E2) and anti-Mullerian hormone (AMH) levels, and the expression of IL-2 and TNF-α in the ovaries. We found that COS significantly increased the organ index of the ovary and immune organs, reduced the rate of follicular atresia, increased the levels of E2 and AMH hormones, and increased the protein expression of IL-2 and TNF-α in the ovary. Then, COS and OGSCs were co-cultured to observe the combination of COS and OGSCs, and measure the survival rate of OGSCs. With increasing time, the fluorescence intensity of cells gradually increased, and the cytokines IL-2 and TNF-α significantly promoted the proliferation of OGSCs. In conclusion, COS could significantly improve the ovarian and immune function of chemotherapy model mice, and improve the survival rate of OGSCs, which provided a preliminary blueprint for further exploring the mechanism of COS in protecting ovarian function.

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“…Because of its widespread distribution and expression in three key signalling centres in vertebrate embryos (the notochord, the floor plate and the zone of polarizing activity), Shh is the most extensively studied vertebrate Hh family member. Yet, all Hhs activate the same conserved signalling pathway downstream of Ptc receptors to regulate embryonic patterning in vertebrate and invertebrate embryos [ 19 , 20 ], as well as stem and progenitor cell populations in the adult [ 21 , 22 ]. Shh misexpression leads to several forms of cancer [ 23 ], and loss of Shh function causes developmental midline defects in mice, chicks and humans [ 24 , 25 , 26 , 27 ].…”

Section: Conserved Post-translational Hh Lipidationmentioning

confidence: 99%

Taking the Occam’s Razor Approach to Hedgehog Lipidation and Its Role in Development

Manikowski

Kastl

Grobe

2018

JDB

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All Hedgehog (Hh) proteins signal from producing cells to distant receiving cells despite being synthesized as N-and C-terminally lipidated, membrane-tethered molecules. To explain this paradoxical situation, over the past 15 years, several hypotheses have been postulated that tie directly into this property, such as Hh transport on cellular extensions called cytonemes or on secreted vesicles called lipophorins and exosomes. The alternative situation that tight membrane association merely serves to prevent unregulated Hh solubilization has been addressed by biochemical and structural studies suggesting Hh extraction from the membrane or proteolytic Hh release. While some of these models may act in different organisms, tissues or developmental programs, others may act together to specify Hh short- and long-range signaling in the same tissues. To test and rank these possibilities, we here review major models of Hh release and transport and hypothesize that the (bio)chemical and physical properties of firmly established, homologous, and functionally essential biochemical Hh modifications are adapted to specify and determine interdependent steps of Hh release, transport and signaling, while ruling out other steps. This is also described by the term “congruence”, meaning that the logical combination of biochemical Hh modifications can reveal their true functional implications. This combined approach reveals potential links between models of Hh release and transport that were previously regarded as unrelated, thereby expanding our view of how Hhs can steer development in a simple, yet extremely versatile, manner.

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Role of the Hedgehog Signaling Pathway in Regulating the Behavior of Germline Stem Cells

Cited by 16 publications

References 77 publications

GAS5/miR-21 Axis as a Potential Target to Rescue ZCL-082-Induced Autophagy of Female Germline Stem Cells In Vitro

GAS5/miR-21 Axis as a Potential Target to Rescue ZCL-082-Induced Autophagy of Female Germline Stem Cells In Vitro

The role of Chito-oligosaccharide in regulating ovarian germ stem cells function and restoring ovarian function in chemotherapy mice

Taking the Occam’s Razor Approach to Hedgehog Lipidation and Its Role in Development

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