scholarly journals FGF9, activin and TGFβ promote testicular characteristics in an XX gonad organ culture model

Reproduction ◽  
2016 ◽  
Vol 152 (5) ◽  
pp. 529-543 ◽  
Author(s):  
Sonja E Gustin ◽  
Jessica M Stringer ◽  
Kirsten Hogg ◽  
Andrew H Sinclair ◽  
Patrick S Western
Keyword(s):  
Growth Factors ◽  
Germ Line ◽  
Supporting Cell ◽  
Testicular Development ◽  
Male Germ Line ◽  
Testis Development ◽  
Culture Model ◽  
Determining Factors ◽  
Testis Cord

Testis development is dependent on the key sex-determining factors SRY and SOX9, which activate the essential ligand FGF9. Although FGF9 plays a central role in testis development, it is unable to induce testis formation on its own. However, other growth factors, including activins and TGFβs, also present testis during testis formation. In this study, we investigated the potential of FGF9 combined with activin and TGFβ to induce testis development in cultured XX gonads. Our data demonstrated differing individual and combined abilities of FGF9, activin and TGFβ to promote supporting cell proliferation, Sertoli cell development and male germ line differentiation in cultured XX gonads. FGF9 promoted proliferation of supporting cells in XX foetal gonads at rates similar to those observed in vivo during testis cord formation in XY gonads but was insufficient to initiate testis development. However, when FGF9, activin and TGFβ were combined, aspects of testicular development were induced, including the expression of Sox9, morphological reorganisation of the gonad and deposition of laminin around germ cells. Enhancing β-catenin activity diminished the testis-promoting activities of the combined growth factors. The male promoting activity of FGF9 and the combined growth factors directly or indirectly extended to the germ line, in which a mixed phenotype was observed. FGF9 and the combined growth factors promoted male germ line development, including mitotic arrest, but expression of pluripotency genes was maintained, rather than being repressed. Together, our data provide evidence that combined signalling by FGF9, activin and TGFβ can induce testicular characteristics in XX gonads.

scholarly journals Thyroid hormone action in the developing testis: intergenerational epigenetics

2020 ◽  
Vol 244 (3) ◽  
pp. R33-R46 ◽  
Author(s):  
Arturo Hernandez ◽  
M Elena Martinez
Keyword(s):  
Thyroid Hormone ◽  
Germ Line ◽  
Reproductive Hormones ◽  
Hormone Action ◽  
Next Generation ◽  
Male Germ Line ◽  
Epigenetic Information ◽  
Testis Development ◽  
Thyroid Hormone Action ◽  
Altered Thyroid

Male fertility involves the successful transmission of the genetic code to the next generation. It requires appropriately timed cellular processes during testis development, adequate support of spermatogenesis by hormonal cues from the reproductive axis and cellular cross-talk between germ and somatic cells. In addition to being the vessel of the father’s genome, increasing evidence shows that the mature sperm carries valuable epigenetic information – the epigenome – that, after fecundation, influences the development of the next generation, affecting biological traits and disease susceptibility. The epigenome of the germ line is susceptible to environmental factors, including exogenous chemicals and diet, but it is also affected by endogenous molecules and pathophysiological conditions. Factors affecting testis development and the epigenetic information of the germ line are critical for fertility and of relevance to the non-genetic but heritable component in the etiology of complex conditions. Thyroid hormones are one of those factors and their action, when untimely, produces profound effects on the developing testis, affecting spermatogenesis, steroidogenesis, testis size, reproductive hormones and fertility. Altered thyroid hormone states can also change the epigenetic information of the male germ line, with phenotypic consequences for future generations. In the context of past literature concerning the consequences of altered thyroid hormone action for testis development, here we review recent findings about the pathophysiological roles of the principal determinants of testicular thyroid hormone action. We also discuss limited work on the effects of thyroid hormone on the male germ line epigenome and the implications for the intergenerational transmission of phenotypes via epigenetic mechanisms.

Discrete cell- and stage-specific localisation of fibroblast growth factors and receptor expression during testis development

2000 ◽  
Vol 164 (2) ◽  
pp. 149-159 ◽  
Author(s):  
B Cancilla ◽  
A Davies ◽  
M Ford-Perriss ◽  
GP Risbridger
Keyword(s):  
Growth Factors ◽  
Expression Profiles ◽  
Fibroblast Growth Factors ◽  
Receptor Expression ◽  
Adjacent Cell ◽  
Testicular Development ◽  
Fibroblast Growth ◽  
Testis Development ◽  
Functional Variants ◽  
Alternative Mrna Splicing

Fibroblast growth factors (FGFs) are a family of heparin binding proteins involved in many biological processes. These growth factors act through tyrosine kinase receptors (FGFRs); we have previously used immunohistochemistry to study FGFRs-1-4 in foetal, immature and adult rat testes, and found a discrete cell- and stage-specific localisation. Alternative mRNA splicing of FGFRs-1-3 leads to functional variants (IIIb and IIIc) with distinct ligand binding affinities, therefore we have identified the specific expression of functional FGFR variants and the expression and localisation of FGF ligands in testes from foetal, immature and adult rats. Using reverse transcriptase-polymerase chain reaction (RT-PCR), we found that mRNAs for FGFR-1 IIIb and IIIc, FGFR-2 IIIc, FGFR-3 IIIc and FGFR-4 were expressed in foetal, immature and adult testes. Ligands FGFs-1-5, and -8, which can signal through these receptors, were also expressed in testes at each age. Localisation of the ligands FGFs-1, -3 and -4 to rat testes by immunohistochemistry showed a discrete cell- and stage-specific localisation that altered during testis development. This study has shown that the ligands FGFs-1, -3 and -4 are expressed in the testis and have the capacity to signal through appropriate receptors that are also co-localised or expressed in adjacent cell types in the testis. Collectively, the expression profiles of the seven FGFR variants and FGFs-1-5 and -8 suggest a functional importance in testicular development and spermatogenesis. It is concluded that, future studies on the role of other FGF ligands, in particular FGFs-1-4, are warranted.

Effect of Silver Nanoparticles on SRC Activity in Male Germ-line Stem Cells

2006 ◽  
Author(s):  
Laura K. Braydich-Stolle ◽  
Saber Hussain ◽  
John J. Schlager ◽  
Marie-Claude Hofmann
Keyword(s):  
Stem Cells ◽  
Silver Nanoparticles ◽  
Germ Line ◽  
Male Germ Line

scholarly journals Growth Factor Therapy for Parkinson’s Disease: Alternative Delivery Systems

2021 ◽  
pp. 1-7
Author(s):  
Sarah Jarrin ◽  
Abrar Hakami ◽  
Ben Newland ◽  
Eilís Dowd
Keyword(s):  
Parkinson’S Disease ◽  
Gene Therapy ◽  
Parkinson's Disease ◽  
Growth Factors ◽  
Growth Factor ◽  
Ex Vivo ◽  
Brain Regions ◽  
Delivery Systems ◽  
Alternative Delivery

Despite decades of research and billions in global investment, there remains no preventative or curative treatment for any neurodegenerative condition, including Parkinson’s disease (PD). Arguably, the most promising approach for neuroprotection and neurorestoration in PD is using growth factors which can promote the growth and survival of degenerating neurons. However, although neurotrophin therapy may seem like the ideal approach for neurodegenerative disease, the use of growth factors as drugs presents major challenges because of their protein structure which creates serious hurdles related to accessing the brain and specific targeting of affected brain regions. To address these challenges, several different delivery systems have been developed, and two major approaches—direct infusion of the growth factor protein into the target brain region and in vivo gene therapy—have progressed to clinical trials in patients with PD. In addition to these clinically evaluated approaches, a range of other delivery methods are in various degrees of development, each with their own unique potential. This review will give a short overview of some of these alternative delivery systems, with a focus on ex vivo gene therapy and biomaterial-aided protein and gene delivery, and will provide some perspectives on their potential for clinical development and translation.

Development of Testis Cords and the Formation of Efferent Ducts in Xenopus laevis: Differences and Similarities with Other Vertebrates

2021 ◽  
pp. 1-14
Author(s):  
Yuanyuan Li ◽  
Jinbo Li ◽  
Man Cai ◽  
Zhanfen Qin
Keyword(s):  
Cell Proliferation ◽  
Xenopus Laevis ◽  
Germ Cells ◽  
Sertoli Cells ◽  
Testis Development ◽  
Larval Stages ◽  
Efferent Ducts ◽  
Steroidogenic Cells ◽  
Testis Cord ◽  
Anterior Posterior

The knowledge of testis development in amphibians relative to amniotes remains limited. Here, we used Xenopus laevis to investigate the process of testis cord development. Morphological observations revealed the presence of segmental gonomeres consisting of medullary knots in male gonads at stages 52–53, with no distinct gonomeres in female gonads. Further observations showed that cell proliferation occurs at specific sites along the anterior-posterior axis of the future testis at stage 50, which contributes to the formation of medullary knots. At stage 53, adjacent gonomeres become close to each other, resulting in fusion; then (pre-)Sertoli cells aggregate and form primitive testis cords, which ultimately become testis cords when germ cells are present inside. The process of testis cord formation in X. laevis appears to be more complex than in amniotes. Strikingly, steroidogenic cells appear earlier than (pre-)Sertoli cells in differentiating testes of X. laevis, which differs from earlier differentiation of (pre-)Sertoli cells in amniotes. Importantly, we found that the mesonephros is connected to the testis gonomere at a specific site at early larval stages and that these connections become efferent ducts after metamorphosis, which challenges the previous concept that the mesonephric side and the gonadal side initially develop in isolation and then connect to each other in amphibians and amniotes.

scholarly journals Spontaneous Fusion of MSC with Breast Cancer Cells Can Generate Tumor Dormancy

2021 ◽  
Vol 22 (11) ◽  
pp. 5930
Author(s):  
Catharina Melzer ◽  
Juliane von der Ohe ◽  
Tianjiao Luo ◽  
Ralf Hass
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Tumor Development ◽  
Cellular Interactions ◽  
Hybrid Cells ◽  
Induced Tumors ◽  
Culture Model ◽  
Gene Expression Levels

Direct cellular interactions of MDA-MB-231cherry breast cancer cells with GFP-transduced human mesenchymal stroma/stem-like cells (MSCGFP) in a co-culture model resulted in spontaneous cell fusion by the generation of MDA-MSC-hyb5cherry GFP breast cancer hybrid cells. The proliferative capacity of MDA-MSC-hyb5 cells was enhanced about 1.8-fold when compared to the parental MDA-MB-231cherry breast cancer cells. In contrast to a spontaneous MDA-MB-231cherry induced tumor development in vivo within 18.8 days, the MDA-MSC-hyb5 cells initially remained quiescent in a dormancy-like state. At distinct time points after injection, NODscid mice started to develop MDA-MSC-hyb5 cell-induced tumors up to about a half year later. Following tumor initiation, however, tumor growth and formation of metastases in various different organs occurred rapidly within about 10.5 days. Changes in gene expression levels were evaluated by RNA-microarray analysis and revealed certain increase in dormancy-associated transcripts in MDA-MSC-hyb5. Chemotherapeutic responsiveness of MDA-MSC-hyb5 cells was partially enhanced when compared to MDA-MB-231 cells. However, some resistance, e.g., for taxol was detectable in cancer hybrid cells. Moreover, drug response partially changed during the tumor development of MDA-MSC-hyb5 cells; this suggests the presence of unstable in vivo phenotypes of MDA-hyb5 cells with increased tumor heterogeneity.

scholarly journals An integrated framework for quantifying immune-tumour interactions in a 3D co-culture model

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Gheed Al-Hity ◽  
FengWei Yang ◽  
Eduard Campillo-Funollet ◽  
Andrew E. Greenstein ◽  
Hazel Hunt ◽  
...  
Keyword(s):  
Immune System ◽  
Immune Cell ◽  
In Vitro Models ◽  
Proof Of Concept ◽  
Culture Model ◽  
Spheroid Growth ◽  
Confocal Images ◽  
Cancer Spheroids

AbstractInvestigational in vitro models that reflect the complexity of the interaction between the immune system and tumours are limited and difficult to establish. Herein, we present a platform to study the tumour-immune interaction using a co-culture between cancer spheroids and activated immune cells. An algorithm was developed for analysis of confocal images of the co-culture to evaluate the following quantitatively; immune cell infiltration, spheroid roundness and spheroid growth. As a proof of concept, the effect of the glucocorticoid stress hormone, cortisol was tested on 66CL4 co-culture model. Results were comparable to 66CL4 syngeneic in vivo mouse model undergoing psychological stress. Furthermore, administration of glucocorticoid receptor antagonists demonstrated the use of this model to determine the effect of treatments on the immune-tumour interplay. In conclusion, we provide a method of quantifying the interaction between the immune system and cancer, which can become a screening tool in immunotherapy design.

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