scholarly journals Loss of Mafb and Maf distorts myeloid cell ratios and disrupts fetal mouse testis vascularization and organogenesis

2021 ◽  
Author(s):  
Shu-Yun Li ◽  
Xiaowei Gu ◽  
Anna Heinrich ◽  
Emily G. Hurley ◽  
Blanche Capel ◽  
...  
Keyword(s):  
Sertoli Cells ◽  
Immune Cell ◽  
Gonad Development ◽  
Myeloid Cell ◽  
Cell Types ◽  
Double Knockout ◽  
Fetal Mouse ◽  
Testis Differentiation ◽  
Male Specific ◽  
Testis Cord

AbstractTestis differentiation is initiated when Sry in pre-Sertoli cells directs the gonad toward a male-specific fate. Sertoli cells are essential for testis development, but cell types within the interstitial compartment, such as immune and endothelial cells, are also critical for organ formation. Our previous work implicated macrophages in fetal testis morphogenesis, but little is known about genes underlying immune cell development during organogenesis. Here we examine the role of the immune-associated genes Mafb and Maf in mouse fetal gonad development, and we demonstrate that deletion of these genes leads to aberrant hematopoiesis manifested by supernumerary gonadal monocytes. Mafb;Maf double knockout embryos underwent initial gonadal sex determination normally, but exhibited testicular hypervascularization, testis cord formation defects, Leydig cell deficit, and a reduced number of germ cells. In general, Mafb and Maf alone were dispensable for gonad development; however, when both genes were deleted, we observed significant defects in testicular morphogenesis, indicating that Mafb and Maf work redundantly during testis differentiation. These results demonstrate previously unappreciated roles for Mafb and Maf in immune and vascular development and highlight the importance of interstitial cells in gonadal differentiation.Summary statementDeletion of Mafb and Maf genes leads to supernumerary monocytes in fetal mouse gonads, resulting in vascular, morphogenetic, and differentiation defects during testicular organogenesis.

scholarly journals Loss of Mafb and Maf distorts myeloid cell ratios and disrupts fetal mouse testis vascularization and organogenesis†

2021 ◽  
Author(s):  
Shu-Yun Li ◽  
Xiaowei Gu ◽  
Anna Heinrich ◽  
Emily G Hurley ◽  
Blanche Capel ◽  
...  
Keyword(s):  
Sertoli Cells ◽  
Immune Cell ◽  
Gonad Development ◽  
Myeloid Cell ◽  
Cell Types ◽  
Double Knockout ◽  
Testis Differentiation ◽  
Male Specific ◽  
Testis Cord

Abstract Testis differentiation is initiated when Sry in pre-Sertoli cells directs the gonad toward a male-specific fate. Sertoli cells are essential for testis development, but cell types within the interstitial compartment, such as immune and endothelial cells, are also critical for organ formation. Our previous work implicated macrophages in fetal testis morphogenesis, but little is known about genes underlying immune cell development during organogenesis. Here we examine the role of the immune-associated genes Mafb and Maf in mouse fetal gonad development, and we demonstrate that deletion of these genes leads to aberrant hematopoiesis manifested by supernumerary gonadal monocytes. Mafb; Maf double knockout embryos underwent initial gonadal sex determination normally, but exhibited testicular hypervascularization, testis cord formation defects, Leydig cell deficit, and a reduced number of germ cells. In general, Mafb and Maf alone were dispensable for gonad development; however, when both genes were deleted, we observed significant defects in testicular morphogenesis, indicating that Mafb and Maf work redundantly during testis differentiation. These results demonstrate previously unappreciated roles for Mafb and Maf in immune and vascular development and highlight the importance of interstitial cells in gonadal differentiation.

scholarly journals Mouse Gonad Development in the Absence of the Pro-Ovary Factor WNT4 and the Pro-Testis Factor SOX9

Cells ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 1103
Author(s):  
Furong Tang ◽  
Nainoa Richardson ◽  
Audrey Albina ◽  
Marie-Christine Chaboissier ◽  
Aitana Perea-Gomez
Keyword(s):  
Granulosa Cells ◽  
Gonad Development ◽  
Supporting Cell ◽  
Gonadal Development ◽  
Ovary Development ◽  
Double Knockout ◽  
Cell Identity ◽  
Knockout Mouse Model ◽  
Steroidogenic Cell ◽  
Male Specific

The transcription factors SRY and SOX9 and RSPO1/WNT4/β-Catenin signaling act as antagonistic pathways to drive testis and ovary development respectively, from a common gonadal primordium in mouse embryos. In this work, we took advantage of a double knockout mouse model to study gonadal development when Sox9 and Wnt4 are both mutated. We show that the XX gonad mutant for Wnt4 or for both Wnt4 and Sox9 develop as ovotestes, demonstrating that ectopic SOX9 function is not required for the partial female-to-male sex reversal caused by a Wnt4 mutation. Sox9 deletion in XY gonads leads to ovarian development accompanied by ectopic WNT/β-catenin signaling. In XY Sox9 mutant gonads, SRY-positive supporting precursors adopt a female-like identity and develop as pre-granulosa-like cells. This phenotype cannot be fully prevented by the deletion of Wnt4 or Rspo1, indicating that SOX9 is required for the early determination of the male supporting cell identity independently of repressing RSPO1/WNT4/β-Catenin signaling. However, in XY Sox9 Wnt4 double mutant gonads, pre-granulosa cells are not maintained, as they prematurely differentiate as mature granulosa cells and then trans-differentiate into Sertoli-like cells. Together, our results reveal the dynamics of the specific and independent actions of SOX9 and WNT4 during gonadal differentiation: SOX9 is essential in the testis for early specification of male-supporting cells whereas WNT4 functions in the ovary to maintain female-supporting cell identity and inhibit male-specific vascular and steroidogenic cell differentiation.

scholarly journals Multicomponent plasmid protects mice from spontaneous autoimmune diabetes

2021 ◽  
Author(s):  
Philippe P. Pagni ◽  
Jay Chaplin ◽  
Michael Wijaranakula ◽  
Johnna D. Wesley ◽  
Jaimie Granger ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Immune Cell ◽  
Autoimmune Diabetes ◽  
Phase 1 ◽  
Myeloid Cell ◽  
Cell Types ◽  
Cytokine Combination

Type 1 diabetes is an autoimmune disease in which insulin-secreting β-cells are destroyed, leading to a life-long dependency on exogenous insulin. There are no approved disease-modifying therapies available, and future immunotherapies would need to avoid generalized immune suppression. We developed a novel plasmid expressing preproinsulin2 and a combination of immune-modulatory cytokines (transforming growth factor-beta-1, interleukin [IL] 10 and IL-2) capable of near-complete prevention of autoimmune diabetes in non-obese diabetic mice. Efficacy depended on preproinsulin2, suggesting antigen-specific tolerization, and on the cytokine combination encoded. Diabetes suppression was achieved following either intramuscular or subcutaneous injections. Intramuscular plasmid treatment promoted increased peripheral levels of endogenous IL-10 and modulated myeloid cell types without inducing global immunosuppression. To prepare for first-in-human studies, the plasmid was modified to allow for selection without the use of antibiotic resistance; this modification had no impact on efficacy. This pre-clinical study demonstrates that this multi-component, plasmid-based antigen-specific immunotherapy holds potential for inducing self-tolerance in persons at risk of developing type 1 diabetes. Importantly, the study also informs on relevant cytokine and immune cell biomarkers that may facilitate clinical trials. This therapy is currently being tested for safety and tolerability in a phase 1 trial (ClinicalTrials.gov Identifier: NCT04279613).

Mesonephric cell migration induces testis cord formation and Sertoli cell differentiation in the mammalian gonad

Development ◽  
1999 ◽  
Vol 126 (13) ◽  
pp. 2883-2890 ◽  
Author(s):  
C. Tilmann ◽  
B. Capel
Keyword(s):  
Gene Expression ◽  
Cell Migration ◽  
Single Gene ◽  
Expression Patterns ◽  
Critical Role ◽  
Cell Types ◽  
Specific Gene ◽  
Specific Gene Expression ◽  
Male Specific ◽  
Testis Cord

In mammals a single gene on the Y chromosome, Sry, controls testis formation. One of the earliest effects of Sry expression is the induction of somatic cell migration from the mesonephros into the XY gonad. Here we show that mesonephric cells are required for cord formation and male-specific gene expression in XY gonads in a stage-specific manner. Culturing XX gonads with an XY gonad at their surface, as a ‘sandwich’, resulted in cell migration into the XX tissue. Analysis of sandwich gonads revealed that in the presence of migrating cells, XX gonads organized cord structures and acquired male-specific gene expression patterns. From these results, we conclude that mesonephric cell migration plays a critical role in the formation of testis cords and the differentiation of XY versus XX cell types.

scholarly journals Reprogramming of Sertoli cells to fetal-like Leydig cells by Wt1 ablation

2015 ◽  
Vol 112 (13) ◽  
pp. 4003-4008 ◽  
Author(s):  
Lianjun Zhang ◽  
Min Chen ◽  
Qing Wen ◽  
Yaqiong Li ◽  
Yaqing Wang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Somatic Cell ◽  
Progenitor Cells ◽  
Sertoli Cell ◽  
Sertoli Cells ◽  
Leydig Cells ◽  
Gonad Development ◽  
Cell Types ◽  
Lineage Tracing ◽  
Specific Gene

Sertoli and Leydig cells, the two major somatic cell types in the testis, have different morphologies and functions. Both are essential for gonad development and spermatogenesis. However, whether these cells are derived from the same progenitor cells and the mechanism regulating the differentiation between these two cell types during gonad development remains unclear. A previous study showed that overactivation of Ctnnb1 (cadherin-associated protein, beta 1) in Sertoli cells resulted in Sertoli cell tumors. Surprisingly, in the present study, we found that simultaneous deletion of Wilms’ Tumor Gene 1 (Wt1) and overactivation of Ctnnb1 in Sertoli cells led to Leydig cell-like tumor development. Lineage tracing experiments revealed that the Leydig-like tumor cells were derived from Sertoli cells. Further studies confirmed that Wt1 is required for the maintenance of the Sertoli cell lineage and that deletion of Wt1 resulted in the reprogramming of Sertoli cells to Leydig cells. Consistent with this interpretation, overexpression of Wt1 in Leydig cells led to the up-regulation of Sertoli cell-specific gene expression and the down-regulation of steroidogenic gene expression. These results demonstrate that the distinction between Sertoli cells and Leydig cells is regulated by Wt1, implying that these two cell types most likely originate from the same progenitor cells. This study thus provides a novel concept for somatic cell fate determination in testis development that may also represent an etiology of male infertility in human patients.

scholarly journals PD-L1 Expression in Systemic Immune Cell Populations as a Potential Predictive Biomarker of Responses to PD-L1/PD-1 Blockade Therapy in Lung Cancer

2019 ◽  
Vol 20 (7) ◽  
pp. 1631 ◽  
Author(s):  
Ana Bocanegra ◽  
Gonzalo Fernandez-Hinojal ◽  
Miren Zuazo-Ibarra ◽  
Hugo Arasanz ◽  
Maria Garcia-Granda ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Immune Cell ◽  
Expression Profiles ◽  
Myeloid Cell ◽  
Predictive Biomarker ◽  
Cell Types ◽  
Immune Checkpoint Blockade ◽  
Cell Populations ◽  
Patient Stratification ◽  
Tumor Expression

PD-L1 tumor expression is a widely used biomarker for patient stratification in PD-L1/PD-1 blockade anticancer therapies, particularly for lung cancer. However, the reliability of this marker is still under debate. Moreover, PD-L1 is widely expressed by many immune cell types, and little is known on the relevance of systemic PD-L1+ cells for responses to immune checkpoint blockade. We present two clinical cases of patients with non-small cell lung cancer (NSCLC) and PD-L1-negative tumors treated with atezolizumab that showed either objective responses or progression. These patients showed major differences in the distribution of PD-L1 expression within systemic immune cells. Based on these results, an exploratory study was carried out with 32 cases of NSCLC patients undergoing PD-L1/PD-1 blockade therapies, to compare PD-L1 expression profiles and their relationships with clinical outcomes. Significant differences in the percentage of PD-L1+ CD11b+ myeloid cell populations were found between objective responders and non-responders. Patients with percentages of PD-L1+ CD11b+ cells above 30% before the start of immunotherapy showed response rates of 50%, and 70% when combined with memory CD4 T cell profiling. These findings indicate that quantification of systemic PD-L1+ myeloid cell subsets could provide a simple biomarker for patient stratification, even if biopsies are scored as PD-L1 null.

scholarly journals AP-1 complex activation is a conserved signature of immune system aging and a potential regulator of inflammaging in human and mice

2021 ◽  
Author(s):  
Emin Onur Karakaslar ◽  
Muneer Hasham ◽  
Neerja Katiyar ◽  
Ahrim Youn ◽  
Siddhartha Sharma ◽  
...  
Keyword(s):  
Immune System ◽  
Peripheral Blood ◽  
Cell Activation ◽  
Immune Cell ◽  
Human Peripheral Blood ◽  
Myeloid Cell ◽  
Cell Types ◽  
Peripheral Blood Lymphocytes ◽  
Poly I:C ◽  
Human Immune System

Abstract Increased inflammation with age (i.e., inflammaging) is a hallmark of aging conserved in human and mice, but the underlying mechanisms are poorly understood, partially because a systematic comparative study of mouse and human immune system aging is lacking. We uncovered epigenomic/transcriptomic signatures of aging in spleen and peripheral blood lymphocytes from young (3 months) and old (18 months) mice in two strains: C57BL/6J (long-lived) and NZO/HILtJ (short-lived) and compared these to the aging signatures of human peripheral blood cells. The most predominant and conserved genomic signature of aging in human and mice tissues studied here was the epigenetic activation of several AP-1 complex members (Fos, Fosl2, Junb, Jund). Footprinting analyses showed that these transcription factors ‘bind’ more frequently with age and target pro-inflammatory and effector molecules, including the pro-inflammatory Il6. Analysis of single cell RNA-seq data from the mouse aging cell atlas (Tabula Muris Senis) revealed that AP-1 activation with age is a common feature across all immune cell types within spleens, yet macrophages express these molecules more often than other cells. Functional assays confirmed that spleen cells from older animals have increased c-JUN protein binding and increased IL6 production upon myeloid cell activation using poly(I:C) via TLR3. Western blot data revealed that c-JUN activation with age is not post-transcriptional since its phosphorylation levels were similar between young and old mice. Together, these data established that Jun and Fos families in the AP-1 complex are transcriptionally activated with age and target pro-inflammatory molecules and aging-related increases in the binding of these proteins likely modulate increased inflammation with age.

scholarly journals Multicomponent plasmid protects mice from spontaneous autoimmune diabetes

2021 ◽  
Author(s):  
Philippe P. Pagni ◽  
Jay Chaplin ◽  
Michael Wijaranakula ◽  
Johnna D. Wesley ◽  
Jaimie Granger ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Immune Cell ◽  
Autoimmune Diabetes ◽  
Phase 1 ◽  
Myeloid Cell ◽  
Cell Types ◽  
Cytokine Combination

Type 1 diabetes is an autoimmune disease in which insulin-secreting β-cells are destroyed, leading to a life-long dependency on exogenous insulin. There are no approved disease-modifying therapies available, and future immunotherapies would need to avoid generalized immune suppression. We developed a novel plasmid expressing preproinsulin2 and a combination of immune-modulatory cytokines (transforming growth factor-beta-1, interleukin [IL] 10 and IL-2) capable of near-complete prevention of autoimmune diabetes in non-obese diabetic mice. Efficacy depended on preproinsulin2, suggesting antigen-specific tolerization, and on the cytokine combination encoded. Diabetes suppression was achieved following either intramuscular or subcutaneous injections. Intramuscular plasmid treatment promoted increased peripheral levels of endogenous IL-10 and modulated myeloid cell types without inducing global immunosuppression. To prepare for first-in-human studies, the plasmid was modified to allow for selection without the use of antibiotic resistance; this modification had no impact on efficacy. This pre-clinical study demonstrates that this multi-component, plasmid-based antigen-specific immunotherapy holds potential for inducing self-tolerance in persons at risk of developing type 1 diabetes. Importantly, the study also informs on relevant cytokine and immune cell biomarkers that may facilitate clinical trials. This therapy is currently being tested for safety and tolerability in a phase 1 trial (ClinicalTrials.gov Identifier: NCT04279613).

Annulate lamellae in the Sertoli cells of guinea pig testis after unilateral torsion of the spermatic cord

1984 ◽  
Vol 42 ◽  
pp. 196-197
Author(s):  
J. Chakraborty ◽  
A. P. Sinha Hikim ◽  
J. S. Jhunjhunwala
Keyword(s):  
Sertoli Cells ◽  
Guinea Pigs ◽  
Spermatic Cord ◽  
Present Report ◽  
Cell Types ◽  
Annulate Lamellae ◽  
Spermatogenic Cells ◽  
Electron Microscopic ◽  
Structural Details ◽  
First Time

Although the presence of annulate lamellae was noted in many cell types, including the rat spermatogenic cells, this structure was never reported in the Sertoli cells of any rodent species. The present report is based on a part of our project on the effect of torsion of the spermatic cord to the contralateral testis. This paper describes for the first time, the fine structural details of the annulate lamellae in the Sertoli cells of damaged testis from guinea pigs.One side of the spermatic cord of each of six Hartly strain adult guinea pigs was surgically twisted (540°) under pentobarbital anesthesia (1). Four months after induction of torsion, animals were sacrificed, testes were excised and processed for the light and electron microscopic investigations. In the damaged testis, the majority of seminiferous tubule contained a layer of Sertoli cells with occasional spermatogonia (Fig. 1). Nuclei of these Sertoli cells were highly pleomorphic and contained small chromatinic clumps adjacent to the inner aspect of the nuclear envelope (Fig. 2).

scholarly journals Interleukin-17 and Th17 Lymphocytes Directly Impair Motoneuron Survival of Wildtype and FUS-ALS Mutant Human iPSCs

2021 ◽  
Vol 22 (15) ◽  
pp. 8042
Author(s):  
Mengmeng Jin ◽  
Katja Akgün ◽  
Tjalf Ziemssen ◽  
Markus Kipp ◽  
Rene Günther ◽  
...  
Keyword(s):  
Motor Neurons ◽  
Th17 Cells ◽  
Immune Cell ◽  
Cell Types ◽  
Positive Control ◽  
Interleukin 17 ◽  
Fused In Sarcoma ◽  
Th17 Lymphocytes ◽  
Human Ipscs ◽  
Als Patients

Amyotrophic lateral sclerosis (ALS) is a progressive disease leading to the degeneration of motor neurons (MNs). Neuroinflammation is involved in the pathogenesis of ALS; however, interactions of specific immune cell types and MNs are not well studied. We recently found a shift toward T helper (Th)1/Th17 cell-mediated, pro-inflammatory immune responses in the peripheral immune system of ALS patients, which positively correlated with disease severity and progression. Whether Th17 cells or their central mediator, Interleukin-17 (IL-17), directly affects human motor neuron survival is currently unknown. Here, we evaluated the contribution of Th17 cells and IL-17 on MN degeneration using the co-culture of iPSC-derived MNs of fused in sarcoma (FUS)-ALS patients and isogenic controls with Th17 lymphocytes derived from ALS patients, healthy controls, and multiple sclerosis (MS) patients (positive control). Only Th17 cells from MS patients induced severe MN degeneration in FUS-ALS as well as in wildtype MNs. Their main effector, IL-17A, yielded in a dose-dependent decline of the viability and neurite length of MNs. Surprisingly, IL-17F did not influence MNs. Importantly, neutralizing IL-17A and anti-IL-17 receptor A treatment reverted all effects of IL-17A. Our results offer compelling evidence that Th17 cells and IL-17A do directly contribute to MN degeneration.

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