Biology subjects

Yilmazer, A.

Publications and source records attributed to Yilmazer, A..

6 recordsLinked to original sources

bioRxiv2025

Functional Dichotomy of Developmental Foxp3+ Treg Cell Subsets in the Visceral Adipose Tissue of Lean and Obese Mice

Chronic inflammation and loss of Foxp3+ regulatory T (Treg) cells in the visceral adipose tissue (VAT) are hallmarks of the pathogenesis of insulin resistance and obesity. This study explores the roles of VAT Treg cells from thymic (tTreg) and peripheral (pTreg) developmental origin, revealing their opposing roles in metabolic inflammation. Obesity destabilized VAT tTreg cells, causing them to clonally expand into obesogenic Foxp3-IFN-{gamma}+ T effector cells, enhancing pro-inflammatory type 1 responses. Genetic tTreg ablation prevented this shift, promoting anti-inflammatory type 2 response, reduced body weight, and improved insulin resistance. Compared to their tTreg counterpart, pTreg cells were functionally well adapted to maintain VAT homeostasis and protect against obesity. Genetic pTreg ablation promoted spontaneous obesity symptoms even with physiological calorie intake, and worsened VAT inflammation and liver steatosis on a high-calorie diet. These findings highlight tTreg instability as a pathogenic threat and pTreg cells as crucial regulators of metabolic homeostasis. HighlightsO_LIVAT Tregs of lean mice originate from both thymic and peripheral Treg development C_LIO_LIHigh-calorie diet destabilizes tTregs that clonally expand into obesogenic IFN-{gamma}+ Th1 cells C_LIO_LIGenetic tTreg deficiency improves steady-state metabolism and prevents diet-induced obesity C_LIO_LIGenetic pTreg deficiency promotes obesity in both sexes even with normal calorie intake C_LIO_LIVAT pTregs are particularly adapted to regulate VAT homeostasis, including adipogenesis C_LI In BriefObesity and type 2 diabetes are characterized by insulin resistance, regulatory T (Treg) cell loss, and chronic inflammation in visceral adipose tissue (VAT). In this context, Yilmazer et al. dissect the functional roles of tTreg and pTreg cells. They show that VAT pTreg cells are particularly adapted to exert non-redundant homeostatic functions, and that pTreg deficiency predisposes to obesity even with normal calorie intake. In contrast, VAT tTreg cells can contribute to local inflammation by dedifferentiating into Foxp3- Th1-polarized effector cells. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/642664v1_ufig1.gif" ALT="Figure 1"> View larger version (60K): org.highwire.dtl.DTLVardef@19c740corg.highwire.dtl.DTLVardef@86d52borg.highwire.dtl.DTLVardef@152a88org.highwire.dtl.DTLVardef@19b7b13_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2023

Selective ablation of thymic and peripheral Foxp3+ regulatory T cell development

Foxp3+ Treg cells of thymic (tTreg) and peripheral (pTreg) developmental origin are thought to synergistically act to ensure immune homeostasis, with self-reactive tTreg cells primarily constraining autoimmune responses. We exploited tTreg-specific GFP/Cre recombinase activity to selectively ablate either tTreg ({Delta}tTreg) or pTreg ({Delta}pTreg) cell development. In contrast to the tTreg cell behavior in {Delta}pTreg mice, pTreg cells with a highly activated suppressor phenotype replenished the Treg cell pool of C57BL/6.{Delta}tTreg mice, preventing early mortality and fatal autoimmunity. Even with advancing age, pTreg cells largely maintained immune tolerance in C57BL/6.{Delta}tTreg mice. However, only two generations of (C57BL/6>NOD) backcrossing precipitated severe disease lethality associated with a distinct, partially overlapping pattern of organ-specific autoimmunity. Genetic association studies defined a small set of autoimmune risk loci sufficient to unleash a particularly severe form of diabetes, including genes known to impinge on Treg cell biology. Thus, pTreg cells exhibit an unexpectedly high functional adaptability, emphasizing their importance as mediators of bystander effects to ensure self-tolerance. SUMMARYThis study in complementary loss-of-function mouse models uncovers an unexpected functional plasticity of pTreg cells in constraining systemic autoimmune responses in the absence of tTreg cells and identifies tTreg cells as primary regulators of {beta}-cell autoimmunity in type 1 diabetes.

immunology↗

bioRxiv2022

Predicting the Reprogrammability of Human Cells Based on Transcriptome Data and SGD Classifier with Elastic-Net Regularization

Cell reprogramming has shown considerable importance in recent years; however, the programmability of cells and efficiency of reprogramming varies across different cell types. Considering several weeks of cell programming process and costly programming agents used through the process, every failure in reprogramming comes with a significant burden. Better planning for reprogramming experiments could be possible if there is a way of predicting the outcome of reprogramming before the experiments using transcriptome data. In this study, we have accessed the transcriptome data of successful or unsuccessful programming studies published in literature and constructed a Stochastic Gradient Descent (SGD) classifier with Elastic-Net regularization for predicting whether the cell lines are reprogrammable. We tested our classifier using 10-fold cross validation over cell lines and on each cell separately. Our results showed that it is possible to predict the outcome of cell reprogramming with accuracies up to 98% and Area Under the Curve (AUC) scores up to 0.98%. Considering the success of our experimental outcomes we conclude that an outcome of a cell reprogramming experiment can be predicted with high accuracy using machine learning on transcriptome data.

bioengineering↗

bioRxiv2022

Favipiravir, umifenovir and camostat mesylate: a comparative study against SARS-CoV-2

Since the first cases the coronavirus disease caused by SARS-CoV-2 (COVID-19) reported in December 2019, worldwide continuous efforts have been placed both for the prevention and treatment of this infectious disease. As new variants of the virus emerge, the need for an effective antiviral treatment continues. The concept of preventing SARS-CoV-2 on both pre-entry and post-entry stages has not been much studied. Therefore, we compared the antiviral activities of three antiviral drugs which have been currently used in the clinic. In silico docking analyses and in vitro viral infection in Vero E6 cells were performed to delineate their antiviral effectivity when used alone or in combination. Both in silico and in vitro results suggest that the combinatorial treatment by favipiravir and umifenovir or camostat mesylate has more antiviral activity against SARS-CoV-2 rather than single drug treatment. These results suggest that inhibiting both viral entry and viral replication at the same time is much more effective for the antiviral treatment of SARS-CoV-2.

pharmacology and toxicology↗

bioRxiv2020

Ribavirin shows antiviral activity against SARS-CoV-2 and downregulates the activity of TMPRSS2 and the expression of ACE2 in vitro

Ribavirin is a guanosine analog and has a broad-spectrum antiviral activity against RNA viruses. Based on this, we aimed to show the anti-SARS-CoV-2 activity of this drug molecule via in vitro, in silico and molecular techniques. Ribavirin showed antiviral activity in Vero E6 cells following SARS-CoV-2 infection. In silico analysis suggested that Ribarivin has a broad-spectrum impact on Vero E6 cells. According to the detailed molecular techniques, Ribavirin was shown to decrease TMPRSS2 expression both at mRNA and protein level 48 hours after treatment. The suppressive effect of Ribavirin in ACE2 protein expression was shown to be dependent on cell types. Finally, proteolytic activity assays showed that Ribavirin also showed an inhibitory effect on TMPRSS2 enzyme. As a conclusion, Ribavirin is a potential antiviral drug for the treatment against SARS-CoV-2, and it interferes with the effect of TMPRSS2 and ACE2 expression.

pharmacology and toxicology↗

bioRxiv2017

Non-viral induction of transient cell reprogramming in skeletal muscle to enhance tissue regeneration

Somatic cells can be reprogrammed to pluripotency in vivo by overexpression of defined transcription factors. While their sustained expression triggers tumorigenesis, transient reprogramming induces pluripotency-like features and proliferation only temporarily, without teratoma formation. We sought to achieve transient reprogramming within mouse skeletal muscle with a localized injection of plasmid DNA (pDNA) and hypothesized that this would enhance regeneration after severe injury. Intramuscular administration of reprogramming pDNA rapidly upregulated pluripotency (Nanog, Ecat1, Rex1) and early myogenesis genes (Pax3) in the healthy gastrocnemius of various mouse strains. Mononucleated cells expressing such markers appeared promptly in clusters among myofibers, but proliferated only transiently and did not lead to the generation of teratomas. Nanog was also upregulated in the gastrocnemius when reprogramming factors were administered 7 days after laceration of its medial head. Enhanced tissue regeneration after reprogramming was manifested by the accelerated appearance of centro-nucleated myofibers and reduced fibrosis. These results suggest that in vivo transient reprogramming may constitute a novel strategy towards the acceleration of regeneration following muscle injury, based on the induction of transiently-proliferative, pluripotent-like cells in situ. Further research to achieve clinically meaningful functional regeneration is warranted.

developmental biology↗