PPARgamma Deficiency Counteracts Thymic Senescence

Ernszt, Dávid; Banfai, Krisztina; Kellermayer, Zoltán; Pap, Attila; Lord, Janet M.; Pongrácz, Judit E.; Kvell, Krisztián

doi:10.3389/fimmu.2017.01515

Cited by 13 publications

(11 citation statements)

References 56 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This is supported by literature data and our own results showing that a significant portion of exosomal Wnt4 is surface-displayed and that Wnt4-binding Frizzled receptors (Fz4 and Fz6) are up-regulated in senescent TECs (8). Combined, our previous and current results suggest that as Wnt4 secretion decreases with age and since cortical areas show preferential binding of the remaining Wnt4 (a key factor of TEC identity) at an old age, age-related medullary involution may precede cortical involution due to the medullary lack of Wnt4-effect (10, 14, 47). To our knowledge, this is a novel molecular level explanation of accelerated medullary involution.…”

Section: Discussionsupporting

confidence: 62%

Transgenic Exosomes for Thymus Regeneration

et al. 2019

Self Cite

View full text Add to dashboard Cite

During senescence, Wnt4 expression is down-regulated (unlike their Frizzled receptors), while PPARgamma expression increases in the thymus. Together, these changes allow for thymic degeneration to occur, observed as adipose involution. However, when restored, Wnt4 can efficiently counteract PPARgamma and prevent thymic senescence from developing. The Wnt-pathway activator miR27b has also been reported to inhibit PPARgamma. Our goal was to evaluate the Wnt4 and miR27b levels of Wnt4-transgenic thymic epithelial cell (TEC)-derived exosomes, show their regenerative potential against age-related thymic degeneration, and visualize their binding and distribution both in vitro and in vivo . First, transgenic exosomes were harvested from Wnt4 over-expressing TECs and analyzed by transmission electron microscopy. This unveiled exosomes ranging from 50 to 100 nm in size. Exosomal Wnt4 protein content was assayed by ELISA, while miR27b levels were measured by TaqMan qPCR, both showing elevated levels in transgenic exosomes relative to controls. Of note, kit-purified TEI (total exosome isolate) outperformed UC (ultracentrifugation)-purified exosomes in these parameters. In addition, a significant portion of exosomal Wnt4 proved to be displayed on exosomal surfaces. For functional studies, steroid (Dexamethasone or DX)-induced TECs were used as cellular aging models in which DX-triggered cellular aging was efficiently prevented by transgenic exosomes. Finally, DiI lipid-stained exosomes were applied on the mouse thymus sections and also iv-injected into mice, for in vitro binding and in vivo tracking, respectively. We have observed distinct staining patterns using DiI lipid-stained transgenic exosomes on sections of young and aging murine thymus samples. Moreover, in vivo injected DiI lipid-stained transgenic exosomes showed detectable homing to the thymus. Of note, Wnt4-transgenic exosome homing outperformed control (Wnt5a-transgenic) exosome homing. In summary, our findings indicate that exosomal Wnt4 and miR27b can efficiently counteract thymic adipose involution. Although extrapolation of mouse results to the human setting needs caution, our results appoint transgenic TEC exosomes as promising tools of immune rejuvenation and contribute to the characterization of the immune-modulatory effects of extracellular vesicles in the context of regenerative medicine.

show abstract

Section: Discussionsupporting

confidence: 62%

Transgenic Exosomes for Thymus Regeneration

et al. 2019

Self Cite

View full text Add to dashboard Cite

show abstract

“…The cause: low levels of neutralizing antibody titers due to lacking naïve T-cells required for T-B cooperation. This, however, is also rescued by PPARgamma deficiency [38].…”

Section: Natural Resistance To Senescencementioning

confidence: 94%

“…It is the lack of androgen-effect that prevents thymus involution on one hand, but hampers the endocrine system on the other hand. Recently another medical condition termed FPLD3 (familial partial lipodystrophy type 3) has also been associated with the lack of thymus involution [38]. FPLD3 also derails the hormonal system by affecting PPARgamma activity.…”

Section: Natural Resistance To Senescencementioning

confidence: 99%

“…Unfortunately, this tolerance is impaired at old age [40][41][42] Loss of oral tolerance is a potential link to increasing food intolerance prevalence [43][44][45][46]. However, tolerance is rescued by PPARgamma deficiency at senior age [38]. In senior individuals protection from seasonal flu strains declines despite annual vaccination [47][48][49].…”

Section: Natural Resistance To Senescencementioning

confidence: 99%

See 1 more Smart Citation

Thymic Senescence

Kvell¹

2020

Thymus

Self Cite

View full text Add to dashboard Cite

Thymic senescence develops in every person, although at different pace. Thymic senescence significantly lowers the production of naive T cells, leading to increased incidence of infections, cancer and autoimmune diseases. Certain external factors can accelerate thymic senescence. These include chemicals (copper-chelators), hormones (androgens), infections (viruses, fungi, protozoa). Others may slow the aging process of the thymus including perturbations to the hormonal (sex-steroid) system, genetic alterations (PPARgamma deficiency) or chemical compounds (PPARgamma antagonists). Thymic senescence research may provide insight to underlying molecular events and potentially appoint novel therapeutic targets for senescence intervention strategies. These hold promise to postpone thymus senescence and enhance T cell production. That would result in a decreased incidence of infections, cancer and autoimmune diseases, currently affecting the elderly. The attributed drop in healthcare costs and gain in quality of life share tremendous economic and social interest.

show abstract

“…Peroxisome proliferator-activated receptor γ (PPARγ) is a key player in the differentiation of adipocytes, and constitutive PPARγ activation induces ectopic adipogenesis and promotes age-related thymic involution in mice ( Youm et al, 2010 ; Ernszt et al, 2017 ). Furthermore, rosiglitazone, a potent PPARγ agonist, has been successfully used to induce adipogenic differentiation of OP9-DL1 cells and primary TSCs in vitro ( Yang et al, 2009 ; Tan et al, 2017 ).…”

Section: Introductionmentioning

confidence: 99%

Notch1 Inhibits Rosiglitazone-Induced Adipogenic Differentiation in Primary Thymic Stromal Cells

Wang

Tan

et al. 2018

Front. Pharmacol.

View full text Add to dashboard Cite

Adipocyte deposition is believed to be a primary characteristic of age-related thymic involution. Herein, we cultured primary thymic stromal cells (TSCs), used rosiglitazone, a potent peroxisome proliferator-activated receptor γ (PPARγ) agonist, to induce adipogenic differentiation, and investigated the differentially expressed genes during adipogenic differentiation by using RNA-sequencing analysis. Furthermore, the effects of Notch1 on rosiglitazone-induced adipogenic differentiation of TSCs as well as the underlying mechanisms were also investigated. As a result, we identified a total of 1737 differentially expressed genes, among which 965 genes were up-regulated and 772 genes were down-regulated in rosiglitazone-treated cells compared with control cells. Gene ontology (GO) enrichment analysis showed that the GO terms were enriched in metabolic process, intracellular, and protein binding. Kyoto encyclopedia of genes and genomes (KEGG) analysis showed that a number of pathways, including ubiquitin mediated proteolysis, PPAR signaling pathway, and mammalian target of rapamycin (mTOR) signaling pathway were predominantly over-represented. Meanwhile, overexpression of Notch1 suppressed and inhibition of Notch1 promoted rosiglitazone-induced adipogenic differentiation in TSCs, and the pro-adipogenic effects of the Notch inhibitor DAPT were associated with the activation of autophagy. Taken together, our results suggest that Notch1 is a key regulator in thymic adipogenesis and may serve as a potential target to hinder thymic adiposity in age-related thymic involution.

show abstract

PPARgamma Deficiency Counteracts Thymic Senescence

Cited by 13 publications

References 56 publications

Transgenic Exosomes for Thymus Regeneration

Transgenic Exosomes for Thymus Regeneration

Thymic Senescence

Notch1 Inhibits Rosiglitazone-Induced Adipogenic Differentiation in Primary Thymic Stromal Cells

Contact Info

Product

Resources

About