scholarly journals MicroRNAs Regulate Thymic Epithelium in Age-Related Thymic Involution via Down- or Upregulation of Transcription Factors

2017 ◽  
Vol 2017 ◽  
pp. 1-9 ◽  
Author(s):  
Minwen Xu ◽  
Xiaoli Zhang ◽  
Ruiyun Hong ◽  
Dong-Ming Su ◽  
Liefeng Wang
Keyword(s):  
Transcription Factors ◽  
Epithelial Cells ◽  
Regulatory Networks ◽  
Current Understanding ◽  
Untranslated Regions ◽  
Thymic Epithelial Cells ◽  
Thymic Involution ◽  
Thymic Function ◽  
Thymic Epithelium ◽  
Age Related

Age-related thymic involution is primarily induced by defects in nonhematopoietic thymic epithelial cells (TECs). It is characterized by dysfunction of multiple transcription factors (TFs), such as p63 and FoxN1, and also involves other TEC-associated regulators, such as Aire. These TFs and regulators are controlled by complicated regulatory networks, in which microRNAs (miRNAs) act as a key player. miRNAs can either directly target the 3′-UTRs (untranslated regions) of the TFs to suppress TF expression or target TF inhibitors to reduce or increase TF inhibitor expression and thereby indirectly enhance or inhibit TF expression. Here, we review the current understanding and recent studies about how miRNAs are involved in age-related thymic involution via regulation of TEC-autonomous TFs. We also discuss potential strategies for targeting miRNAs to rejuvenate age-related declined thymic function.

scholarly journals Inactivation of the RB family prevents thymus involution and promotes thymic function by direct control of Foxn1 expression

2013 ◽  
Vol 210 (6) ◽  
pp. 1087-1097 ◽  
Author(s):  
Phillip M. Garfin ◽  
Dullei Min ◽  
Jerrod L. Bryson ◽  
Thomas Serwold ◽  
Badreddin Edris ◽  
...  
Keyword(s):  
T Cells ◽  
Thymic Epithelial Cells ◽  
Direct Control ◽  
Thymic Involution ◽  
Thymic Function ◽  
Thymic Epithelium ◽  
Thymus Involution ◽  
Independent Mechanism ◽  
E2f Transcription Factors ◽  
Increased Activity

Thymic involution during aging is a major cause of decreased production of T cells and reduced immunity. Here we show that inactivation of Rb family genes in young mice prevents thymic involution and results in an enlarged thymus competent for increased production of naive T cells. This phenotype originates from the expansion of functional thymic epithelial cells (TECs). In RB family mutant TECs, increased activity of E2F transcription factors drives increased expression of Foxn1, a central regulator of the thymic epithelium. Increased Foxn1 expression is required for the thymic expansion observed in Rb family mutant mice. Thus, the RB family promotes thymic involution and controls T cell production via a bone marrow–independent mechanism, identifying a novel pathway to target to increase thymic function in patients.

scholarly journals Thymic rejuvenation via induced thymic epithelial cells (iTECs) from FOXN1-overexpressing fibroblasts to counteract inflammaging

2020 ◽  
Author(s):  
Jiyoung Oh ◽  
Weikan Wang ◽  
Rachel Thomas ◽  
Dong-Ming Su
Keyword(s):  
T Cell ◽  
Epithelial Cells ◽  
Negative Selection ◽  
De Novo ◽  
The Elderly ◽  
Thymic Epithelial Cells ◽  
Thymic Involution ◽  
Embryonic Fibroblasts ◽  
Central Tolerance ◽  
Age Related

AbstractAge-associated systemic, chronic, sterile inflammatory condition (inflammaging) is partially attributed to increased self (auto)-reactivity, resulting from disruption of central tolerance in the aged, involuted thymus. Age-related thymic involution causally results from gradually declined expression of the transcription factor forkhead box N1 (FOXN1) in thymic epithelial cells (TECs), while exogenous FOXN1 in TECs can significantly rescue age-related thymic involution. Given the findings that induced TECs (iTECs) from FOXN1-overexpressing embryonic fibroblasts can generate an ectopic de novo thymus under the kidney capsule and intra-thymically injected natural young TECs can lead to middle-aged thymus regrowth, we sought to expand upon these two findings by applying them as a novel thymic rejuvenation strategy with two types of promoter-driven (Rosa26CreERT and FoxN1Cre) Cre-mediated iTECs. We engrafted iTECs, rather than natural young TECs, directly into the aged thymus and/or peri-thymus and found a significantly rejuvenated architecture and function in the native aged murine thymus. The engrafted iTECs drove regrowth of the aged thymus in both male and female mice, showing not only increased thymopoiesis, but also reinforcement of thymocyte negative selection, thereby, reducing senescent T cells and auto-reactive T cell-mediated inflammaging phenotypes in old mice. Therefore, this is a promising thymic rejuvenation strategy with preclinical significance, which can potentially rescue declined thymopoiesis and impaired negative selection to significantly, albeit partially, restore the defective central tolerance and reduce subclinical chronic inflammatory symptoms in the elderly.Graphical AbstractA novel rejuvenation strategy via the FOXN1-TEC axis using induced two types of FOXN1-overexpressing embryonic fibroblasts (termed iTECs) by intrathymic injection is able to counteract age-related thymic involution, which rescued negative selection, thereby, reducing peripheral T cell-associated inflammaging conditions.

scholarly journals Neuropeptides Exert Direct Effects on Rat Thymic Epithelial Cells in Culture

1998 ◽  
Vol 6 (1-2) ◽  
pp. 95-104 ◽  
Author(s):  
Gail M. Head ◽  
R. Mentlein ◽  
Birte Von Patay ◽  
J. E.G. Downing ◽  
Marion D. Kendall
Keyword(s):  
Epithelial Cells ◽  
Lucifer Yellow ◽  
Tritiated Thymidine ◽  
Single Cells ◽  
Thymic Epithelial Cells ◽  
Dye Coupling ◽  
Direct Effects ◽  
Adrenergic Agonist ◽  
Thymic Epithelium ◽  
Functional Aspects

To determine if major thymic neuropeptides and neurotransmitters can directly influence the functional activity of cultured rat thymic epithelium, neuropeptides and neurotransmitters were applied, and intercellular communication, proliferation, and thymulin secretion assessed. After injections of a mixture of lucifer yellow dextran (too large to pass gap junctions) and cascade blue (which does) into single cells, some neuropeptides decrease dye coupling: 0.1 mM GABA (P< 0.0001), 100 nM NPY (P< 0.0001), 100 nM VIP (P< 0.001), 100 nM CGRP (P< 0.001), 100 nM SP (P< 0.01), and 0.1 mM histamine (P< 0.01), whereas 0.1 mM 5-HT, mM acetylcholine, and 1μM isoproterenol (β-adrenergic agonist) had no effect. Proliferation (incorporation of tritiated thymidine) was increased by CGRP (P= 0.004) and histamine (P< 0.02), but decreased by isoproterenol (P= 0.002), 5-HT (P= 0.003), and acetylcholine (P< 0.05). The percentage of multinucleate cells was decreased after isoproterenol (2.5%), and increased after 5-HT (21.3%), GABA (15%), and histamine (15.1%). Compared to controls, thymulin in the supernatant was decreased after challenge with acetylcholine (52%), isoproterenol (71%), 5-HT (73%), and histamine (84%). This study demonstrates direct effects of neuropeptides and neurotransmitters on functional aspects of cultured thymic epithelial cells.

scholarly journals Age-related decrease of somatostatin receptor number in the normal human thymus

2000 ◽  
Vol 279 (4) ◽  
pp. E791-E798 ◽  
Author(s):  
Diego Ferone ◽  
Rosario Pivonello ◽  
P. Martin Van Hagen ◽  
Marlijn Waaijers ◽  
Joke Zuijderwijk ◽  
...  
Keyword(s):  
Structural Changes ◽  
Somatostatin Receptor ◽  
Thymic Epithelial Cells ◽  
Thymic Involution ◽  
Human Thymus ◽  
Age Related ◽  
Tissue Homogenates ◽  
Normal Human ◽  
Receptor Number ◽  
Age Range

The thymus exhibits a pattern of aging oriented toward a physiological involution. The structural changes start with a steady decrease of thymocytes, whereas no major variations occur in the number of thymic epithelial cells (TEC). The data concerning the role of hormones and neuropeptides in thymic involution are equivocal. We recently demonstrated the presence of somatostatin (SS) and three different SS receptor (SSR) subtypes in the human thymus. TEC selectively expressed SSR subtype 1 (sst1) and sst2a. In the present study we investigated whether SSR number is age related in the thymus. Binding of the sst2-preferring ligand125I-Tyr3-octreotide was evaluated in a large series of normal human thymuses of different age by SSR autoradiography and ligand binding on tissue homogenates. The score at autoradiography and the number of SSR at membrane homogenate binding (Bmax) were inversely correlated with the thymus age ( r = −0.84, P < 0.001; r = −0.82, P < 0.001, respectively). The autoradiographic score was positively correlated with the Bmaxvalues ( r = 0.74, P < 0.001). Because the TEC number in the age range considered remains unchanged, the decrease of octreotide binding sites might be due to a reduction of sst2areceptor number on TEC. The age-related expression of a receptor involved mainly in controlling secretive processes is in line with the evidence that the major changes occurring in TEC with aging are related to their capabilities in producing thymic hormones. In conclusion, SS and SSR might play a role in the involution of the human thymus. These findings underline the links between the neuroendocrine and immune systems and support the concept that neuropeptides participate in development of cellular immunity in humans.

scholarly journals TGF-β signaling in thymic epithelial cells regulates thymic involution and postirradiation reconstitution

Blood ◽  
2008 ◽  
Vol 112 (3) ◽  
pp. 626-634 ◽  
Author(s):  
Mathias M. Hauri-Hohl ◽  
Saulius Zuklys ◽  
Marcel P. Keller ◽  
Lukas T. Jeker ◽  
Thomas Barthlott ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
Epithelial Cells ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Thymic Epithelial Cells ◽  
Thymic Involution ◽  
Stromal Compartment ◽  
Hematopoietic Stem

Abstract The thymus constitutes the primary lymphoid organ responsible for the generation of naive T cells. Its stromal compartment is largely composed of a scaffold of different subsets of epithelial cells that provide soluble and membrane-bound molecules essential for thymocyte maturation and selection. With senescence, a steady decline in the thymic output of T cells has been observed. Numeric and qualitative changes in the stromal compartment of the thymus resulting in reduced thymopoietic capacity have been suggested to account for this physiologic process. The precise cellular and molecular mechanisms underlying thymic senescence are, however, only incompletely understood. Here, we demonstrate that TGF-β signaling in thymic epithelial cells exerts a direct influence on the cell's capacity to support thymopoiesis in the aged mouse as the physiologic process of thymic senescence is mitigated in mice deficient for the expression of TGF-βRII on thymic epithelial cells. Moreover, TGF-β signaling in these stromal cells transiently hinders the early phase of thymic reconstitution after myeloablative conditioning and hematopoietic stem cell transplantation. Hence, inhibition of TGF-β signaling decelerates the process of age-related thymic involution and may hasten the reconstitution of regular thymopoiesis after hematopoietic stem cell transplantation.

RB Controls Size, Cellularity, and T Cell Output of the Mouse Thymus

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 835-835
Author(s):  
Phillip M. Garfin ◽  
Patrick Viatour ◽  
Dullei Min ◽  
Jerrod Bryson ◽  
Kenneth I. Weinberg ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Epithelial Cells ◽  
Conflicts Of Interest ◽  
Thymic Epithelial Cells ◽  
Main Function ◽  
Thymic Involution ◽  
Regulatory Relationship ◽  
Thymic Tissue ◽  
Rb Pathway

Abstract Abstract 835 The establishment of the thymic microenvironment early in life is crucial for the production functional T cells. Conversely, thymic involution results in a decreased T cell output. Thymic involution has important health implications especially following bone marrow transplant. Our objective is to determine molecular and cellular mechanisms that will allow for regeneration of involuted thymic tissue, restore production of naïve T cells, and improve immune function while improving our understanding of immunobiology. In this pursuit, we have focused on the Retinoblastoma family of tumor suppressor proteins. The main function of the RB pathway is to restrict passage through the G1/S transition of the cell cycle. RB and its two family members, p107 and p130, mediate the action of a broad range of cellular signals to control the proliferation, survival, and differentiation status of a large number of mammalian cell types. We found that inactivation of the RB pathway in the thymus by early deletion of RB family genes prevents thymic involution, promotes expansion of functional thymic epithelial cells (TECs), and increases thymic T cell output. Moreover, we have identified a direct regulatory relationship between RB and the Foxn1 transcription factor Via E2F transcription factors, where RB/E2F complexes directly repress the Foxn1 promoter, thereby promoting involution. Thus, the RB family is a critical mediator of extra- and intra-cellular signals to regulate thymic epithelial cells and thymus function, and decreasing RB pathway function may promote regeneration of the involuted thymus and restoration of naïve T cell production in patients. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Heterogeneity of thymic epithelial cell (TEC) keratins--immunohistochemical and biochemical evidence for a subset of highly differentiated TEC in the mouse.

1985 ◽  
Vol 33 (7) ◽  
pp. 687-694 ◽  
Author(s):  
J F Nicolas ◽  
W Savino ◽  
A Reano ◽  
J Viac ◽  
J Brochier ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Epithelial Cell ◽  
Epithelial Cells ◽  
High Molecular Weight ◽  
Thymic Epithelial Cells ◽  
Thymic Epithelial Cell ◽  
Small Subset ◽  
Thymic Epithelium ◽  
Differentiated Cells ◽  
Medullary Epithelial Cells

The mouse thymic epithelial network was studied using three different anti-keratin antibodies. One of these antibodies, KL1, exclusively recognized a small subset of medullary epithelial cells characterized by its content of a high molecular weight keratin (63 kD). Since epithelial differentiation is known to be associated with the acquisition of high molecular weight keratins, KL1-positive cells, which express the Ia antigen and secrete thymulin, may represent a subset of highly differentiated cells among mouse thymic epithelial cells (TEC). These data reflect the heterogeneity of the thymic epithelium and support the concept that distinct TEC subsets might provide the thymus with different microenvironments.

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