Production of BMP4 by endothelial cells is crucial for endogenous thymic regeneration

Wertheimer, Tobias; Velardi, Enrico; Tsai, Jennifer J.; Cooper, Kenneth W.; Xiao, Shiyun; Kloss, Christopher C.; Ottmüller, Katja; Mokhtari, Zeinab; Brede, Christian; deRoos, Paul; Kinsella, Sinéad; Palikuqi, Brisa; Ginsberg, Michael; Young, Lauren; Kreines, Fabiana M.; Lieberman, Sophia R.; Lazrak, Amina; Guo, Peipei; Malard, Florent; Smith, Odette M.; Shono, Yusuke; Jenq, Robert R.; Hanash, Alan M.; Nolan, Daniel J.; Butler, Jason M.; Beilhack, Andreas; Manley, Nancy R.; Rafii, Shahin; Dudakov, Jarrod A; Brink, Marcel R.M. van den

doi:10.1126/sciimmunol.aal2736

Cited by 98 publications

(151 citation statements)

References 70 publications

Supporting

Mentioning

148

Contrasting

Order By: Relevance

“…In conclusion, our study further extends the pervasive role of Foxn1 in thymus biology, as it was shown to be involved in all models of thymic growth, regeneration, and involution to this day (14,15,34,53,55,56). Also, unlike what is observed following irradiation-induced involution (15), no evidence of BMPR signaling or of damage to the epithelial population was detected in postpartum thymic regeneration. These data imply that the mechanisms involved in triggering thymic regeneration differ depending on the context leading to thymic involution.…”

Section: Discussionsupporting

confidence: 73%

“…A recent study showed that secretion of BMP4 by thymic endothelial cells promotes thymic regeneration following acute involution induced by sub-lethal total body irradiation (15). Increased BMP4 signaling was observed in thymic stromal cells 4-7 days following irradiation, and was accompanied by an upregulation of Foxn1 and its target genes in TECs.…”

Section: Expression Of Foxn1 Is Modulated During Postpartum Regenerationmentioning

confidence: 99%

“…Based on the analysis of cell population numbers (Figure 1), we distinguished two phases in the process of postpartum regeneration: (i) D0-D12: early regeneration, during which thymic cellularity gradually increases, and (ii) D16-D28: late regeneration, when thymic cellularity exceeds that of NPC. We first analyzed the two genes previously reported to be instrumental in other models of thymic regeneration in adults: Foxn1 and Bmp4 (14,15).…”

Section: Expression Of Foxn1 Is Modulated During Postpartum Regenerationmentioning

confidence: 99%

“…Bredenkamp et al (14) showed that overexpression of Foxn1 in TECs, a key transcription factor involved in TEC differentiation and necessary for the expression of genes involved in the regulation of thymopoiesis, was sufficient to induce thymic regeneration of fully involuted thymus in aged mice (12 or 24 months old) (14). Wertheimer et al (15) more recently showed that production of BMP4 by thymic endothelial cells promoted thymic regeneration following sublethal irradiation, and acted by inducing the expression of Foxn1 and its targets in TECs (15). However, we do not know whether these mechanisms are at play in other models, such as postpartum thymic regeneration.…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Qualitative Changes in Cortical Thymic Epithelial Cells Drive Postpartum Thymic Regeneration

et al. 2020

View full text Add to dashboard Cite

During gestation, sex hormones cause a significant thymic involution which enhances fertility. This thymic involution is rapidly corrected following parturition. As thymic epithelial cells (TECs) are responsible for the regulation of thymopoiesis, we analyzed the sequential phenotypic and transcriptomic changes in TECs during the postpartum period in order to identify mechanisms triggering postpartum thymic regeneration. In particular, we performed flow cytometry analyses and deep RNA-sequencing on purified TEC subsets at several time points before and after parturition. We report that pregnancy-induced involution is not caused by loss of TECs since their number does not change during or after pregnancy. However, during pregnancy, we observed a significant depletion of all thymocyte subsets downstream of the double-negative 1 (DN1) differentiation stage. Variations in thymocyte numbers correlated with conspicuous changes in the transcriptome of cortical TECs (cTECs). The transcriptomic changes affected predominantly cTEC expression of Foxn1, its targets and several genes that are essential for thymopoiesis. By contrast, medullary TECs (mTECs) showed very little transcriptomic changes in the early postpartum regenerative phase, but seemed to respond to the expansion of single-positive (SP) thymocytes in the late phase of regeneration. Together, these results show that postpartum thymic regeneration is orchestrated by variations in expression of a well-defined subset of cTEC genes, that occur very early after parturition.

show abstract

Section: Discussionsupporting

confidence: 73%

Section: Expression Of Foxn1 Is Modulated During Postpartum Regenerationmentioning

confidence: 99%

Section: Expression Of Foxn1 Is Modulated During Postpartum Regenerationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Qualitative Changes in Cortical Thymic Epithelial Cells Drive Postpartum Thymic Regeneration

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Its receptor, Bmpr2, is primarily expressed on cTEC lo and mTEC lo progenitors (42), and was proposed to have a role in maintaining progenitor populations at the expense of differentiation (10). However, Bmp4 induced self-renewal of progenitors may also have a role in thymus regeneration following damage, as demonstrated following irradiation (43).…”

Section: Discussionmentioning

confidence: 99%

Gender Disparity Impacts on Thymus Aging and LHRH Receptor Antagonist-Induced Thymic Reconstitution Following Chemotherapeutic Damage

et al. 2020

View full text Add to dashboard Cite

One of the main consequences of thymus aging is the decrease in naïve T cell output. This condition accelerates at the onset of puberty, and presents as a major clinical complication for cancer patients who require cytoablative therapy. Specifically, the extensive use of chemotherapeutics, such as cyclophosphamide, in such treatments damage thymic structure and eliminate the existing naïve T cell repertoire. The resulting immunodeficiency can lead to increased incidence of opportunistic infections, tumor growth relapse and/or autoimmune diseases, particularly in older patients. Thus, strategies aimed at rejuvenating the aged thymus following chemotherapeutic damage are required. Previous studies have revealed that sex hormone deprivation in male mice is capable of regenerating the thymic microenvironment following chemotherapy treatment, however, further investigation is crucial to identify gender-based differences, and the molecular mechanisms involved during thymus regeneration. Through phenotypic analyzes, we identified gender-specific alterations in thymocytes and thymic epithelial cell (TEC) subsets from the onset of puberty. By middle-age, females presented with a higher number of thymocytes in comparison to males, yet a decrease in their Aire + medullary TEC/thymocyte ratio was observed. This reduction could be associated with an increased risk of autoimmune disease in middle-aged women. Given the concurrent increase in female Aire + cTEC/thymocyte ratio, we proposed that there may be an impediment in Aire + mTEC hi differentiation, and Aire + cTEC hi as its upstream precursor. The regenerative effects of LHRH receptor antagonist, degarelix, on TEC subsets was also less pronounced in middle-aged females compared to males, possibly due to slower progression of thymic involution in the former, which presented with greater TEC hi proportions. Furthermore, following cyclophosphamide treatment, degarelix enhanced thymocyte and mature TEC subset recovery, with faster recovery kinetics observed in females. These events were found to involve both reactivation and proliferation of thymic epithelial progenitor cells. Taken together, the findings from this study portray Hun et al. Gender Disparity in the Aging Thymus a relationship between gender disparity and thymus aging, and highlight the potential benefits of LHRH receptor antagonist treatment for thymic regeneration. Further research is required, however, to determine how gender may impact on the mechanisms underpinning these events.

show abstract

Thymus Microenvironment: Maintenance, Ageing and Strategies for Thymus Regeneration Following Damage

Alsharif¹,

Chidgey²

2022

Encyclopedia of Life Sciences

View full text Add to dashboard Cite

The thymus is the major site of T‐lymphocyte production. Nonlymphoid elements, referred to as the thymic stroma, create the thymic microenvironment required to govern differentiation, maturation and tolerance induction of haematopoietic precursors into immune‐competent, nonautoreactive T cells. Thymic epithelial cells (TECs) are integral to thymopoiesis but are affected by ageing. From the onset of puberty, a proportional imbalance of TEC subpopulations coincides with a dramatic numerical loss of developing T cells. By middle‐age numerical loss of TECs accompanies further loss of thymocytes. Ongoing functional impediment of bipotent thymic epithelial progenitor cells (TEPC) has been proposed as one possible underlying cause and is more apparent in males. As such, endogenous recovery following thymic damage, such as from chemotherapy, in middle‐aged males relies heavily on proliferation of residual immature and mature TECs than through homeostatic differentiation of bipotent TEPC evident in middle‐aged females. Various strategies have been proposed to enhance thymus recovery following cytoablative therapies; however, thus far, temporary suppression of sex hormone production appears to have the most wide‐ranging impact on enhancing mature TEC replenishment and thymopoiesis. Key Concepts Thymic epithelial cells are critical for T cell development. Single‐cell transcriptomics and mapping identified more TEC subsets than first realised. Mature thymic medullary epithelial cells are essential for the presentation of self‐antigens for central tolerance induction. During age‐related thymus involution, an imbalance in TEC subsets accompanies the numerical loss of developing T cells from the onset of puberty. Postnatal bipotent thymic epithelial progenitor cells (TEPC) undergo functional attenuation from puberty with sexual dimorphism apparent. Increased reliance on activation and proliferation of enduring single‐lineage cortical and medullary TEC precursors for mature TEC maintenance during ageing. Thymic damage induces homeostatic TEC replenishment via bipotent TEPC in middle‐aged females but is restricted to proliferation and differentiation of single lineage progenitors in middle‐aged males. Temporary suppression of sex hormone production as a strategy for thymus regeneration releases the postpubertal TEPC functional block in males. Therapeutic strategies with clinical potential include adoptive transfer of in vitro generated progenitor T cells, exogenous administration of cytokines and growth factors, and temporary sex steroid inhibition.

show abstract

Production of BMP4 by endothelial cells is crucial for endogenous thymic regeneration

Cited by 98 publications

References 70 publications

Qualitative Changes in Cortical Thymic Epithelial Cells Drive Postpartum Thymic Regeneration

Qualitative Changes in Cortical Thymic Epithelial Cells Drive Postpartum Thymic Regeneration

Gender Disparity Impacts on Thymus Aging and LHRH Receptor Antagonist-Induced Thymic Reconstitution Following Chemotherapeutic Damage

Thymus Microenvironment: Maintenance, Ageing and Strategies for Thymus Regeneration Following Damage

Contact Info

Product

Resources

About