Morphological and immunohistochemical changes to thymic epithelial cells in the irradiated and recovering rat thymus

Irifune, Tatsuya; Tamechika, Masakatsu; Adachi, Yasuhiro; Tokuda, Nobuko; Sawada, Teruo; Fukumoto, Tetsuo

doi:10.1679/aohc.67.149

Cited by 9 publications

(12 citation statements)

References 16 publications

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“…Because of the general alterations of the Aire-deficient medullary compartment described here and previously (20), we evaluated the impact of Aire deficiency on p63 expression by TE, reasoning that Aire could affect other pathways regulating MTEC differentiation. As shown in Figure 4, and in agreement with previous reports (35–38), p63 expression was widespread among epithelial cells in cortical and medullary compartments, with a higher density of p63 + cells in the medulla (Figure 4a). Within the medullary compartment, there was little overlap between p63 expression and either Aire or high levels of K8 (Figure 4b & c).…”

Section: Resultssupporting

confidence: 92%

“…The impact of p63-deficiency on thymic epithelium indicates that p63 contributes to the maintenance and/or behavior of TE at proximal stages of their differentiation (8, 9). Although there are indications that p63 expression identifies progenitor epithelial cells (15), the extensive expression of p63 by thymic epithelial cells (35–38); this report) indicates that p63 expression in the thymus is not restricted to this relatively rare population (4) and includes transit amplifying cells as well. There is debate regarding the role of p63 in epithelial differentiation, where it has been implicated in differentiation, cell fate specification, proliferation, survival, senescence, apoptosis, cell-cell and cell-matrix interaction programs (reviewed in (13, 16, 45)).…”

Section: Discussionmentioning

confidence: 67%

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Alterations of the Medullary Epithelial Compartment in the Aire-Deficient Thymus: Implications for Programs of Thymic Epithelial Differentiation

Dooley¹,

Erickson²,

Farr

2008

The Journal of Immunology

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A widely held model of thymic epithelial differentiation is based on patterns of keratin expression, where a K8+K5+ progenitor gives rise to K8+K5/K14− cortical thymic epithelium (CTEC), and medullary thymic epithelium (MTEC) are K8−K5+K14+. The thymic phenotype of p63-deficient mice indicates that p63 is an important regulator of proximal stages of thymic epithelial differentiation. In this study, we have examined several features of the thymic medullary compartment in wild-type and Aire-deficient thymi in an effort to integrate the proapoptotic activity of Aire with these different perspectives of TE differentiation. Patterns of keratin and p63 expression by MTEC described here are difficult to reconcile with postmitotic MTEC that express a K8−K14+ phenotype and suggest that the patterns of p63 and keratin expression reflecting differentiation programs of other epithelial tissues provide a useful framework for revising models of TE differentiation. Alterations of the Aire−/− MTEC compartment included reduced expression of p63, increased frequency of MTEC expressing truncated Aire protein, and shifts in the pattern of keratin expression and epithelial morphology. These data suggest a scenario where cellular targets of Aire-mediated apoptosis are postmitotic MTEC that have not yet completed their terminal differentiation program. According to this view, the minor population of globular K8+K14−/low MTEC observed in the Aire+/+ thymus and significantly expanded in the Aire−/− thymic medulla represent end-stage, terminally differentiated MTEC. These Aire-dependent alterations of the MTEC compartment suggest that the activity of Aire is not neutral with respect to the program of MTEC differentiation.

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Section: Resultssupporting

confidence: 92%

Section: Discussionmentioning

confidence: 67%

Alterations of the Medullary Epithelial Compartment in the Aire-Deficient Thymus: Implications for Programs of Thymic Epithelial Differentiation

Dooley¹,

Erickson²,

Farr

2008

The Journal of Immunology

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“…P63 deficient mice exhibit a severely hypoplastic non-functional thymus [59], [60] and appears to show the effect in early TECs development. P63 expression has been reported to identify epithelial stem cells [84] however, the abundance of p63-expressing cells in the thymus (Figure 8 & [79], [85], [86], [87], [88]) and other tissues like bladder epithelium indicates that p63 expression is maintained in the immediate progeny of the stem cells as well. In the skin, p63 expression is associated with K14 + progenitor cells in the basal layer and is lost as the cells lose proliferative potential and differentiate [62].…”

Section: Discussionmentioning

confidence: 95%

DKK1 Mediated Inhibition of Wnt Signaling in Postnatal Mice Leads to Loss of TEC Progenitors and Thymic Degeneration

et al. 2010

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BackgroundThymic epithelial cell (TEC) microenvironments are essential for the recruitment of T cell precursors from the bone marrow, as well as the subsequent expansion and selection of thymocytes resulting in a mature self-tolerant T cell repertoire. The molecular mechanisms, which control both the initial development and subsequent maintenance of these critical microenvironments, are poorly defined. Wnt signaling has been shown to be important to the development of several epithelial tissues and organs. Regulation of Wnt signaling has also been shown to impact both early thymocyte and thymic epithelial development. However, early blocks in thymic organogenesis or death of the mice have prevented analysis of a role of canonical Wnt signaling in the maintenance of TECs in the postnatal thymus.Methodology/Principal FindingsHere we demonstrate that tetracycline-regulated expression of the canonical Wnt inhibitor DKK1 in TECs localized in both the cortex and medulla of adult mice, results in rapid thymic degeneration characterized by a loss of ΔNP63+ Foxn1+ and Aire+ TECs, loss of K5K8DP TECs thought to represent or contain an immature TEC progenitor, decreased TEC proliferation and the development of cystic structures, similar to an aged thymus. Removal of DKK1 from DKK1-involuted mice results in full recovery, suggesting that canonical Wnt signaling is required for the differentiation or proliferation of TEC populations needed for maintenance of properly organized adult thymic epithelial microenvironments.Conclusions/SignificanceTaken together, the results of this study demonstrate that canonical Wnt signaling within TECs is required for the maintenance of epithelial microenvironments in the postnatal thymus, possibly through effects on TEC progenitor/stem cell populations. Downstream targets of Wnt signaling, which are responsible for maintenance of these TEC progenitors may provide useful targets for therapies aimed at counteracting age associated thymic involution or the premature thymic degeneration associated with cancer therapy and bone marrow transplants.

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“…With these cytotoxic therapies, the total thymus anlage is decreased, raising the likelihood that immunohistochemical studies may be subject to variations in the size and depth of sections examined. Using this technique, while studies concur that thymocytes are more radiosensitive than TEC, 37–39 assessments of TEC alterations after radiation have differed. Some have suggested that the major effects may occur in the medulla with selective depletion of UEA+ medullary TEC 40,41 and medullary dendritic cells 42 .…”

Section: Introductionmentioning

confidence: 99%

Single Cell Analysis of Complex Thymus Stromal Cell Populations: Rapid Thymic Epithelia Preparation Characterizes Radiation Injury

Williams

Mella

Lucas

et al. 2009

Clinical Translational Sci

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Thymic epithelial cells (TECs) and dendritic cells are essential for the maintenance of thymopoiesis. Because these stromal elements defi ne the progenitor niche, provide critical survival signals and growth factors, and direct positive and negative selection, detailed study of these populations is necessary to understand important elements for thymic renewal after cytotoxic injury. Study of TEC is currently hindered by lengthy enzymatic separation techniques with decreased viability. We present a new rapid separation technique that yields consistent viable TEC numbers in a quarter of the prior preparation time. Using this new procedure, we identify changes in stromal populations following total body irradiation (TBI). By fl ow cytometry, we show that TBI signifi cantly depletes UEA+ medullary TEC, while sparing Ly51+ CD45− cells. Further characterization of the Ly51+ subset reveals enrichment of fi broblasts (CD45− Ly51+ MHCII−), while cortical TECs (CD45− Ly51+ MHCII+) were markedly reduced. Dendritic cells (CD11c+ CD45+) were also decreased following TBI. These data suggest that cytotoxic preparative regimens may impair thymic renewal by reducing critical populations of cortical and medullary TEC, and that such thymic damage can be assessed by this new rapid separation technique, thereby providing a means of assessing optimal conditioning pretransplant for enhancing thymic-dependent immune reconstitution posttransplant.

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Morphological and immunohistochemical changes to thymic epithelial cells in the irradiated and recovering rat thymus

Cited by 9 publications

References 16 publications

Alterations of the Medullary Epithelial Compartment in the Aire-Deficient Thymus: Implications for Programs of Thymic Epithelial Differentiation

Alterations of the Medullary Epithelial Compartment in the Aire-Deficient Thymus: Implications for Programs of Thymic Epithelial Differentiation

DKK1 Mediated Inhibition of Wnt Signaling in Postnatal Mice Leads to Loss of TEC Progenitors and Thymic Degeneration

Single Cell Analysis of Complex Thymus Stromal Cell Populations: Rapid Thymic Epithelia Preparation Characterizes Radiation Injury

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