46: Androgen Withdrawal Modulates Thymopoiesis by Inducing Thymic Epithelial Cell Proliferation and Increasing Precursor Niche

Biology of Blood and Marrow Transplantation(2008)

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Abstract
Impaired thymopoiesis contributes to immune deficiency following allogeneic stem cell transplantation. Emerging clinical literature suggests that graft-versus-host disease may be exacerbated and graft-versus-leukemia effect compromised in the setting of thymic insufficiency. Data have demonstrated that the thymus is damaged following the transplant preparative regimen, with a depletion of UEA+ thymic epithelial cells. We show that castration of male mice results in thymic renewal, as demonstrated by increased thymocyte number, intrathymic T cell receptor excision circles, and the number of early thymic progenitors (ETP: Lin- CD25- c-kit hi CD44 hi) as early as eight days post-castration. These observations suggested a mechanism of enhanced thymopoieis that occurs through increased immigration of thymocyte precursors. Studies with adoptively transferred congenic marrow progenitors confirm that enhanced ETP immigration is an early event following androgen withdrawal. Data also demonstrate a significant increase in UEA+ thymic epithelial cell proliferation by BRDU+ incorporation in the initial time frame following castration, implicating thymic epithelial cell proliferation in this thymic expansion, and suggesting that there may be an increase in thymic niche regulating ETP uptake. We have further identified an increase in a stromal derived protein important for ETP uptake by Western blot in total thymus lysates consistent with a mechanism of an increased ETP niche. Preliminary data also suggest that the mRNA encoding this protein is increased in sorted thymic epithelial subsets, with the greatest increase in the UEA+ medullary TEC cells, implicating these medullary epithelial cells in ETP entry. Taken together, we show that androgen withdrawal leads to UEA+ medullary cell proliferation with augmented ETP niche and entry. Thus, we identify ETP uptake as a critical and dynamically controlled point of thymic regulation.
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Key words
androgen withdrawal modulates thymopoiesis,thymic epithelial cell proliferation
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