Neural crest-derived mesenchymal cells support thymic reconstitution after lethal irradiation.

Abstract

Abstract The thymus is composed of thymocytes and stromal cells including thymic epithelial and mesenchymal cells. Thymic mesenchymal cells are originated from Neural Crest (NC) cells and the mesoderm. Although it is known that NC-derived (NCd) cells contribute to thymus organogenesis and thymus development, their specific role in T cell regeneration is unclear. To evaluate the regenerative ability of NCd mesenchymal cells in the thymus, we used lethally irradiated mice to examine the effect of ionizing irradiation (IR) on the thymus size, thymocytes and the thymic stromal cells (thymic epithelial cells (TECs) and thymic mesenchymal cells). Additionally, we ablated NC-derived mesenchymal cells via in vitro diphtheria toxin (DT) administration in double transgenic mice (Wnt1-Cre/+; Rosa YFP/DTRmice) that express NC-specific Cre and Cre-driven DT receptor (DTR) and transplanted the thymus depleted of NC-derived mesenchyme under the renal capsules of non-irradiated C57BL/6 (CD45.1) mice. IR reduced the size of the thymus, the absolute numbers and percentages of thymocytes, primarily (CD4 +CD8 +) T cells and TECs. Moreover, IR reduced the number of thymic mesenchymal cells but not that of NC-derived mesenchymal cells. NC-derived mesenchymal cells upregulated several hematopoietic factors such as Flt3l, Periostin, Scf, and Bmp4after irradiation and supported thymic reconstitution. Taken together, our findings indicate that NC-derived mesenchymal cells are not only radio-resistant, but also produce molecules that may support early T-cell development for thymic reconstitution after irradiation .