VEGF-mediated cross-talk within the neonatal murine thymus

Abstract

Although the mechanisms of cross-talk that regulate the hematopoietic and epithelial compartments of the thymus are well established, the interactions of these compartments with the thymic endothelium have been largely ignored. Current understanding of the thymic vasculature is based on studies of adult thymus. We show that the neonatal period represents a unique phase of thymic growth and differentiation, marked by endothelium that is organized as primitive, dense networks of capillaries dependent on vascular endothelial growth factor (VEGF). VEGF dependence in neonates is mediated by significantly higher levels of both VEGF production and endothelial VEGF receptor 2 (VEGF-R2) expression than in the adult thymus. VEGF is expressed locally in the neonatal thymus by immature, CD4 ؊ CD8 ؊ "double negative" (DN) thymocytes and thymic epithelium. Relative to adult thymus, the neonatal thymus has greater thymocyte proliferation, and a predominance of immature thymocytes and cortical thymic epithelial cells (cTECs). Inhibition of VEGF signaling during the neonatal period results in rapid loss of the dense capillaries in the thymus and a marked reduction in the number of thymocytes. These data demonstrate that, during the early postnatal period, VEGF mediates cross-talk between the thymocyte and endothelial compartments of the thymus. IntroductionThe anatomy of the adult thymus and the mechanisms of cross-talk between its hematopoietic and epithelial compartments have been extensively studied through a variety of murine genetic and transplantation models. 1 The thymic epithelial cells (TECs) of the medulla and cortex have specialized roles in directing thymocyte proliferation, differentiation, and survival through both membranebound and soluble molecules. In turn, TEC development and survival is influenced by the presence of thymocytes at specific stages of development, through as yet undefined molecular mechanisms. 2,3 The role of the third compartment of the thymus, the vascular endothelium, has been generally considered to be limited to its function as a conduit for the delivery of circulating, marrow-derived thymic precursor cells; little attention has been paid to possible mechanisms of cross-talk that may regulate the thymic vascular compartment and the role of the endothelium in thymic development.The anatomy of the blood vessels in the adult thymus that deliver circulating stem and progenitor cells is closely linked to the organization of the TEC compartment. 4 The architecture of the adult thymic vasculature is hierarchic, consisting of arterioles that enter the thymus at the corticomedullary junction (CMJ) and form capillaries that ascend into the cortex in a series of anastomoses. At the periphery of the cortex, the capillaries form a fine network of branching arcades that then curve back down to the medulla, where they merge into larger postcapillary venules. 4,5 Vascular endothelial growth factor (VEGF) is a potent mitogen that plays a role in angiogenesis, promoting the migration, growth, and survival of...

Modeling the development of the post-natal mouse thymus in the absence of bone marrow progenitors

“…The best fit with the experimental data was obtained when different sets of parameters were used in the modeling of the pre-natal and post-natal thymocyte dynamics, suggesting that the processes corresponding to these stages are characterized by different rates. This discontinuity during birth in thymocyte dynamics is supported by experimental data, which showed that in the case of proliferation, the fetal thymus has greater proliferation in thymocytes than the post-natal thymus12, and the neo-natal thymus has a greater proliferation of thymocytes than the adult thymus11. This particular pattern of proliferation is what the models also revealed and suggests that discontinuity in proliferation rates during birth happens normally in the thymus and birth actually resets the development pattern of the thymus for the remainder of the post-natal life.…”

“…Relative to the adult thymus, the neonatal thymus has greater thymocyte proliferation and a predominance of immature thymocytes11. The proliferation of the DN and DP thymocyte populations is higher in the fetal thymus than in the post-natal one12.…”

Acute Thymic Involution and Mechanisms for Recovery

“…This suggests that VEGF plays an important role in ATI (Cimpean et al 2008). A rapid reduction in the dense capillaries within the thymus and a significant decrease in the number of thymocytes were observed when VEGF signaling was inhibited in the neonatal life period compared to the adult stages (Cuddihy et al 2009). More recently, in LPS-induced ATI as a primary event, both VEGF expression in neonatal thymic tissue and number of TECs were shown to decrease simultaneously in a time-dependent fashion (Zhou et al 2016).…”

Molecular Markers for Patients with Thymic Malignancies: not Feasible at Present?

“…VEGF has been involved in the cross-talk between the hematopoietic and epithelial compartments of the neonatal thymus (Cuddihy et al, 2009), but its role in the regulating the growth and proliferation of adult thymocytes remains unclear. Although VEGF and VEGFR were found to be hyperexpressed by immunohistochemistry in thymoma and thymic carcinomas (Cimpean et al, 2008), VEGF levels were previously found to be similar in the sera of patients with thymic tumors and healthy controls (Sasaki et al, 2001).…”