Thymus compartment formation and elaboration of the vascular network

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A crucial but understudied component of the thymic architecture is the network of capillaries and blood vessels sometimes referred to as the thymic blood vessel tree. A capillary network throughout the cortex provides for oxygen delivery, as in other tissues. However, blood vessels in the thymus provide an additional critical function. Although the initial immigration of LPCs into the thymus occurs by directly traversing the epithelium in response to chemokines (64), in the postnatal thymus LPCs enter and leave the thymus via blood vessels located at the cortico-medullary junction, or CMJ (65). In spite of the crucial role blood vessels play in thymus function, almost nothing is known about the development of blood vessels in the thymus during ontogeny. CD31+ endothelial precursors first enter the thymic primordium at E12.5 (66), and the intrathymic vasculature is functionally connected to the vasculature outside the thymus by E14.5 (64) (JL Bryson et al, unpublished data). The architecture of the thymic vasculature relative to thymic compartments was first described by a study using 3D reconstructions of vessels versus medullary regions (67). This study concluded that different regions of the thymus were associated with specific types of vessels: capillaries in the cortex, medium sized vessels associated with medullary regions, and larger vessels without a consistent localization. The association of vasculature with medullary condensations in both wild-type and Rag mutant thymi suggested that interactions between vasculature and mTECs are responsible for organizing the medullary compartment, although the directionality of signaling was not determined. A more recent study also concluded that Fgf7 originating from blood vessels promotes mTEC expansion, although a direct role in mTEC differentiation is less clear (54).

As in all tissues, the vasculature is composed of more than one cell type, with endothelial cells forming vessels that are enclosed by tightly associated mesenchymal cells. In both fetal and adult thymic vasculature, NCC-derived mesenchyme surrounds the endothelial cells (68, 69). Thus, NCC-endothelial progenitor interactions are likely necessary for correct formation of the vasculature. NCC-derived pericytes also participate directly in vascular function in the postnatal thymus, as those at the CMJ have been shown to promote thymocyte egress via expression of S1P (70). TECs are also closely associated with fetal and postnatal thymic vasculature, and proper TEC differentiation is required for both initial (66) and later development and maturation of the fetal thymic vasculature (JL Bryson, et al. unpublished data). However, the signals mediating this crosstalk have not been definitively identified. One obvious candidate is vascular endothelial growth factor, or VEGF. TECs, thymic mesenchyme, and a subset of immature thymocytes (CD25+ DN cells) have all been implicated as sources of VEGF in the fetal thymus (66, 69, 71), and may direct remodeling of the thymic vasculature during perinatal medullary expansion (71). Current evidence suggests that TEC-derived VEGF may be important for formation of the capillary bed in the thymic cortex (69, 71), while mesenchyme-derived VEGF may support the development of larger vessels (69). The functional significance of apparent VEGF expression on immature thymocytes is less clear. Furthermore, VEGF is unlikely to be the only signaling pathway involved in the complex process of thymic vascularization. Thus, multiple crosstalk signals between TECs, NC mesenchyme, and endothelial cells (and possibly thymocytes) are likely required for proper patterning and maturation of the thymic vasculature.