Mesenchymal Cells Regulate Retinoic Acid Receptor-Dependent Cortical Thymic Epithelial Cell Homeostasis

Abstract

The vitamin A metabolite and transcriptional modulator retinoic acid (RA) is recognized as an important regulator of epithelial cell homeostasis in several tissues. Despite the known importance of the epithelial compartment of the thymus in T cell development and selection, the potential role of RA in the regulation of thymic cortical and medullary epithelial cell homeostasis has yet to be addressed. In this study, using fetal thymus organ cultures, we demonstrate that endogenous RA signaling promotes thymic epithelial cell (TEC) cell-cycle exit and restricts TEC cellularity preferentially in the cortical TEC compartment. Combined gene expression, biochemical, and functional analyses identified mesenchymal cells as the major source of RA in the embryonic thymus. In reaggregate culture experiments, thymic mesenchyme was required for RA-dependent regulation of TEC expansion, highlighting the importance of mesenchyme-derived RA in modulating TEC turnover. The RA-generating potential of mesenchymal cells was selectively maintained within a discrete Ly51intgp38+ subset of Ly51+ mesenchyme in the adult thymus, suggesting a continual role for mesenchymal cell-derived RA in postnatal TEC homeostasis. These findings identify RA signaling as a novel mechanism by which thymic mesenchyme influences TEC development.

Retinoic Acid Receptor γ Regulates B and T Lymphopoiesis via Nestin-Expressing Cells in the Bone Marrow and Thymic Microenvironments

“…Our observation that the proportions of cTECs were significantly downregulated further supports previous studies showing that PDGFRa-expressing mesenchyme regulates the proliferation of epithelial cells, and hence thymic size (31). Interestingly, a separate study using fetal thymus organ cultures showed that RA signaling regulated the proliferation and differentiation of cTECs via mesenchymal cells (57). Our data suggest that RARg signaling in Nespositive NC mesenchyme cells is a key regulator of cTECs and thymic size.…”

“…Furthermore, the thymic mesenchyme was identified as the major source of RA in the embryonic thymus (57). Moreover, a subset of CDR1 + thymic mesenchyme maintained the RA generation potential in the adult thymus (57 PDGFRa. In further support, the Nes-targeted cells identified in our studies reside in perivascular regions (Fig.…”

“…Interestingly, a recent study has shown that RA signaling regulates TEC proliferation in vitro (57). Furthermore, the thymic mesenchyme was identified as the major source of RA in the embryonic thymus (57).…”

“…Interestingly, a recent study has shown that RA signaling regulates TEC proliferation in vitro (57). Furthermore, the thymic mesenchyme was identified as the major source of RA in the embryonic thymus (57). Moreover, a subset of CDR1 + thymic mesenchyme maintained the RA generation potential in the adult thymus (57 PDGFRa.…”

Thymic Mesenchymal Cells Have a Distinct Transcriptomic Profile

“…This is notably the case for thymic MCs. During development, thymic MCs regulate the proliferation of thymic epithelial cells through production of fibroblast growth factor (FGF)-7 and -10, insulin-like growth factor (IGF)-1 and -2, and retinoic acid (7)(8)(9)(10)(11). However, little is known of the role of thymic MCs during postnatal life, aside from the fact that CD248 + MCs play a role in revascularizing thymuses during infectiondependent regeneration and that FSP1 + MCs are essential for the maintenance of the medullary thymic epithelium (12,13).…”