Thymic epithelial cell expansion through matricellular protein CYR61 boosts progenitor homing and T-cell output

Abstract

Thymic epithelial cells (TEC) are heterogeneous stromal cells that generate microenvironments required for the formation of T cells within the thymus. Defects in TEC lead to immunodeficiency or autoimmunity. Here we identify TEC as the major source of cysteinerich protein 61 (CYR61), a matricellular protein implicated in cell proliferation and migration. Binding of CYR61 to LFA-1, ICAM-1 and integrin a6 supports the adhesion of TEC and thymocytes as well as their interaction. Treatment of thymic lobes with recombinant CYR61 expands the stromal compartment by inducing the proliferation of TEC and activates Akt signalling. Engraftment of CYR61-overexpressing thymic lobes into athymic nude mice drastically boosts the yield of thymic output via expansion of TEC. This increases the space for the recruitment of circulating hematopoietic progenitors and the development of T cells. Our discovery paves the way for therapeutic interventions designed to restore thymus stroma and T-cell generation.

CCN1/CYR61-mediated meticulous patrolling by Ly6C low monocytes fuels vascular inflammation

“…First described in cardiovascular development and carcinogenesis, CCN1 now is recognized as a mediator in leukocyte migration and inflammatory processes (15,16) and in the development of the thymus (17). CCN1 exhibits chemoattractant properties for human and murine inflammatory monocytes by promoting their adhesion and migration through integrin CD11b and the cell-surface heparin sulfate proteoglycan syndecan-4 (15,16,(18)(19)(20)(21).…”

PSMB11 Orchestrates the Development of CD4 and CD8 Thymocytes via Regulation of Gene Expression in Cortical Thymic Epithelial Cells

“…Positive selection is accompanied by periods of migration interrupted by brief migratory pauses (24). Acting in synergy with chemokines, the ECM components facilitate thymocyte migration and compartmentalization and also support thymocyte adhesion to TECs, with the thymic medulla containing a denser laminin network than the cortex (23,25,26). We found that several groups of ECM-related genes were upregulated in Psmb11 2/2 cTECs (Fig.…”

YAP promotes proliferation, chemoresistance, and angiogenesis in human cholangiocarcinoma through TEAD transcription factors

“…Differential expression of selected genes was independently verified by RT‐PCR including HuCCT1‐YAPS94A cells. RT‐PCR confirmed up‐regulation of YAP target genes ANKRD1, CYR61, CTGF (promoting proliferation), and MFAP5 (promoting tumor vascularization) and down‐regulation of TNFSF10 (encoding tumor necrosis factor–related apoptosis‐inducing ligand (TRAIL); promoting cell death) in YAP overexpressing HuCCT1 cells (Fig. D).…”