Endothelial cells promote endogenous thymic regeneration via BMP4 signaling and activation of Foxn1 (HEM7P.224)

Although the thymus has a remarkable capacity for repair following damage, the mechanisms underlying this endogenous regeneration remain poorly understood. Here we reveal a critical role for endothelial cells (ECs) in aiding thymic recovery following acute injury. We found that ECs represent a highly damage-resistant niche in the thymus and, moreover, rather than just being passive conduits that deliver oxygen and nutrients, ECs are active participants in organ function producing distinct paracrine factors that orchestrate tissue repair. In particular, we demonstrated that after damage ECs induce upregulation by cortical thymic epithelial cells (TECs) of Foxn1, a key transcription factor implicated in TEC development and thymic regeneration. Further investigation revealed that the mechanism by which ECs induced upregulation of Foxn1 was via a soluble factor that could be inhibited by Noggin, strongly suggesting the involvement of BMP signaling. Consistent with this, ECs were found to be potent producers of BMP4 after thymic damage and inhibition of BMP4 signals by ECs, achieved either pharmacologically or genetically, led to significantly worse thymic recovery after acute injury caused by TBI. These findings not only provide the first evidence of the role of ECs in endogenous thymic regeneration but, given the significant clinical need for strategies to promote immunity, also offer an innovative therapy to boost thymic function.