Production of BMP4 by endothelial cells is crucial for endogenous thymic regeneration

Abstract

The thymus is extremely sensitive to damage but also has a remarkable ability to repair itself. However, the mechanisms underlying this endogenous regeneration remain poorly understood and this capacity diminishes considerably with age. Here we show that thymic endothelial cells (ECs) comprise a critical pathway of regeneration, via their production of BMP4. ECs increased their production of BMP4 after thymic damage, and abrogating BMP4 signalling or production by either pharmacologic or genetic inhibition impaired thymic repair. EC-derived BMP4 acted on thymic epithelial cells (TECs) to increase their expression of Foxn1, a key transcription factor involved in TEC development, maintenance and regeneration; and its downstream targets such as Dll4, itself a key mediator of thymocyte development and regeneration. These studies demonstrate the importance of the BMP4 pathway in endogenous tissue regeneration and offer a potential clinical approach to enhance T cell immunity.

Qualitative Changes in Cortical Thymic Epithelial Cells Drive Postpartum Thymic Regeneration

“…In conclusion, our study further extends the pervasive role of Foxn1 in thymus biology, as it was shown to be involved in all models of thymic growth, regeneration, and involution to this day (14,15,34,53,55,56). Also, unlike what is observed following irradiation-induced involution (15), no evidence of BMPR signaling or of damage to the epithelial population was detected in postpartum thymic regeneration. These data imply that the mechanisms involved in triggering thymic regeneration differ depending on the context leading to thymic involution.…”

“…A recent study showed that secretion of BMP4 by thymic endothelial cells promotes thymic regeneration following acute involution induced by sub-lethal total body irradiation (15). Increased BMP4 signaling was observed in thymic stromal cells 4-7 days following irradiation, and was accompanied by an upregulation of Foxn1 and its target genes in TECs.…”

“…Based on the analysis of cell population numbers (Figure 1), we distinguished two phases in the process of postpartum regeneration: (i) D0-D12: early regeneration, during which thymic cellularity gradually increases, and (ii) D16-D28: late regeneration, when thymic cellularity exceeds that of NPC. We first analyzed the two genes previously reported to be instrumental in other models of thymic regeneration in adults: Foxn1 and Bmp4 (14,15).…”

“…Bredenkamp et al (14) showed that overexpression of Foxn1 in TECs, a key transcription factor involved in TEC differentiation and necessary for the expression of genes involved in the regulation of thymopoiesis, was sufficient to induce thymic regeneration of fully involuted thymus in aged mice (12 or 24 months old) (14). Wertheimer et al (15) more recently showed that production of BMP4 by thymic endothelial cells promoted thymic regeneration following sublethal irradiation, and acted by inducing the expression of Foxn1 and its targets in TECs (15). However, we do not know whether these mechanisms are at play in other models, such as postpartum thymic regeneration.…”

Gender Disparity Impacts on Thymus Aging and LHRH Receptor Antagonist-Induced Thymic Reconstitution Following Chemotherapeutic Damage

“…Its receptor, Bmpr2, is primarily expressed on cTEC lo and mTEC lo progenitors (42), and was proposed to have a role in maintaining progenitor populations at the expense of differentiation (10). However, Bmp4 induced self-renewal of progenitors may also have a role in thymus regeneration following damage, as demonstrated following irradiation (43).…”