Research ArticleTHYMUS

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

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Science Immunology  12 Jan 2018:
Vol. 3, Issue 19, eaal2736
DOI: 10.1126/sciimmunol.aal2736

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Regeneration circuits in the thymus

Chemotherapy and radiation treatments in cancer patients damage a number of tissues and organs, including the thymus. Prolonged thymic damage can lead to T cell deficiency and increase susceptibility to the development of opportunistic infections and malignancies. Here, Wertheimer et al. have examined thymic regeneration in mice after sublethal total body radiation and document a critical role for bone morphogenetic protein 4 (BMP4) signaling in thymic regeneration. They found endothelial cells to be a critical source of BMP4 and propose that BMP4 produced by endothelial cells induces the expression of the transcription factor FOXN1 in thymic epithelial cells to promote thymic regeneration. These studies should eventually facilitate the development of treatment regimens to promote immune competence in patients undergoing chemotherapy and radiation treatments.

Abstract

The thymus is not only 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. We show that thymic endothelial cells (ECs) comprise a critical pathway of regeneration via their production of bone morphogenetic protein 4 (BMP4). ECs increased their production of BMP4 after thymic damage, and abrogating BMP4 signaling 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, 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.

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