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

Tobias Wertheimer, Enrico Velardi, Jennifer Tsai, Kirsten Cooper, Shiyun Xiao, Christopher C. Kloss, Katja J. Ottmüller, Zeinab Mokhtari, Christian Brede, Paul deRoos, Sinéad Kinsella, Brisa Palikuqi, Michael Ginsberg, Lauren F. Young, Fabiana Kreines, Sophia R. Lieberman, Amina Lazrak, Peipei Guo, Florent Malard, Odette M. SmithYusuke Shono, Robert R. Jenq, Alan M. Hanash, Daniel J. Nolan, Jason M. Butler, Andreas Beilhack, Nancy R. Manley, Shahin Rafii, Jarrod A. Dudakov, Marcel R.M. van den Brink

Research output: Contribution to journalArticlepeer-review

65 Scopus citations

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.

Original languageEnglish
Article numbereaal2736
JournalScience immunology
Volume3
Issue number19
DOIs
StatePublished - 2018
Externally publishedYes

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