Authors: | Wertheimer, T.; Velardi, E.; Tsai, J.; Cooper, K.; Xiao, S.; Kloss, C. C.; Ottmuller, K. J.; Mokhtari, Z.; Brede, C.; deRoos, P.; Kinsella, S.; Palikuqi, B.; Ginsberg, M.; Young, L. F.; Kreines, F.; Lieberman, S. R.; Lazrak, A.; Guo, P.; Malard, F.; Smith, O. M.; Shono, Y.; Jenq, R. R.; Hanash, A. M.; Nolan, D. J.; Butler, J. M.; Beilhack, A.; Manley, N. R.; Rafii, S.; Dudakov, J. A.; van den Brink, M. R. M. |
Article Title: | Production of BMP4 by endothelial cells is crucial for endogenous thymic regeneration |
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 Foxnl, 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. |
Keywords: | self-renewal; differentiation; epithelial-cells; hematopoietic stem-cells; bone-marrow-transplantation; vascular niche; delta-like 4; adult thymus; angiocrine signals; foxn1 |
Journal Title: | Science Immunology |
Volume: | 3 |
Issue: | 19 |
ISSN: | 2470-9468 |
Publisher: | Amer Assoc Advancement Science |
Date Published: | 2018-01-12 |
Start Page: | eaal2736 |
Language: | English |
ACCESSION: | WOS:000434330300001 |
DOI: | 10.1126/sciimmunol.aal2736 |
PROVIDER: | wos |
PMCID: | PMC5795617 |
PUBMED: | 29330161 |
Notes: | Article -- UNSP eaa12736 -- Source: Wos |