Regeneration of the aged thymus by a single transcription factor.
Thymic involution is central to the decline in immune system function that occurs with age. By regenerating the thymus, it may therefore be possible to improve the ability of the aged immune system to respond to novel antigens. Recently, diminished expression of the thymic epithelial cell (TEC)-specific transcription factor Forkhead box N1 (FOXN1) has been implicated as a component of the mechanism regulating age-related involution. The effects of upregulating FOXN1 function in the aged thymus are, however, unknown. Here, we show that forced, TEC-specific upregulation of FOXN1 in the fully involuted thymus of aged mice results in robust thymus regeneration characterized by increased thymopoiesis and increased naive T cell output. We demonstrate that the regenerated organ closely resembles the juvenile thymus in terms of architecture and gene expression profile, and further show that this FOXN1-mediated regeneration stems from an enlarged TEC compartment, rebuilt from progenitor TECs. Collectively, our data establish that upregulation of a single transcription factor can substantially reverse age-related thymic involution, identifying FOXN1 as a specific target for improving thymus function and, thus, immune competence in patients. More widely, they demonstrate that organ regeneration in an aged mammal can be directed by manipulation of a single transcription factor, providing a provocative paradigm that may be of broad impact for regenerative biology.
Medical Research Council Centre for Regenerative Medicine, Institute for Stem Cell Research, School of Biological Sciences, University of Edinburgh, SCRM Building, 5 Little France Drive, Edinburgh EH16 4UU, UK.
Nicholas
N
Bredenkamp
Craig S
CS
Nowell
C Clare
CC
Blackburn
D000375:Aging / Q000502:physiology*; D000818:Animals; D049109:Cell Proliferation; D060833:Cellular Microenvironment; D004847:Epithelial Cells / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D018655:Lymphocyte Count; D051379:Mice; D008822:Mice, Transgenic; D023421:Models, Animal; D010641:Phenotype; D012038:Regeneration / Q000502:physiology*; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology; D013950:Thymus Gland / Q000166:cytology / Q000502:physiology*; D015854:Up-Regulation
D051858:Forkhead Transcription Factors; C090140:Whn protein
FOXN1; Mouse; Organ regeneration; Thymic involution