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Regeneration of the aged thymus by a single transcription factor.

TitleRegeneration of the aged thymus by a single transcription factor.
Publication TypeJournal Article
Year of Publication2014
AuthorsBredenkamp N, Nowell CS, C Blackburn C
JournalDevelopment
Volume141
Issue8
Pagination1627-37
Date Published2014 Apr
ISSN1477-9129
KeywordsAging, Animals, Cell Proliferation, Cellular Microenvironment, Epithelial Cells, Forkhead Transcription Factors, Lymphocyte Count, Mice, Mice, Transgenic, Models, Animal, Phenotype, Regeneration, Stem Cells, T-Lymphocytes, Thymus Gland, Up-Regulation
Abstract

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.

DOI10.1242/dev.103614
Alternate JournalDevelopment
PubMed ID24715454
PubMed Central IDPMC3978836
Grant ListG0300058 / / Medical Research Council / United Kingdom
MR/K017047/10 / / Medical Research Council / United Kingdom
P01 1P01AI076514-01A1 / AI / NIAID NIH HHS / United States
Publication institute
CRM