Document details
Thymic crosstalk restrains the pool of cortical thymic epithelial cells with progenitor properties(Article)
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- aInstituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal
- bThymus Development and Function Laboratory, Infection and Immunity Unit, Instituto de Biologia Molecular e Celular, Porto, Portugal
- cDoctoral Program in Cell and Molecular Biology, Instituto de Ciências Biomédicas, Universidade do Porto, Porto, Portugal
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Abstract
Cortical (cTEC) and medullary (mTEC) thymic epithelial cells establish key microenvironments for T-cell differentiation and arise from thymic epithelial cell progenitors (TEP). However, the nature of TEPs and the mechanism controlling their stemness in the postnatal thymus remain poorly defined. Using TEC clonogenic assays as a surrogate to survey TEP activity, we found that a fraction of cTECs generates specialized clonal-derived colonies, which contain cells with sustained colony-forming capacity (ClonoTECs). These ClonoTECs are EpCAM+MHCII-Foxn1lo cells that lack traits of mature cTECs or mTECs but co-express stem-cell markers, including CD24 and Sca-1. Supportive of their progenitor identity, ClonoTECs reintegrate within native thymic microenvironments and generate cTECs or mTECs in vivo. Strikingly, the frequency of cTECs with the potential to generate ClonoTECs wanes between the postnatal and young adult immunocompetent thymus, but it is sustained in alymphoid Rag2-/-Il2rg-/- counterparts. Conversely, transplantation of wild-type bone marrow hematopoietic progenitors into Rag2-/-Il2rg-/- mice and consequent restoration of thymocyte-mediated TEC differentiation diminishes the frequency of colony-forming units within cTECs. Our findings provide evidence that the cortical epithelium contains a reservoir of epithelial progenitors whose abundance is dynamically controlled by continual interactions with developing thymocytes across lifespan. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Indexed keywords
| EMTREE drug terms: | ataxin 1beta actinCD24 antigencytokeratin 8epithelial cell adhesion moleculegreen fluorescent proteinred fluorescent protein |
|---|---|
| EMTREE medical terms: | adultanimal cellArticlecell differentiationcell levelcell selectionclonogenic assaycoculturecolony forming cellcolony forming unitcomparative studycontrolled studydilutionepithelium cellfeeder cellflow cytometryfluorescence imagingimmunofluorescence microscopyin vitro studymousenonhumanorgan culturepriority journalprotein expressionthymocytethymusthymus transplantationyoung adultanimalcell clonecytologyepithelium cellhumanimmunologylymphocyte activationmetabolismphysiologystem cellthymus |
| MeSH: | AnimalsCell DifferentiationClone CellsEpithelial CellsHumansLymphocyte ActivationMiceStem CellsThymocytesThymus Gland |
Chemicals and CAS Registry Numbers:
red fluorescent protein, 251925-26-5
Funding details
| Funding sponsor | Funding number | Acronym |
|---|---|---|
| Programa Operacional Temático Factores de Competitividade | ||
| China National Funds for Distinguished Young Scientists | ||
| PTDC/SAU-IMU/117057/2010,FCOMP-01-0124-FEDER-021075 | ||
| Fundação para a Ciência e a Tecnologia See opportunities | POCI-01-0145-FEDER-007274 | |
| POCI | ||
| Deutsches Krebsforschungszentrum | ||
| European Research Council | ||
| European Metrology Programme for Innovation and Research | 637843 - TEC_Pro |
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1
We thank Thomas Boehm (Max Planck Institute of Immunology and Epigenetics, Freiburg, Germany) for Foxn1eGFP reporter mice. We thank Dr. Hans-Reimer Rodewald (German Cancer Research Center, Heidelberg, Germany) for the anti-Foxn1 antibody. We thank Dr. Leonor Ara?jo for technical support and Drs. Chiara Perrod and Gema Romera-Cardenas for critical reading the manuscript. We also thank Dr. Sofia Lamas and the caretakers from the animal facility for the assistance with animal experimentation. C.M., A.R.R., and N.L.A. conceived and designed experiments, performed experiments, analyzed the data, and wrote the manuscript. P.M.R., R.D.P., and C.L. performed experiments and analyzed data. N.L.A. conceptualized the original idea. This work has received funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (grant agreement No 637843 - TEC_Pro), from FEDER - Fundo Europeu de Desenvolvimento Regional funds through the COMPETE 2020 - Operacional Programme for Competitiveness and Internationalisation (POCI), Portugal 2020,?and by Portuguese funds through FCT - Funda??o para a Ci?ncia e a Tecnologia/Minist?rio da Ci?ncia, Tecnologia e Ensino Superior in the framework of the project ?Institute for Research and Innovation in Health Sciences? (POCI-01-0145-FEDER-007274) and FEDER funds through the Operational Competitiveness Programme ? COMPETE and by National Funds through FCT ? Funda??o para a Ci?ncia e a Tecnologia under the project FCOMP-01-0124-FEDER-021075 (PTDC/SAU-IMU/117057/2010). N.L.A., P.M.R., A.R.R., C.M., and R.D.P. are supported by the Investigator program, Post-doctoral and PhD fellowships from FCT (Portugal).
- ISSN: 00142980
- CODEN: EJIMA
- Source Type: Journal
- Original language: English
- DOI: 10.1002/eji.201746922
- PubMed ID: 28318017
- Document Type: Article
- Publisher: Wiley-VCH Verlag
Alves, N.L.; Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal;
© Copyright 2017 Elsevier B.V., All rights reserved.
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