Long-term persistence of functional thymic epithelial progenitor cells in vivo under conditions of low FOXN1 expression

TY - JOUR

T1 - Long-term persistence of functional thymic epithelial progenitor cells in vivo under conditions of low FOXN1 expression

AU - Jin, Xin

AU - Nowell, Craig S

AU - Ulyanchenko, Svetlana

AU - Stenhouse, Frances H

AU - Blackburn, C Clare

PY - 2014/12/22

Y1 - 2014/12/22

N2 - Normal thymus function reflects interactions between developing T-cells and several thymic stroma cell types. Within the stroma, key functions reside in the distinct cortical and medullary thymic epithelial cell (TEC) types. It has been demonstrated that, during organogenesis, all TECs can be derived from a common thymic epithelial progenitor cell (TEPC). The properties of this common progenitor are thus of interest. Differentiation of both cTEC and mTEC depends on the epithelial-specific transcription factor FOXN1, although formation of the common TEPC from which the TEC lineage originates does not require FOXN1. Here, we have used a revertible severely hypomorphic allele of Foxn1, Foxn1R, to test the stability of the common TEPC in vivo. By reactivating Foxn1 expression postnatally in Foxn1R/- mice we demonstrate that functional TEPCs can persist in the thymic rudiment until at least 6 months of age, and retain the potential to give rise to both cortical and medullary thymic epithelial cells (cTECs and mTECs). These data demonstrate that the TEPC-state is remarkably stable in vivo under conditions of low Foxn1 expression, suggesting that manipulation of FOXN1 activity may prove a valuable method for long term maintenance of TEPC in vitro.

AB - Normal thymus function reflects interactions between developing T-cells and several thymic stroma cell types. Within the stroma, key functions reside in the distinct cortical and medullary thymic epithelial cell (TEC) types. It has been demonstrated that, during organogenesis, all TECs can be derived from a common thymic epithelial progenitor cell (TEPC). The properties of this common progenitor are thus of interest. Differentiation of both cTEC and mTEC depends on the epithelial-specific transcription factor FOXN1, although formation of the common TEPC from which the TEC lineage originates does not require FOXN1. Here, we have used a revertible severely hypomorphic allele of Foxn1, Foxn1R, to test the stability of the common TEPC in vivo. By reactivating Foxn1 expression postnatally in Foxn1R/- mice we demonstrate that functional TEPCs can persist in the thymic rudiment until at least 6 months of age, and retain the potential to give rise to both cortical and medullary thymic epithelial cells (cTECs and mTECs). These data demonstrate that the TEPC-state is remarkably stable in vivo under conditions of low Foxn1 expression, suggesting that manipulation of FOXN1 activity may prove a valuable method for long term maintenance of TEPC in vitro.

KW - Alleles

KW - Animals

KW - Epithelial Cells/cytology

KW - Female

KW - Forkhead Transcription Factors/genetics

KW - Genotype

KW - Immunohistochemistry

KW - Keratins/metabolism

KW - Male

KW - Mice

KW - Mice, Inbred BALB C

KW - Mice, Knockout

KW - Pregnancy Proteins/metabolism

KW - Stem Cells/cytology

KW - Thymus Gland/cytology

U2 - 10.1371/journal.pone.0114842

DO - 10.1371/journal.pone.0114842

M3 - Journal article

C2 - 25531271

SN - 1932-6203

VL - 9

SP - e114842

JO - PLoS Computational Biology

JF - PLoS Computational Biology

IS - 12

ER -