Abstract
Thymic aging precedes that of other organs and is initiated by the gradual loss of thymic epithelial cells (TECs). Based on in vitro culture and transplantation assays, recent studies have reported on the presence of thymic epithelial progenitor cells (TEPCs) in young adult mice. However, the physiological role and properties of TEPC populations reported to date remain unclear. Using an in vivo label-retention assay, we previously identified a population of quiescent but non-senescent TECs. The goals of this study were therefore (i) to evaluate the contribution of these quiescent TECs to thymic regeneration following irradiation-induced acute thymic injury and (ii) to characterize their phenotypic and molecular profiles using flow cytometry, immunohistology, and transcriptome sequencing. We report that while UEA1+ cells cycle the most in steady state, they are greatly affected by irradiation, leading to cell loss and proliferative arrest following acute thymic involution. On the opposite, the UEA1– subset of quiescent TECs is radioresistant and proliferate in situ following acute thymic involution, thereby contributing to thymic regeneration in 28- to 30-week-old mice. UEA1– quiescent TECs display an undifferentiated phenotype (co-expression of K8 and K5 cytokeratins) and express high levels of genes that regulate stem cell activity in different tissues (e.g., Podxl and Ptprz1). In addition, two features suggest that UEA1– quiescent TECs occupy discrete stromal niches: (i) their preferential location in clusters adjacent to the cortico-medullary junction and (ii) their high expression of genes involved in cross talk with mesenchymal cells. The ability of UEA1– quiescent TECs to participate to TEC regeneration qualifies them as in vivo progenitor cells particularly relevant in the context of regeneration following acute thymic injury.
Highlights
In all vertebrates, the thymus is the sole organ that can generate functional classic (TCRαβ+) T lymphocytes [1]
Together with their quiescent state, their resistance to radiations and their undifferentiated phenotype (K5+K8+) the ability of UEA1– LRCs to participate to thymic epithelial cells (TECs) regeneration after acute injury qualifies them as thymic epithelial progenitor cells (TEPCs)
It has been shown that cells which are extracted from their normal environment and transplanted can acquire stem cell properties that they do not display under steady-state conditions [19, 60]
Summary
The thymus is the sole organ that can generate functional classic (TCRαβ+) T lymphocytes [1]. Thymic epithelial cells (TECs) are responsible for the unique properties of the thymus: they orchestrate each steps of T-cell development and regulate thymic output [2, 3]. The production of naive T cells gradually decreases with age, a decline caused by the Progenitors in Adult Thymic Epithelium loss of TECs, which entails a reduction in the TCR repertoire diversity [4]. More severe injuries inflicted by chemotherapy or radiation therapy can overwhelm the regenerative potential of the thymic epithelium and lead to prolonged immune deficiency [14, 15]. Since tissue repair is usually driven by stem-progenitor cells, identification of thymic epithelial progenitor cells (TEPCs) responding to thymic injury should provide key insights into the mechanisms of thymic regeneration
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