Description
FOXN1 overexpression programmes mouse embryonic stem cells into thymic epithelial cells.Abstract:
The thymus is a central organ of the immune system, required for production of a functional, self-tolerant T cell repertoire; however, it is one of the first organs to degenerate during normal healthy aging. The forkhead transcription factor FOXN1 is the master regulator of thymic epithelial cell (TEC) differentiation and maintenance, orchestrating thymus function throughout life. We have previously shown that TEC-specific transgenic upregulation of FOXN1 reverses thymic involution in aged mice, and that enforced FOXN1 expression converts mouse embryonic fibroblasts into induced TECs (iTECs) capable of forming an organised and fully functional thymus upon transplantation. These findings identified FOXN1 as a key programming factor and a promising target for the development of stem cell-based strategies to improve thymus function in immunocompromised patients. To provide a clinically relevant starting cell type from which to generate iTECs for translational studies, we have now extended our FOXN1-mediated programming approach to pluripotent stem cells. We found that FOXN1 overexpression in mouse embryonic stem cells (mESCs) led to morphological changes consistent with conversion to epithelial cell identity. This was accompanied by the expression of a number of TEC-specific FOXN1 target genes, including Ccl25, Dll4, Cxcl12 and KitL, confirming programming of mESCs into iTECs. Sustained induction of low levels of endogenous Foxn1 was also observed, indicating that FOXN1 can positively auto-regulate. Further phenotypic and functional analyses are currently underway to assess the capacity of FOXN1-programmed mESCs to support T cell development in vitro, and to form a functional thymus upon transplantation in mice.
| Period | 2 Nov 2017 |
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| Held at | Daphne Jackson Trust, United Kingdom |