An organized and functional thymus generated from FOXN1-reprogrammed fibroblasts

Nat Cell Biol. 2014 Sep;16(9):902-8. doi: 10.1038/ncb3023. Epub 2014 Aug 24.

Abstract

A central goal of regenerative medicine is to generate transplantable organs from cells derived or expanded in vitro. Although numerous studies have demonstrated the production of defined cell types in vitro, the creation of a fully intact organ has not been reported. The transcription factor forkhead box N1 (FOXN1) is critically required for development of thymic epithelial cells (TECs), a key cell type of the thymic stroma. Here, we show that enforced Foxn1 expression is sufficient to reprogramme fibroblasts into functional TECs, an unrelated cell type across a germ-layer boundary. These FOXN1-induced TECs (iTECs) supported efficient development of both CD4(+) and CD8(+) T cells in vitro. On transplantation, iTECs established a complete, fully organized and functional thymus, that contained all of the TEC subtypes required to support T-cell differentiation and populated the recipient immune system with T cells. iTECs thus demonstrate that cellular reprogramming approaches can be used to generate an entire organ, and open the possibility of widespread use of thymus transplantation to boost immune function in patients.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cell Differentiation
  • Cells, Cultured
  • Epithelial Cells / physiology
  • Epithelial Cells / transplantation
  • Female
  • Fibroblasts / physiology*
  • Forkhead Transcription Factors / biosynthesis*
  • Forkhead Transcription Factors / genetics
  • Gene Expression
  • Male
  • Mice
  • Mice, 129 Strain
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Regenerative Medicine
  • T-Lymphocytes / physiology
  • Thymus Gland / cytology*

Substances

  • Forkhead Transcription Factors
  • Whn protein