Project description:Natural hematopoietic stem cells are currently the only cell resource to generate entire T lymphopoiesis in vivo. Altenatively, functional and non-tumorigenic T lymphocytes converted from the other cell types remain unsuccessful. Evidence is still lacking about the concept that 'lineage-switching factors' (LSFs) exist in HSC, whose re-activation in progeny cells can accomplish lineage conversions. Here we show that upon ectopic expression of Hoxb5(a HSC-specific transcription factor), the Pro-/Pre-B cells were induced into functional early T cell progenitors(iETPs) in vivo. The reprogramming process initiated in the bone marrow and accomplished in the thymus at ETP stage. Strikingly, the T lymphocytes derived from iETPs resemble their natural counterparts in transcriptome pattern, hierarchical differentiation, tissue distribution and immune functions. Our observations pave the way for achieving lineage regeneration by direct reprogramming autologous somatic cells in vivo. Further, our success in haematopoietic system may build a paradigm for LSF-mediated regeneration of other tissues.
Project description:Deletion of master regulators of the B cell lineage reprograms B cells into T cells. Here we found that the transcription factor Hoxb5, which is expressed in uncommitted hematopoietic progenitor cells but is not present in cells committed to the B cell or T cell lineage, was able to reprogram pro-pre-B cells into functional early T cell lineage progenitors. This reprogramming started in the bone marrow and was completed in the thymus and gave rise to T lymphocytes with transcriptomes, hierarchical differentiation, tissue distribution and immunological functions that closely resembled those of their natural counterparts. Hoxb5 repressed B cell 'master genes', activated regulators of T cells and regulated crucial chromatin modifiers in pro-pre-B cells and ultimately drove the B cell fate-to-T cell fate conversion. Our results provide a de novo paradigm for the generation of functional T cells through reprogramming in vivo.
Project description:We performed the single cell RNA-seq for the Hoxb5 Mac-1+CD48+ SK cells, bone marrow HSC, bone marrow MPP, and fetal liver HSC by Smart-Seq2.