BioProject

Hematopoietic stem cell (HSC) transplantation has the potential to cure blood disorders but is limited by donor availability. More...

Hematopoietic stem cell (HSC) transplantation has the potential to cure blood disorders but is limited by donor availability. Hence innovative approaches to engineer HSC are critically needed. HoxB4 over-expression in mouse embryonic stem cell-derived HSC (ESC-HSC) confers long-term engraftment, yet lacks efficient lymphogenesis. Transcriptome comparison of ESC-HSC versus embryo-derived HSC showed that ESC-HSC are deficient in expression programs activated by Notch. Therefore, we aim to improve ESC-HSC by further providing Notch signals through Notch1 intra-cellular domain transgene activation or by ligand stimulation. Here, we report that Notch-enhanced ESC-HSC (nESC-HSC) confer clonal multipotentiality with robust lymphopoiesis that endows adaptive immunity. Notably, nESC-HSC further evolve to a hybrid cell-type co-expressing gene regulatory networks of hematopoietic stem/progenitor cells and differentiated lineages at single-cell level that accounts for multipotentiality. Our work reveals a proof-of-concept model of HSC engineering by assembling self-renewing factor and lineage-guiding pathway into one product-cell that functionally recapitulate HSC in vivo. Overall design: The gene expression of murine hematopoietic stem cells, ESC, and HSC-like cells derived from differentiation of embryonic stem cells and subsequently transplanted were determined by single cell RNA-Seq. Less...