Engineered Murine HSCs Reconstitute Multi-lineage Hematopoiesis and Adaptive Immunity

Yi Fen Lu, Patrick Cahan, Samantha Ross, Julie Sahalie, Patricia M. Sousa, Brandon K. Hadland, Wenqing Cai, Erik Serrao, Alan N. Engelman, Irwin D. Bernstein, George Q. Daley

Research output: Contribution to journalArticlepeer-review

Abstract

Hematopoietic stem cell (HSC) transplantation is curative for malignant and genetic blood disorders, but is limited by donor availability and immune-mismatch. Deriving HSCs from patient-matched embryonic/induced-pluripotent stem cells (ESCs/iPSCs) could address these limitations. Prior efforts in murine models exploited ectopic HoxB4 expression to drive self-renewal and enable multi-lineage reconstitution, yet fell short in delivering robust lymphoid engraftment. Here, by titrating exposure of HoxB4-ESC-HSC to Notch ligands, we report derivation of engineered HSCs that self-renew, repopulate multi-lineage hematopoiesis in primary and secondary engrafted mice, and endow adaptive immunity in immune-deficient recipients. Single-cell analysis shows that following engraftment in the bone marrow niche, these engineered HSCs further specify to a hybrid cell type, in which distinct gene regulatory networks of hematopoietic stem/progenitors and differentiated hematopoietic lineages are co-expressed. Our work demonstrates engineering of fully functional HSCs via modulation of genetic programs that govern self-renewal and lineage priming.

Original languageEnglish (US)
Pages (from-to)3178-3192
Number of pages15
JournalCell Reports
Volume17
Issue number12
DOIs
StatePublished - Dec 20 2016

Keywords

  • ESC-HSC
  • HSC engineering
  • HoxB4
  • Notch
  • adaptive immunity
  • adult globin
  • hematopoietic stem cell
  • lineage-priming

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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