Induction of multipotential hematopoietic progenitors from human pluripotent stem cells via respecification of lineage-restricted precursors

Sergei Doulatov, Linda T. Vo, Stephanie S. Chou, Peter G. Kim, Natasha Arora, Hu Li, Brandon K. Hadland, Irwin D. Bernstein, James J. Collins, Leonard I. Zon, George Q. Daley

Research output: Contribution to journalArticlepeer-review

165 Scopus citations

Abstract

Human pluripotent stem cells (hPSCs) represent a promising source of patient-specific cells for disease modeling, drug screens, and cellular therapies. However, the inability to derive engraftable human hematopoietic stem and progenitor cells (HSPCs) has limited their characterization to in vitro assays. We report a strategy to respecify lineage-restricted CD34 +CD45+ myeloid precursors derived from hPSCs into multilineage progenitors that can be expanded in vitro and engrafted in vivo. HOXA9, ERG, and RORA conferred self-renewal and multilineage potential in vitro and maintained primitive CD34+CD38- cells. Screening cells via transplantation revealed that two additional factors, SOX4 and MYB, conferred engraftment. Progenitors specified with all five factors gave rise to reproducible short-term engraftment with myeloid and erythroid lineages. Erythroid precursors underwent hemoglobin switching in vivo, silencing embryonic and activating adult globin expression. Our combinatorial screening approach establishes a strategy for obtaining transcription-factor-mediated engraftment of blood progenitors from human pluripotent cells.

Original languageEnglish (US)
Pages (from-to)459-470
Number of pages12
JournalCell Stem Cell
Volume13
Issue number4
DOIs
StatePublished - Oct 3 2013

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Cell Biology

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