title: Hierarchical and ontogenic positions serve to define the molecular basis of human hematopoietic stem cell behavior.
abstract: The molecular basis governing functional behavior of human hematopoietic stem cells (HSCs) is largely unknown. Here, using in vitro and in vivo assays, we isolate and define progenitors versus repopulating HSCs from multiple stages of human development for global gene expression profiling. Accounting for both the hierarchical relationship between repopulating cells and their progenitors, and the enhanced HSC function unique to early stages of ontogeny, the human homologs of Hairy Enhancer of Split-1 (HES-1) and Hepatocyte Leukemia Factor (HLF) were identified as candidate regulators of HSCs. Transgenic human hematopoietic cells expressing HES-1 or HLF demonstrated enhanced in vivo reconstitution ability that correlated to increased cycling frequency and inhibition of apoptosis, respectively. Our report identifies regulatory factors involved in HSC function that elicit their effect through independent systems, suggesting that a unique orchestration of pathways fundamental to all human cells is capable of controlling stem cell behavior.
authors.affiliation: Stem Cell Biology and Regenerative Medicine, Robarts Research Institute, London, Ontario, Canada.
authors.forename: Farbod
authors.initials: F
authors.lastname: Shojaei
authors.forename: Jennifer
authors.initials: J
authors.lastname: Trowbridge
authors.forename: Lisa
authors.initials: L
authors.lastname: Gallacher
authors.forename: Lou
authors.initials: L
authors.lastname: Yuefei
authors.forename: David
authors.initials: D
authors.lastname: Goodale
authors.forename: Francis
authors.initials: F
authors.lastname: Karanu
authors.forename: Krysta
authors.initials: K
authors.lastname: Levac
authors.forename: Mickie
authors.initials: M
authors.lastname: Bhatia
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D051792:Basic Helix-Loop-Helix Proteins; D050976:Basic-Leucine Zipper Transcription Factors; D002453:Cell Cycle / Q000235:genetics / Q000502:physiology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D006410:Hematopoiesis / Q000235:genetics / Q000502:physiology; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000235:genetics / Q000502:physiology; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D000072056:Transcription Factor HES-1; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology; D014162:Transfection; D014183:Transplantation, Heterologous
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D050976:Basic-Leucine Zipper Transcription Factors; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D011994:Recombinant Proteins; D000072056:Transcription Factor HES-1; D014157:Transcription Factors; C490671:HLF protein, human; C078493:HES1 protein, human