Hierarchical and Ontogenic Positions Serve to Define the Molecular Basis of Human Hematopoietic Stem Cell Behavior

• Published in: Developmental cell 2005-05, Vol.8 (5), p.651-663
• Main Authors: Shojaei, Farbod, Trowbridge, Jennifer, Gallacher, Lisa, Yuefei, Lou, Goodale, David, Karanu, Francis, Levac, Krysta, Bhatia, Mickie
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis - genetics; Apoptosis - physiology; Basic Helix-Loop-Helix Transcription Factors; Basic-Leucine Zipper Transcription Factors; Biological and medical sciences; Cell Cycle - genetics; Cell Cycle - physiology; Cell differentiation, maturation, development, hematopoiesis; Cell physiology; DNA-Binding Proteins - genetics; DNA-Binding Proteins - physiology; Fundamental and applied biological sciences. Psychology; Gene Expression Profiling; Gene Expression Regulation, Developmental; Hematopoiesis - genetics; Hematopoiesis - physiology; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells - cytology; Hematopoietic Stem Cells - metabolism; Homeodomain Proteins - genetics; Homeodomain Proteins - physiology; Humans; Mice; Mice, Inbred NOD; Mice, SCID; Molecular and cellular biology; Recombinant Proteins - genetics; Recombinant Proteins - metabolism; Transcription Factor HES-1; Transcription Factors - genetics; Transcription Factors - physiology; Transfection; Transplantation, Heterologous
• ISSN: 1534-5807; 1878-1551
• DOI: 10.1016/j.devcel.2005.03.004

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.