1. Hierarchical and ontogenic positions serve to define the molecular basis of human hematopoietic stem cell behavior
- Author
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Jennifer J. Trowbridge, Francis Karanu, Krysta Levac, Mickie Bhatia, Lou Yuefei, Lisa Gallacher, Farbod Shojaei, and David Goodale
- Subjects
Transplantation, Heterologous ,Apoptosis ,Mice, SCID ,Biology ,Transfection ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Mice, Inbred NOD ,medicine ,Basic Helix-Loop-Helix Transcription Factors ,Animals ,Humans ,Progenitor cell ,Enhancer ,Molecular Biology ,Transcription factor ,030304 developmental biology ,Genetics ,Homeodomain Proteins ,0303 health sciences ,Gene Expression Profiling ,Cell Cycle ,Hematopoietic Stem Cell Transplantation ,Hematopoietic stem cell ,Gene Expression Regulation, Developmental ,Cell Biology ,Hematopoietic Stem Cells ,Recombinant Proteins ,Cell biology ,Hematopoiesis ,Gene expression profiling ,DNA-Binding Proteins ,Haematopoiesis ,medicine.anatomical_structure ,Basic-Leucine Zipper Transcription Factors ,030220 oncology & carcinogenesis ,Transcription Factor HES-1 ,Stem cell ,Developmental Biology ,Transcription Factors - Abstract
SummaryThe 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.
- Published
- 2004