Hierarchical and ontogenic positions serve to define the molecular basis of human hematopoietic stem cell behavior

Farbod Shojaei; Jennifer Trowbridge; Lisa Gallacher; Lou Yuefei; David Goodale; Francis Karanu; Krysta Levac; Mickie Bhatia

doi:10.1016/j.devcel.2005.03.004

Hierarchical and ontogenic positions serve to define the molecular basis of human hematopoietic stem cell behavior

Dev Cell. 2005 May;8(5):651-63. doi: 10.1016/j.devcel.2005.03.004.

Authors

Farbod Shojaei¹, Jennifer Trowbridge, Lisa Gallacher, Lou Yuefei, David Goodale, Francis Karanu, Krysta Levac, Mickie Bhatia

Affiliation

¹ Stem Cell Biology and Regenerative Medicine, Robarts Research Institute, London, Ontario, Canada.

PMID: 15866157
DOI: 10.1016/j.devcel.2005.03.004

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis / genetics
Apoptosis / physiology
Basic Helix-Loop-Helix Transcription Factors
Basic-Leucine Zipper Transcription Factors
Cell Cycle / genetics
Cell Cycle / physiology
DNA-Binding Proteins / genetics
DNA-Binding Proteins / physiology
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
Recombinant Proteins / genetics
Recombinant Proteins / metabolism
Transcription Factor HES-1
Transcription Factors / genetics
Transcription Factors / physiology
Transfection
Transplantation, Heterologous

Substances

Basic Helix-Loop-Helix Transcription Factors
Basic-Leucine Zipper Transcription Factors
DNA-Binding Proteins
HLF protein, human
Homeodomain Proteins
Recombinant Proteins
Transcription Factor HES-1
Transcription Factors
HES1 protein, human