title: Identification of non-cell-autonomous networks from engineered feeder cells that enhance murine hematopoietic stem cell activity.
abstract: In a previous gain-of-function screen, we identified 18 nuclear factors that enhance mouse hematopoietic stem cell (HSC) activity in vitro. Of these factors, the majority was believed to augment HSC function intrinsically. In the current study, we investigated the mechanisms of action of the previously identified agonists of HSC activity and tested whether human HSCs are also responsive to these factors. Our results unexpectedly revealed that the majority of the identified factors confer a competitive advantage to mouse HSCs in a non-cell-autonomous manner. Five of these factors, namely FOS, SPI1, KLF10, TFEC, and PRDM16, show robust transcriptional cross-regulation and are often associated with osteoclastogenesis. These findings define at least one novel non-cell-autonomous network in engineered niches. Surprisingly, and in contrast to their important effect on mouse HSCs, all engineered niches failed to significantly enhance the activity of human HSCs. This last finding further supports a lack of conservation in determinants that control HSC self-renewal in mouse versus human cells.
authors: Molecular Genetics of Stem Cells Laboratory, Institute of Research in Immunology and Cancer, University of Montreal, Montreal, Quebec, Canada.
authors: Eric
authors: E
authors: Deneault
authors: Brian T
authors: BT
authors: Wilhelm
authors: Anne
authors: A
authors: Bergeron
authors: Frédéric
authors: F
authors: Barabé
authors: Guy
authors: G
authors: Sauvageau
mesh_terms: D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics; D051765:Early Growth Response Transcription Factors / Q000235:genetics; D061252:Feeder Cells / Q000166:cytology / Q000378:metabolism*; D020869:Gene Expression Profiling; D053263:Gene Regulatory Networks; D005818:Genetic Engineering; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D041681:NIH 3T3 Cells; D009687:Nuclear Proteins / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D010010:Osteoclasts / Q000166:cytology / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015534:Trans-Activators / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D000099232:Proto-Oncogene Protein Spi-1
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D004268:DNA-Binding Proteins; D051765:Early Growth Response Transcription Factors; D051741:Kruppel-Like Transcription Factors; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D016760:Proto-Oncogene Proteins c-fos; D015534:Trans-Activators; D014157:Transcription Factors; D000099232:Proto-Oncogene Protein Spi-1; C569958:KLF10 protein, mouse; C521133:Prdm16 protein, mouse; C484069:Tcfec protein, mouse