Long-term maintenance of human hematopoietic stem/progenitor cells by expression of BMI1
- 1 March 2008
- journal article
- Published by American Society of Hematology in Blood
- Vol. 111 (5), 2621-2630
- https://doi.org/10.1182/blood-2007-08-106666
Abstract
The polycomb group (PcG) gene BMI1 has been identified as one of the key epigenetic regulators of cell fates during different stages of development in multiple murine tissues. In a clinically relevant model, we demonstrate that enforced expression of BMI1 in cord blood CD34+ cells results in long-term maintenance and self-renewal of human hematopoietic stem and progenitor cells. Long-term culture-initiating cell frequencies were increased upon stable expression of BMI1 and these cells engrafted more efficiently in NOD-SCID mice. Week 5 cobblestone area-forming cells (CAFCs) were replated to give rise to secondary CAFCs. Serial transplantation studies in NOD-SCID mice revealed that secondary engraftment was only achieved with cells overexpressing BMI1. Importantly, BMI1-transduced cells proliferated in stroma-free cytokine-dependent cultures for more than 20 weeks, while a stable population of approximately 1% to 5% of CD34+ cells was preserved that retained colony-forming capacity. Whereas control cells lost most of their NOD-SCID engraftment potential after 10 days of ex vivo culturing in absence of stroma, NOD-SCID multilineage engraftment was retained by overexpression of BMI1. Thus, our data indicate that self-renewal of human hematopoietic stem cells is enhanced by BMI1, and we classify BMI1 as an intrinsic regulator of human stem/progenitor cell self-renewal.Keywords
This publication has 44 references indexed in Scilit:
- Bmi1 cooperates with Dnmt1-associated protein 1 in gene silencingBiochemical and Biophysical Research Communications, 2007
- Polycomb silencers control cell fate, development and cancerNature Reviews Cancer, 2006
- Genome-wide analysis of Polycomb targets in Drosophila melanogasterNature Genetics, 2006
- Genome-wide profiling of PRC1 and PRC2 Polycomb chromatin binding in Drosophila melanogasterNature Genetics, 2006
- Polycomb complexes repress developmental regulators in murine embryonic stem cellsNature, 2006
- Genome-wide mapping of Polycomb target genes unravels their roles in cell fate transitionsGenes & Development, 2006
- Control of Developmental Regulators by Polycomb in Human Embryonic Stem CellsCell, 2006
- Association of BMI1 with Polycomb Bodies Is Dynamic and Requires PRC2/EZH2 and the Maintenance DNA Methyltransferase DNMT1Molecular and Cellular Biology, 2005
- Polycomb Group Proteins Ring1A/B Link Ubiquitylation of Histone H2A to Heritable Gene Silencing and X InactivationDevelopmental Cell, 2004
- Polycomb repression: from cellular memory to cellular proliferation and cancerBiochimica et Biophysica Acta (BBA) - Reviews on Cancer, 2002