title: Long-term maintenance of human hematopoietic stem/progenitor cells by expression of BMI1.
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.
authors.affiliation: Department of Cell Biology, Section Stem Cell Biology, University Medical Center, University of Groningen, Deusinglaan 1, Groningen, The Netherlands.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Rizo
authors.forename: Bert
authors.initials: B
authors.lastname: Dontje
authors.forename: Edo
authors.initials: E
authors.lastname: Vellenga
authors.forename: Gerald
authors.initials: G
authors.lastname: de Haan
authors.forename: Jan Jacob
authors.initials: JJ
authors.lastname: Schuringa
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000378:metabolism; D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D017209:Apoptosis; D049109:Cell Proliferation; D002478:Cells, Cultured; D046528:Chimerism; D005260:Female; D005312:Fetal Blood / Q000166:cytology; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D009687:Nuclear Proteins / Q000378:metabolism*; D063150:Polycomb Repressive Complex 1; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism*; D012190:Retroviridae; D017154:Stromal Cells / Q000166:cytology; D013997:Time Factors
chemical_list: D018952:Antigens, CD34; C069077:BMI1 protein, human; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D063150:Polycomb Repressive Complex 1; D051997:ADP-ribosyl Cyclase 1