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Blood, 1 March 2008, Vol. 111, No. 5, pp. 2621-2630.
Prepublished online as a Blood First Edition Paper on December 21, 2007; DOI 10.1182/blood-2007-08-106666.
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Submitted August 13, 2007
Accepted December 17, 2007
Long-term maintenance of human hematopoietic stem/progenitor cells by expression of BMI1
Aleksandra Rizo, Bert Dontje, Edo Vellenga, Gerald de Haan, and Jan Jacob Schuringa*
Department of Cell Biology, Section Stem Cell Biology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
Department of Hematology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
* Corresponding author; email: j.schuringa{at}int.umcg.nl.
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. LTC-IC frequencies were increased upon stable expression of BMI1 and BMI1-transduced cells engrafted more efficiently in NOD-SCID mice. Week 5 CAFCs from stromal cocultures could be serially replated to give rise to secondary CAFCs. Serial transplantation studies in mice revealed that secondary NOD-SCID engraftment was only achieved with cells overexpressing BMI1. Importantly, BMI1-transduced cells could proliferate in stroma-free cytokine-dependent cultures for over 20 weeks while a stable population of about 1-5% of CD34+ progenitor cells was preserved that retained the capacity to form CFCs. While 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.
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