Pyrimidoindole derivatives are agonists of human hematopoietic stem cell self-renewal
Iman Fares(Institute for Research in Immunology and Cancer), Jalila Chagraoui(Institute for Research in Immunology and Cancer), Yves Gareau(Université de Montréal), Stéphane Gingras(Université de Montréal), Réjean Ruel(Université de Montréal), Nadine Mayotte(Institute for Research in Immunology and Cancer), Elizabeth Csaszar(University of Toronto), David J. H. F. Knapp(University of British Columbia), Paul H. Miller(University of British Columbia), Mor Ngom(University of British Columbia), Suzan Imren(University of British Columbia), Denis-Claude Roy(Hôpital Maisonneuve-Rosemont), Kori L. Watts(University of Washington), Hans‐Peter Kiem(University of Washington), Robert Herrington(Ontario Institute for Cancer Research), Norman N. Iscove(Ontario Institute for Cancer Research), R. Keith Humphries(University of British Columbia), Connie J. Eaves(University of British Columbia), Sandra Cohen(Hôpital Maisonneuve-Rosemont), Anne Marinier(Université de Montréal), Peter W. Zandstra(University of Toronto), Guy Sauvageau(Hôpital Maisonneuve-Rosemont)
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Abstract
The small number of hematopoietic stem and progenitor cells in cord blood units limits their widespread use in human transplant protocols. We identified a family of chemically related small molecules that stimulates the expansion ex vivo of human cord blood cells capable of reconstituting human hematopoiesis for at least 6 months in immunocompromised mice. The potent activity of these newly identified compounds, UM171 being the prototype, is independent of suppression of the aryl hydrocarbon receptor, which targets cells with more-limited regenerative potential. The properties of UM171 make it a potential candidate for hematopoietic stem cell transplantation and gene therapy.
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