title: Phenotypic and Functional Alterations of Hematopoietic Stem and Progenitor Cells in an In Vitro Leukemia-Induced Microenvironment.
abstract: An understanding of the cell interactions occurring in the leukemic microenvironment and their functional consequences for the different cell players has therapeutic relevance. By co-culturing mesenchymal stem cells (MSC) with the REH acute lymphocytic leukemia (ALL) cell line, we have established an in vitro leukemic niche for the functional evaluation of hematopoietic stem/progenitor cells (HSPC, CD34+ cells). We showed that the normal homeostatic control exerted by the MSC over the HSPC is considerably lost in this leukemic microenvironment: HSPC increased their proliferation rate and adhesion to MSC. The adhesion molecules CD54 and CD44 were consequently upregulated in HSPC from the leukemic niche. Consequently, with this adhesive phenotype, HSPC showed less Stromal derived factor-1 (SDF-1)-directed migration. Interestingly, multipotency was severely affected with an important reduction in the absolute count and the percentage of primitive progenitor colonies. It was possible to simulate most of these HSPC alterations by incubation of MSC with a REH-conditioned medium, suggesting that REH soluble factors and their effect on MSC are important for the observed changes. Of note, these HSPC alterations were reproduced when primary leukemic cells from an ALL type B (ALL-B) patient were used to set up the leukemic niche. These results suggest that a general response is induced in the leukemic niche to the detriment of HSPC function and in favor of leukemic cell support. This in vitro leukemic niche could be a valuable tool for the understanding of the molecular events responsible for HSPC functional failure and a useful scenario for therapeutic evaluation.
authors.affiliation: Cellular and Molecular Physiology, Biomedical Research Institute, Faculty of Medicine, Universidad Nacional de Colombia, Bogotá D.C. 111321, Colombia. jpvernoth@unal.edu.co.
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Vernot
authors.affiliation: Cellular and Molecular Physiology, Biomedical Research Institute, Faculty of Medicine, Universidad Nacional de Colombia, Bogotá D.C. 111321, Colombia. xmbonillaf@unal.edu.co.
authors.forename: Ximena
authors.initials: X
authors.lastname: Bonilla
authors.affiliation: Inmunobiology and Cellular Biology, Faculty of Science, Pontificia Universidad Javeriana, Bogotá D.C. 110231, Colombia. vivianar@javeriana.edu.co.
authors.forename: Viviana
authors.initials: V
authors.lastname: Rodriguez-Pardo
authors.affiliation: Cellular and Molecular Physiology, Biomedical Research Institute, Faculty of Medicine, Universidad Nacional de Colombia, Bogotá D.C. 111321, Colombia. npvanegasa@unal.edu.co.
authors.forename: Natalia-Del Pilar
authors.initials: NP
authors.lastname: Vanegas
mesh_terms: D018952:Antigens, CD34 / Q000378:metabolism; D015415:Biomarkers; D002448:Cell Adhesion; D002450:Cell Communication; D002454:Cell Differentiation; D002465:Cell Movement; D049109:Cell Proliferation; D018920:Coculture Techniques; D016207:Cytokines / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D007938:Leukemia / Q000378:metabolism* / Q000473:pathology*; D008198:Lymph Nodes / Q000378:metabolism; D059630:Mesenchymal Stem Cells; D010641:Phenotype; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000378:metabolism / Q000473:pathology; D055153:Stem Cell Niche; D059016:Tumor Microenvironment
chemical_list: D018952:Antigens, CD34; D015415:Biomarkers; D016207:Cytokines
keywords: REH-conditioned medium; adhesion; cell malfunction; hematopoietic stem cells; leukemic niche; mesenchymal stem cell; microenvironment; multipotency; progenitor cells; proliferation