title: MicroRNAs and Metabolites in Serum Change after Chemotherapy: Impact on Hematopoietic Stem and Progenitor Cells.
abstract: Hematopoietic regeneration after high dose chemotherapy necessitates activation of the stem cell pool. There is evidence that serum taken after chemotherapy comprises factors stimulating proliferation and self-renewal of CD34(+) hematopoietic stem and progenitor cells (HSPCs)--however, the nature of these feedback signals is yet unclear. Here, we addressed the question if specific microRNAs (miRNAs) or metabolites are affected after high dose chemotherapy. Serum taken from the same patients before and after chemotherapy was supplemented for in vitro cultivation of HSPCs. Serum taken after chemotherapy significantly enhanced HSPC proliferation, better maintained a CD34(+) immunophenotype, and stimulated colony forming units. Microarray analysis revealed that 23 miRNAs changed in serum after chemotherapy--particularly, miRNA-320c and miRNA-1275 were down-regulated whereas miRNA-3663-3p was up-regulated. miRNA-320c was exemplarily inhibited by an antagomiR, which seemed to increase proliferation. Metabolomic profiling demonstrated that 44 metabolites were less abundant, whereas three (including 2-hydroxybutyrate and taurocholenate sulphate) increased in serum upon chemotherapy. Nine of these metabolites were subsequently tested for effects on HSPCs in vitro, but none of them exerted a clear concentration dependent effect on proliferation, immunophenotype and colony forming unit formation. Taken together, serum profiles of miRNAs and metabolites changed after chemotherapy. Rather than individually, these factors may act in concert to recruit HSPCs into action for hematopoietic regeneration.
authors.affiliation: Helmholtz Institute for Biomedical Engineering, RWTH Aachen University Medical School, Aachen, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Walenda
authors.affiliation: Miltenyi Biotec GmbH, Bergisch Gladbach, Germany.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Diener
authors.affiliation: Department for Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, RWTH Aachen University Medical School, Aachen, Germany.
authors.forename: Edgar
authors.initials: E
authors.lastname: Jost
authors.affiliation: Metabolon, Inc., Durham, NC, 27519, United States of America.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Morin-Kensicki
authors.affiliation: Department of Obstetrics and Gynecology, RWTH Aachen University Medical School, Aachen, German.
authors.forename: Tamme W
authors.initials: TW
authors.lastname: Goecke
authors.affiliation: Miltenyi Biotec GmbH, Bergisch Gladbach, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Bosio
authors.affiliation: Department for Orthopedics, RWTH Aachen University Medical School, Aachen, Germany.
authors.forename: Björn
authors.initials: B
authors.lastname: Rath
authors.affiliation: Department for Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, RWTH Aachen University Medical School, Aachen, Germany.
authors.forename: Tim H
authors.initials: TH
authors.lastname: Brümmendorf
authors.affiliation: Miltenyi Biotec GmbH, Bergisch Gladbach, Germany.
authors.forename: Ute
authors.initials: U
authors.lastname: Bissels
authors.affiliation: Helmholtz Institute for Biomedical Engineering, RWTH Aachen University Medical School, Aachen, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Wagner
mesh_terms: D018952:Antigens, CD34 / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D016022:Case-Control Studies; D049109:Cell Proliferation; D002478:Cells, Cultured; D003114:Colony-Forming Units Assay; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects*; D006412:Hematopoietic Stem Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000097:blood / Q000188:drug therapy; D008223:Lymphoma / Q000097:blood / Q000188:drug therapy; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000378:metabolism; D035683:MicroRNAs / Q000097:blood* / Q000235:genetics / Q000378:metabolism; D009101:Multiple Myeloma / Q000097:blood / Q000188:drug therapy; D044967:Serum
chemical_list: D018952:Antigens, CD34; D000970:Antineoplastic Agents; C554214:MIRN424 microrna, human; D035683:MicroRNAs