title: Maintenance of mouse hematopoietic stem cells ex vivo by reprogramming cellular metabolism.
abstract: The difficulty in maintaining the reconstituting capabilities of hematopoietic stem cells (HSCs) in culture outside of the bone marrow microenvironment has severely limited their utilization for clinical therapy. This hurdle is largely due to the differentiation of long-term stem cells. Emerging evidence suggests that energy metabolism plays an important role in coordinating HSC self-renewal and differentiation. Here, we show that treatment with alexidine dihydrochloride, an antibiotic and a selective inhibitor of the mitochondrial phosphatase Ptpmt1, which is crucial for the differentiation of HSCs, reprogrammed cellular metabolism from mitochondrial aerobic metabolism to glycolysis, resulting in a remarkable preservation of long-term HSCs ex vivo in part through hyperactivation of adenosine 5'-monophosphate-activated protein kinase (AMPK). In addition, inhibition of mitochondrial metabolism and activation of AMPK by metformin, a diabetes drug, also decreased differentiation and helped maintain stem cells in culture. Thus, manipulating metabolic pathways represents an effective new strategy for ex vivo maintenance of HSCs.
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, Center for Stem Cell and Regenerative Medicine, Case Western Reserve University, Cleveland, OH; and.
authors.forename: Xia
authors.initials: X
authors.lastname: Liu
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, Center for Stem Cell and Regenerative Medicine, Case Western Reserve University, Cleveland, OH; and Division of Hematology/Oncology/Bone Marrow Transplant, Department of Pediatrics, Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, GA.
authors.forename: Hong
authors.initials: H
authors.lastname: Zheng
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, Center for Stem Cell and Regenerative Medicine, Case Western Reserve University, Cleveland, OH; and Division of Hematology/Oncology/Bone Marrow Transplant, Department of Pediatrics, Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, GA.
authors.forename: Wen-Mei
authors.initials: WM
authors.lastname: Yu
authors.affiliation: Division of Hematology/Oncology/Bone Marrow Transplant, Department of Pediatrics, Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, GA.
authors.forename: Todd M
authors.initials: TM
authors.lastname: Cooper
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, Center for Stem Cell and Regenerative Medicine, Case Western Reserve University, Cleveland, OH; and Division of Hematology/Oncology/Bone Marrow Transplant, Department of Pediatrics, Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, GA.
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Bunting
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, Center for Stem Cell and Regenerative Medicine, Case Western Reserve University, Cleveland, OH; and Division of Hematology/Oncology/Bone Marrow Transplant, Department of Pediatrics, Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, GA.
authors.forename: Cheng-Kui
authors.initials: CK
authors.lastname: Qu
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000332:Aerobiosis / Q000187:drug effects; D000818:Animals; D001645:Biguanides / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D065150:Cellular Reprogramming / Q000187:drug effects*; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006019:Glycolysis / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D007004:Hypoglycemic Agents / Q000494:pharmacology; D008687:Metformin / Q000494:pharmacology; D051379:Mice; D010101:Oxygen Consumption / Q000187:drug effects; D051059:PTEN Phosphohydrolase / Q000037:antagonists & inhibitors*; D017027:Protein Tyrosine Phosphatases
chemical_list: D055372:AMP-Activated Protein Kinases; D001645:Biguanides; D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; D008687:Metformin; D051059:PTEN Phosphohydrolase; C492433:Ptpmt1 protein, mouse; D017027:Protein Tyrosine Phosphatases; C001570:alexidine