title: Metabolism Regulates Cellular Functions of Bone Marrow-Derived Cells used for Cardiac Therapy.
abstract: Administration of bone marrow-derived mononuclear cells (BMC) may increase cardiac function after myocardial ischemia. However, the functional capacity of BMC derived from chronic heart failure (CHF) patients is significantly impaired. As modulation of the energy metabolism allows cells to match the divergent demands of the environment, we examined the regulation of energy metabolism in BMC from patients and healthy controls (HC). The glycolytic capacity of CHF-derived BMC is reduced compared to HC, whereas BMC of metabolically activated bone marrow after acute myocardial infarction reveal increased metabolism. The correlation of metabolic pathways with the functional activity of cells indicates an influence of metabolism on cell function. Reducing glycolysis without profoundly affecting ATP-production reversibly reduces invasion as well as colony forming capacity and abolishes proliferation of CD34(+) CD38(-) lin(-) hematopoietic stem and progenitor cells (HSPC). Ex vivo inhibition of glycolysis further reduced the pro-angiogenic activity of transplanted cells in a hind limb ischemia model in vivo. In contrast, inhibition of respiration, without affecting total ATP production, leads to a compensatory increase in glycolytic capacity correlating with increased colony forming capacity. Isolated CD34(+) , CXCR4(+) , and CD14(+) cells showed higher glycolytic activity compared to their negative counterparts. Metabolic activity was profoundly modulated by the composition of media used to store or culture BMC. This study provides first evidence that metabolic alterations influence the functional activity of human HSPC and BMC independent of ATP production. Changing the balance between respiration and glycolysis might be useful to improve patient-derived cells for clinical cardiac cell therapy. Stem Cells 2016;34:2236-2248.
authors.affiliation: Institute for Cardiovascular Regeneration, Centre of Molecular Medicine, Goethe University.
authors.forename: Anja
authors.initials: A
authors.lastname: Derlet
authors.affiliation: Institute for Cardiovascular Regeneration, Centre of Molecular Medicine, Goethe University.
authors.forename: Tina
authors.initials: T
authors.lastname: Rasper
authors.affiliation: LOEWE Center for Cell and Gene Therapy, Internal Medicine III, Goethe University, Hematology/Oncology.
authors.forename: Aaheli
authors.initials: A
authors.lastname: Roy Choudhury
authors.affiliation: LOEWE Center for Cell and Gene Therapy, Internal Medicine III, Goethe University, Hematology/Oncology.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Bothur
authors.affiliation: LOEWE Center for Cell and Gene Therapy, Internal Medicine III, Goethe University, Hematology/Oncology.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Rieger
authors.affiliation: Faculty of Medicine, Institute of Biochemistry I/ZAFES, Goethe University.
authors.forename: Dmitry
authors.initials: D
authors.lastname: Namgaladze
authors.affiliation: Institute for Cardiovascular Regeneration, Centre of Molecular Medicine, Goethe University.
authors.forename: Ariane
authors.initials: A
authors.lastname: Fischer
authors.affiliation: Faculty of Medicine, Institute for Cardiovascular Physiology, Goethe University.
authors.forename: Christoph
authors.initials: C
authors.lastname: Schürmann
authors.affiliation: Faculty of Medicine, Institute for Cardiovascular Physiology, Goethe University.
authors.forename: Ralf P
authors.initials: RP
authors.lastname: Brandes
authors.affiliation: Department for Biomedical Research and Project Evaluation, Fresenius Medical Care Deutschland GmbH, Goethe University, Bad Homburg, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Tschulena
authors.affiliation: Department for Biomedical Research and Project Evaluation, Fresenius Medical Care Deutschland GmbH, Goethe University, Bad Homburg, Germany.
authors.forename: Sonja
authors.initials: S
authors.lastname: Steppan
authors.affiliation: Department of Cardiology, Internal Medicine III, Goethe University, Frankfurt (Main), Germany.
authors.forename: Birgit
authors.initials: B
authors.lastname: Assmus
authors.affiliation: Institute for Cardiovascular Regeneration, Centre of Molecular Medicine, Goethe University.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Dimmeler
authors.affiliation: Department of Cardiology, Internal Medicine III, Goethe University, Frankfurt (Main), Germany.
authors.forename: Andreas M
authors.initials: AM
authors.lastname: Zeiher
authors.affiliation: Institute for Cardiovascular Regeneration, Centre of Molecular Medicine, Goethe University.|Department of Cardiology, Internal Medicine III, Goethe University, Frankfurt (Main), Germany.
authors.forename: Florian H
authors.initials: FH
authors.lastname: Seeger
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology* / Q000378:metabolism*; D019069:Cell Respiration; D003114:Colony-Forming Units Assay; D003470:Culture Media; D006019:Glycolysis; D006333:Heart Failure / Q000473:pathology / Q000628:therapy*; D006614:Hindlimb / Q000098:blood supply / Q000473:pathology; D006801:Humans; D055432:Metabolomics; D008819:Mice, Nude; D035683:MicroRNAs / Q000378:metabolism; D017202:Myocardial Ischemia / Q000473:pathology / Q000628:therapy*; D018919:Neovascularization, Physiologic; D050799:STAT5 Transcription Factor / Q000378:metabolism
chemical_list: D003470:Culture Media; D035683:MicroRNAs; C534715:Mirn30d microRNA, mouse; D050799:STAT5 Transcription Factor
keywords: Bone marrow-derived mononuclear cells; Cardiovascular disease; Cell therapy; Colony forming capacity; Glycolysis