Hematopoietic stem-cell senescence and myocardial repair - Coronary artery disease genotype/phenotype analysis of post-MI myocardial regeneration response induced by CABG/CD133+ bone marrow hematopoietic stem cell treatment in RCT PERFECT Phase 3
Markus Wolfien,
Denise Klatt,
Amankeldi A. Salybekov,
Masaaki Ii,
Miki Komatsu-Horii,
Ralf Gaebel,
Julia Philippou-Massier,
Eric Schrinner,
Hiroshi Akimaru,
Erika Akimaru,
Robert David,
Jens Garbade,
Jan Gummert,
Axel Haverich,
Holger Hennig,
Hiroto Iwasaki,
Alexander Kaminski,
Atsuhiko Kawamoto,
Christian Klopsch,
Johannes T. Kowallick,
Stefan Krebs,
Julia Nesteruk,
Hermann Reichenspurner,
Christian Ritter,
Christof Stamm,
Ayumi Tani-Yokoyama,
Helmut Blum,
Olaf Wolkenhauer,
Axel Schambach,
Takayuki Asahara,
Gustav Steinhoff
Affiliations
Markus Wolfien
Department of Systems Biology and Bioinformatics, University Rostock, Institute of Computer Science, Ulmenstrasse 69, 18057 Rostock, Germany
Denise Klatt
Hannover Medical School, Institute of Experimental Hematology, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany
Amankeldi A. Salybekov
Department of Advanced Medicine Science, Tokai University School of Medicine, Shimokasuya 143, Isehara, Kanagawa 259-1143, Japan
Masaaki Ii
Nanobridge, LLC. 1-3-5-202, Sawaragi-Nishi Ibaraki Osaka 567-0868, Japan
Miki Komatsu-Horii
Institute of Biomedical Research and Innovation, 2-2 Minatojima-minamimachi, Chuo-ku, Kobe 650-0047, Japan
Ralf Gaebel
Reference and Translation Center for Cardiac Stem Cell Therapy, Department Life, Light and Matter and Department of cardiac surgery, University Medicine Rostock, Schillingallee 35, 18055 Rostock, Germany
University Medical Center Goettingen, Institute for Diagnostic and Interventional Radiology, Robert-Koch-Strasse 40, 37075 Göttingen, Germany
Hiroshi Akimaru
Institute of Biomedical Research and Innovation, 2-2 Minatojima-minamimachi, Chuo-ku, Kobe 650-0047, Japan
Erika Akimaru
Institute of Biomedical Research and Innovation, 2-2 Minatojima-minamimachi, Chuo-ku, Kobe 650-0047, Japan
Robert David
Reference and Translation Center for Cardiac Stem Cell Therapy, Department Life, Light and Matter and Department of cardiac surgery, University Medicine Rostock, Schillingallee 35, 18055 Rostock, Germany
Jens Garbade
Department of Cardiac Surgery, Heart Center University Medicine Leipzig, Strümpellstrasse 39, 04289 Leipzig, Germany
Jan Gummert
Heart and diabetes center North Rhine Westfalia, University hospital of the Ruhr university Bochum, Georgstraße 11, 32545 Bad Oeynhausen, Germany
Axel Haverich
Medical school Hannover, Department of heart-, thoracic- and vascular surgery, Carl Neuberg Strasse 1, 30625 Hannover, Germany
Holger Hennig
Department of Systems Biology and Bioinformatics, University Rostock, Institute of Computer Science, Ulmenstrasse 69, 18057 Rostock, Germany
Hiroto Iwasaki
Department of cardiothoracic surgery, Osaka city university, 1-4-3, Asahimachi, Abeno. Osaka, 545-8585. Japan
Alexander Kaminski
Reference and Translation Center for Cardiac Stem Cell Therapy, Department Life, Light and Matter and Department of cardiac surgery, University Medicine Rostock, Schillingallee 35, 18055 Rostock, Germany
Atsuhiko Kawamoto
Institute of Biomedical Research and Innovation, 2-2 Minatojima-minamimachi, Chuo-ku, Kobe 650-0047, Japan
Christian Klopsch
Reference and Translation Center for Cardiac Stem Cell Therapy, Department Life, Light and Matter and Department of cardiac surgery, University Medicine Rostock, Schillingallee 35, 18055 Rostock, Germany
Johannes T. Kowallick
University Medical Center Goettingen, Institute for Diagnostic and Interventional Radiology, Robert-Koch-Strasse 40, 37075 Göttingen, Germany
Reference and Translation Center for Cardiac Stem Cell Therapy, Department Life, Light and Matter and Department of cardiac surgery, University Medicine Rostock, Schillingallee 35, 18055 Rostock, Germany
Hermann Reichenspurner
Department of Cardiac and Vascular Surgery, University heart center Hamburg, Martinistraße. 52, 20246 Hamburg, Germany
Christian Ritter
University Medical Center Goettingen, Institute for Diagnostic and Interventional Radiology, Robert-Koch-Strasse 40, 37075 Göttingen, Germany
Christof Stamm
German Heart Center Berlin, Department of Heart-, Thoracic- and Vascular Surgery, Augustenburger Platz 1, 13353 Berlin, Germany
Ayumi Tani-Yokoyama
Institute of Biomedical Research and Innovation, 2-2 Minatojima-minamimachi, Chuo-ku, Kobe 650-0047, Japan
Department of Systems Biology and Bioinformatics, University Rostock, Institute of Computer Science, Ulmenstrasse 69, 18057 Rostock, Germany
Axel Schambach
Hannover Medical School, Institute of Experimental Hematology, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany
Takayuki Asahara
Department of Advanced Medicine Science, Tokai University School of Medicine, Shimokasuya 143, Isehara, Kanagawa 259-1143, Japan
Gustav Steinhoff
Reference and Translation Center for Cardiac Stem Cell Therapy, Department Life, Light and Matter and Department of cardiac surgery, University Medicine Rostock, Schillingallee 35, 18055 Rostock, Germany; Corresponding author.
Background: Bone marrow stem cell clonal dysfunction by somatic mutation is suspected to affect post-infarction myocardial regeneration after coronary bypass surgery (CABG). Methods: Transcriptome and variant expression analysis was studied in the phase 3 PERFECT trial post myocardial infarction CABG and CD133+ bone marrow derived hematopoetic stem cells showing difference in left ventricular ejection fraction (∆LVEF) myocardial regeneration Responders (n=14; ∆LVEF +16% day 180/0) and Non-responders (n=9; ∆LVEF -1.1% day 180/0). Subsequently, the findings have been validated in an independent patient cohort (n=14) as well as in two preclinical mouse models investigating SH2B3/LNK antisense or knockout deficient conditions. Findings: 1. Clinical: R differed from NR in a total of 161 genes in differential expression (n=23, q<0•05) and 872 genes in coexpression analysis (n=23, q<0•05). Machine Learning clustering analysis revealed distinct RvsNR preoperative gene-expression signatures in peripheral blood acorrelated to SH2B3 (p<0.05). Mutation analysis revealed increased specific variants in RvsNR. (R: 48 genes; NR: 224 genes). 2. Preclinical: SH2B3/LNK-silenced hematopoietic stem cell (HSC) clones displayed significant overgrowth of myeloid and immune cells in bone marrow, peripheral blood, and tissue at day 160 after competitive bone-marrow transplantation into mice. SH2B3/LNK−/− mice demonstrated enhanced cardiac repair through augmenting the kinetics of bone marrow-derived endothelial progenitor cells, increased capillary density in ischemic myocardium, and reduced left ventricular fibrosis with preserved cardiac function. 3. Validation: Evaluation analysis in 14 additional patients revealed 85% RvsNR (12/14 patients) prediction accuracy for the identified biomarker signature. Interpretation: Myocardial repair is affected by HSC gene response and somatic mutation. Machine Learning can be utilized to identify and predict pathological HSC response. Funding: German Ministry of Research and Education (BMBF): Reference and Translation Center for Cardiac Stem Cell Therapy - FKZ0312138A and FKZ031L0106C, German Ministry of Research and Education (BMBF): Collaborative research center - DFG:SFB738 and Center of Excellence - DFG:EC-REBIRTH), European Social Fonds: ESF/IV-WM-B34-0011/08, ESF/IV-WM-B34-0030/10, and Miltenyi Biotec GmbH, Bergisch-Gladbach, Germany. Japanese Ministry of Health : Health and Labour Sciences Research Grant (H14-trans-001, H17-trans-002) Trial registration: ClinicalTrials.gov NCT00950274
