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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
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
EBioMedicine, Volume 57, Article 102862, Year 2020
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Description
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 © 2020 The Author(s)
Authors & Co-Authors
Wolfien, Markus
Germany, Rostock
Universität Rostock
Klatt, Denise
Germany, Hannover
Hannover Medical School
Gaebel, Ralf
Germany, Rostock
Universität Rostock Uniklinikum Und Medizinische Fakultät
David, Robert
Germany, Rostock
Universität Rostock Uniklinikum Und Medizinische Fakultät
Gummert, Jan Fritz
Germany, Bochum
Ruhr-universitat Bochum
Haverich, Axel
Germany, Hannover
Hannover Medical School
Hennig, Holger
Germany, Rostock
Universität Rostock
Krebs, Stefan
Germany, Munich
Ludwig-maximilians-universität München
Reichenspurner, Hermann C.K.
Germany, Hamburg
Universitäre Herz- Und Gefäßzentrum Uke Hamburg Gmbh
Blum, Helmut
Germany, Munich
Ludwig-maximilians-universität München
Wolkenhauer, Olaf
Germany, Rostock
Universität Rostock
Schambach, Axel
Germany, Hannover
Hannover Medical School
Steinhoff, Gustav
Germany, Rostock
Universität Rostock Uniklinikum Und Medizinische Fakultät
Statistics
Citations: 19
Authors: 13
Affiliations: 12
Identifiers
Doi:
10.1016/j.ebiom.2020.102862
ISSN:
23523964
Research Areas
Cancer
Genetics And Genomics
Health System And Policy
Noncommunicable Diseases
Study Design
Randomised Control Trial
Cohort Study
Study Approach
Quantitative