%0 journal article
%@ 2352-3964
%A Wolfien, M.,Klatt, D.,Salybekov, A.A.,Ii, M.,Komatsu-Horii, M.,Gaebel, R.,Philippou-Massier, J.,Schrinner, E.,Akimaru, H.,Akimaru, E.,David, R.,Garbade, J.,Gummert, J.,Haverich, A.,Hennig, H.,Iwasaki, H.,Kaminski, A.,Kawamoto, A.,Klopsch, C.,Kowallick, J.T.,Krebs, S.,Nesteruk, J.,Reichenspurner, H.,Ritter, C.,Stamm, C.,Tani-Yokoyama, A.,Blum, H.,Wolkenhauer, O.,Schambach, A.,Asahara, T.,Steinhoff, G.
%D 2020
%J EBioMedicine
%N 
%P 102862 
%R doi:10.1016/j.ebiom.2020.102862
%T 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
%U https://doi.org/10.1016/j.ebiom.2020.102862
 
%X 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.