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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

167 Pages Posted: 4 Jun 2020

See all articles by Markus Wolfien

Markus Wolfien

University of Rostock

Denise Klatt

Hannover Medical School Instituteof Experimental Hematology

Amankeldi Alshynbekuly Salybekov

Tokai University - Department of Regenerative Medicine Science

Masaaki Ii

Osaka Medical College

Miki Komatsu-Horii

Foundation for Biomedical Research and Innovation (FBRI)

Ralf Gaebel

University of Rostock - University Medicine Rostock (UMR)

Julia Philippou-Massier

Ludwig-Maximilians-Universität München, LAFUGA Genomics, Gene Center

Eric Schrinner

University Medical Centre, Institute for Diagnostic and Interventional Radiology

PERFECT Trial and Vascular Regeneration Investigators Group

Helmut Blum

Ludwig Maximilian University of Munich (LMU)

Olaf Wolkenhauer

University Rostock, Institute of Computer Science, Department of Systems Biology and Bioinformatics

Axel Schambach

Hannover Medical School, Instituteof Experimental Hematology

Takayuki Asahara

Tokai University - Department of Regenerative Medicine Science

Gustav Steinhoff

University of Rostock - University Medicine Rostock (UMR)

Hiroshi Akimaru

IBRI (Institute of Biomedical Research and Innovation)

Erika Akimaru

IBRI (Institute of Biomedical Research and Innovation)

Robert David

University Medicine Rostock (UMR), Department Life, Light and Matter and Department of Cardiac Surgery

Jens Garbade

University of Leipzig - Heart Center, Department of Cardiac Surgery

Jan Gummert

Heart and Diabetes Center North Rhine Westfalia, University Hospital of the Ruhr University Bochum

Axel Haverich

Hannover Medical School, Department of Heart-, Thoracic–And Vascular Surgery

Holger Hennig

University Rostock, Institute of Computer Science, Department of Systems Biology and Bioinformatics

Hiroto Iwasaki

Department of Cardio Thoracic Surger, Osaka City University

Alexander Kaminski

University Medicine Rostock (UMR), Reference and Translation Center for Cardiac Stem Cell Therapy Department Life, Light and Matter and Department of Cardiac Surgery

Atsuhiko Kawamoto

IBRI (Institute of Biomedical Research and Innovation)

Christian Klopsch

University Medicine Rostock (UMR), Reference and Translation Center for Cardiac Stem Cell Therapy Department Life, Light and Matter and Department of Cardiac Surgery

Johannes T Kowallick

University Medical Center Goettingen, Nstitute for Diagnostic and Interventional Radiology

Stefan Krebs

Ludwig-Maximilians-Universität München, LAFUGA Genomics, Gene Center

Julia Nesteruk

University Medicine Rostock (UMR), Reference and Translation Center for Cardiac Stem Cell Therapy Department Life, Light and Matter and Department of Cardiac Surgery

Christian O. Ritter

University Medical Centre, Institute for Diagnostic and Interventional Radiology

Christof Stamm

German Heart Center Berlin, Department of Heart-, Thoracic–And Vascular Surgery

Ayumi Tani-Yokoyama

IBRI (Institute of Biomedical Research and Innovation)

Florian Mathias Wagner

University Heart Center Hamburg GmbH, Department of Cardiac and Vascular Surgery

More...

Abstract

Objective: Clonal hematopoiesis with mutational gene dysregulation of hematopoietic stem cell (HSC) precursors for immune or endothelial progenitor cell response is suspected to affect coronary artery disease bypass surgery (CABG) induced ischemic myocardial repair.

Design: Transcriptome and variant expression analysis was studied in the phase 3 PERFECT (post MI CABG and CD133 + BMSC or Placebo) trial in myocardial regeneration responders (R, n=14; ∆LVEF +16% day 180/0) and non-responders (NR, n=9; ∆LVEF -1∙1% day 180/0), then validated in independent patient cohort (n=14) as well as under mouse SH2B3/LNK antisense or knockout deficient conditions.

Findings: 1. Left ventricular functional recovery was accompanied by an increase in myocardial perfusion (R vs NR, p<0∙05). 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 R vs NR preoperative gene-expression signature in peripheral blood. RvsNR ML-top selected genes were correlated to SH2B3 (p<0∙05). Mutation signature analysis performed by RNASeq revealed increased specific variants in NR vs R. (NR: 224 genes with 268 exon regions; R: 48 genes with 56 exon regions). 2. RvsNR ML-selected gene expression and phenotype was correlated to SH2B3 deficient mouse models. Competitive bone-marrow transplanted mice SH2B3/LNK silenced HSC clones displayed significant overgrowth of myeloid and immune cells in bone marrow, peripheral blood and tissue at day 160 after BMT. SH2B3/LNK-/- mice demonstrated enhanced cardiac repair through augmenting the kinetics of BM-derived EPCs, increased capillary density in ischemic myocardium and reduced left ventricular fibrosis with preserved cardiac function. 3. Validation analysis in 14 additional patients revealed 85% R vs NR prediction accuracy.

Interpretation: Myocardial repair is affected by HSC gene response. Somatic mutation in adaptor proteins may alter response by clonal overgrowth as shown for SH2B3/LNK. ML guided predictions can be utilized to identify and predict pathological HSC response.

Trial Registration: ClinicalTrials.gov NCT00950274

Funding Statement: German Ministry of Research and Education (BMBF): FKZ0312138A, FKZ031L0106C, EU 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)

Declaration of Interests: All authors declare no competing interests.

Ethics Approval Statement: Approval by the Ethical committee, Rostock University Medical Center 2009; No. HV-2009-0012.

Keywords: Clonal hematopoiesis of indeterminate pathology; CHIP: coronary artery disease; cardiac regeneration capacity; randomized double-blinded phase 3 multicentre trial; myocardial repair response; CD133; CD34; hematopoietic stem cell; endothelial progenitor cell; EPC; SH2B3; LNK adaptor; Lnk; SH2B3/LNK-/

Suggested Citation

Wolfien, Markus and Klatt, Denise and Salybekov, Amankeldi Alshynbekuly and Ii, Masaaki and Komatsu-Horii, Miki and Gaebel, Ralf and Philippou-Massier, Julia and Schrinner, Eric and Group, PERFECT Trial and Vascular Regeneration Investigators and Blum, Helmut and Wolkenhauer, Olaf and Schambach, Axel and Asahara, Takayuki and Steinhoff, Gustav and Akimaru, Hiroshi and Akimaru, Erika and David, Robert and Garbade, Jens and Gummert, Jan and Haverich, Axel and Hennig, Holger and Iwasaki, Hiroto and Kaminski, Alexander and Kawamoto, Atsuhiko and Klopsch, Christian and Kowallick, Johannes T and Krebs, Stefan and Nesteruk, Julia and Ritter, Christian O. and Stamm, Christof and Tani-Yokoyama, Ayumi and Mathias Wagner, Florian, 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 (3/27/2020). Available at SSRN: https://ssrn.com/abstract=3564409 or http://dx.doi.org/10.2139/ssrn.3564409

Markus Wolfien (Contact Author)

University of Rostock ( email )

Postfach 10 08 88
Rostock, 18055
Germany

Denise Klatt

Hannover Medical School Instituteof Experimental Hematology ( email )

Carl-Neuberg-Str. 1
Hannover, 30625
Germany

Amankeldi Alshynbekuly Salybekov

Tokai University - Department of Regenerative Medicine Science ( email )

3-20-1 Orido
Shimizu-ku
Shizuoka, 424-8610
Japan

Masaaki Ii

Osaka Medical College ( email )

569-0801 Osaka Prefecture
Takatsuki
Japan

Miki Komatsu-Horii

Foundation for Biomedical Research and Innovation (FBRI) ( email )

2-2 Minatojima-minamimachi
Hyogo, 650-0047
Japan

Ralf Gaebel

University of Rostock - University Medicine Rostock (UMR) ( email )

Rostock
Germany

Julia Philippou-Massier

Ludwig-Maximilians-Universität München, LAFUGA Genomics, Gene Center ( email )

Geschwister-Scholl-Platz 1
Munich, DE Bavaria 80539
Germany

Eric Schrinner

University Medical Centre, Institute for Diagnostic and Interventional Radiology ( email )

Goettingen
Germany

Helmut Blum

Ludwig Maximilian University of Munich (LMU) ( email )

Geschwister-Scholl-Platz 1
Munich, DE Bavaria 80539
Germany

Olaf Wolkenhauer

University Rostock, Institute of Computer Science, Department of Systems Biology and Bioinformatics ( email )

Postfach 10 08 88
Rostock, 18055
Germany

Axel Schambach

Hannover Medical School, Instituteof Experimental Hematology ( email )

Carl-Neuberg-Str. 1
Hannover, 30625
Germany

Takayuki Asahara

Tokai University - Department of Regenerative Medicine Science ( email )

3-20-1 Orido
Shimizu-ku
Shizuoka, 424-8610
Japan

Gustav Steinhoff

University of Rostock - University Medicine Rostock (UMR) ( email )

Rostock
Germany

Hiroshi Akimaru

IBRI (Institute of Biomedical Research and Innovation) ( email )

Japan

Erika Akimaru

IBRI (Institute of Biomedical Research and Innovation) ( email )

Japan

Robert David

University Medicine Rostock (UMR), Department Life, Light and Matter and Department of Cardiac Surgery ( email )

Rostock
Germany

Jens Garbade

University of Leipzig - Heart Center, Department of Cardiac Surgery ( email )

Strümpellstraße 39
04289 Leipzig
Germany

Jan Gummert

Heart and Diabetes Center North Rhine Westfalia, University Hospital of the Ruhr University Bochum ( email )

Universitätsstraße 150
Bochum, NRW 44780
Germany

Axel Haverich

Hannover Medical School, Department of Heart-, Thoracic–And Vascular Surgery ( email )

Carl-Neuberg-Str. 1
Hannover, 30625
Germany

Holger Hennig

University Rostock, Institute of Computer Science, Department of Systems Biology and Bioinformatics ( email )

Postfach 10 08 88
Rostock, 18055
Germany

Hiroto Iwasaki

Department of Cardio Thoracic Surger, Osaka City University ( email )

3-3-138, Sugimoto
Sumiyoshi-ku
Osaka 558-8585
United States

Alexander Kaminski

University Medicine Rostock (UMR), Reference and Translation Center for Cardiac Stem Cell Therapy Department Life, Light and Matter and Department of Cardiac Surgery ( email )

Rostock
Germany

Atsuhiko Kawamoto

IBRI (Institute of Biomedical Research and Innovation) ( email )

Japan

Christian Klopsch

University Medicine Rostock (UMR), Reference and Translation Center for Cardiac Stem Cell Therapy Department Life, Light and Matter and Department of Cardiac Surgery ( email )

Rostock
Germany

Johannes T Kowallick

University Medical Center Goettingen, Nstitute for Diagnostic and Interventional Radiology ( email )

Platz der Gottinger Sieben 3
Gottingen, D-37073
Germany

Stefan Krebs

Ludwig-Maximilians-Universität München, LAFUGA Genomics, Gene Center ( email )

Geschwister-Scholl-Platz 1
Munich, DE Bavaria 80539
Germany

Julia Nesteruk

University Medicine Rostock (UMR), Reference and Translation Center for Cardiac Stem Cell Therapy Department Life, Light and Matter and Department of Cardiac Surgery ( email )

Rostock
Germany

Christian O. Ritter

University Medical Centre, Institute for Diagnostic and Interventional Radiology ( email )

Platz der Gottinger Sieben 3
Gottingen, D-37073
Germany

Christof Stamm

German Heart Center Berlin, Department of Heart-, Thoracic–And Vascular Surgery ( email )

Berlin
Germany

Ayumi Tani-Yokoyama

IBRI (Institute of Biomedical Research and Innovation) ( email )

Japan

Florian Mathias Wagner

University Heart Center Hamburg GmbH, Department of Cardiac and Vascular Surgery ( email )

Martinistraße 52
Hamburg, 20251
Germany

No contact information is available for PERFECT Trial and Vascular Regeneration Investigators Group

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