title: Migration towards SDF-1 selects angiogenin-expressing bone marrow monocytes endowed with cardiac reparative activity in patients with previous myocardial infarction.
abstract: BACKGROUND
  Chemokine-directed migration is crucial for homing of regenerative cells to the infarcted heart and correlates with outcomes of cell therapy trials. Hence, transplantation of chemokine-responsive bone marrow cells may be ideal for treatment of myocardial ischemia. To verify the therapeutic activity of bone marrow mononuclear cells (BM-MNCs) selected by in vitro migration towards the chemokine stromal cell-derived factor-1 (SDF-1) in a mouse model of myocardial infarction (MI), we used BM-MNCs from patients with previous large MI recruited in the TransACT-1&2 cell therapy trials.
  
  
  METHODS
  Unfractioned BM-MNCs, SDF-1-responsive, and SDF-1-nonresponsive BM-MNCs isolated by patients recruited in the TransACT-1&2 cell therapy trials were tested in Matrigel assay to evaluate angiogenic potential. Secretome and antigenic profile were characterized by flow cytometry. Angiogenin expression was measured by RT-PCR. Cells groups were also intramyocardially injected in an in vivo model of MI (8-week-old immune deficient CD1-FOXN1(nu/nu) mice). Echocardiography and hemodynamic measurements were performed before and at 14 days post-MI. Arterioles and capillaries density, infiltration of inflammatory cells, interstitial fibrosis, and cardiomyocyte proliferation and apoptosis were assessed by immunohistochemistry.
  
  
  RESULTS
  In vitro migration enriched for monocytes, while CD34(+) and CD133(+) cells and T lymphocytes remained mainly confined in the non-migrated fraction. Unfractioned total BM-MNCs promoted angiogenesis on Matrigel more efficiently than migrated or non-migrated cells. In mice with induced MI, intramyocardial injection of unfractionated or migrated BM-MNCs was more effective in preserving cardiac contractility and pressure indexes than vehicle or non-migrated BM-MNCs. Moreover, unfractioned BM-MNCs enhanced neovascularization, whereas the migrated fraction was unique in reducing the infarct size and interstitial fibrosis. In vitro studies on isolated cardiomyocytes suggest participation of angiogenin, a secreted ribonuclease that inhibits protein translation under stress conditions, in promotion of cardiomyocyte survival by migrated BM-MNCs.
  
  
  CONCLUSIONS
  Transplantation of bone marrow cells helps post-MI healing through distinct actions on vascular cells and cardiomyocytes. In addition, the SDF-1-responsive fraction is enriched with angiogenin-expressing monocytes, which may improve cardiac recovery through activation of cardiomyocyte response to stress. Identification of factors linking migratory and therapeutic outcomes could help refine regenerative approaches.
authors.affiliation: Bristol Heart Institute, School of Clinical Sciences, University of Bristol, Upper Maudlin Road, Bristol, BS2 8HW, UK. r.ascione@bristol.ac.uk.
authors.forename: Raimondo
authors.initials: R
authors.lastname: Ascione
authors.affiliation: Bristol Heart Institute, School of Clinical Sciences, University of Bristol, Upper Maudlin Road, Bristol, BS2 8HW, UK. Jonathan.Rowlinson@nottingham.ac.uk.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Rowlinson
authors.affiliation: Bristol Heart Institute, School of Clinical Sciences, University of Bristol, Upper Maudlin Road, Bristol, BS2 8HW, UK. elisa.avolio@bristol.ac.uk.
authors.forename: Elisa
authors.initials: E
authors.lastname: Avolio
authors.affiliation: Bristol Heart Institute, School of Clinical Sciences, University of Bristol, Upper Maudlin Road, Bristol, BS2 8HW, UK. rajesh.katare@otago.ac.nz.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Katare
authors.affiliation: Bristol Heart Institute, School of Clinical Sciences, University of Bristol, Upper Maudlin Road, Bristol, BS2 8HW, UK. Marco.Meloni@glasgow.ac.uk.
authors.forename: Marco
authors.initials: M
authors.lastname: Meloni
authors.affiliation: Bristol Heart Institute, School of Clinical Sciences, University of Bristol, Upper Maudlin Road, Bristol, BS2 8HW, UK. Helen.Spencer@bristol.ac.uk.
authors.forename: Helen L
authors.initials: HL
authors.lastname: Spencer
authors.affiliation: Bristol Heart Institute, School of Clinical Sciences, University of Bristol, Upper Maudlin Road, Bristol, BS2 8HW, UK. Giuseppe.Mangialardi@bristol.ac.uk.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Mangialardi
authors.affiliation: Bristol Heart Institute, School of Clinical Sciences, University of Bristol, Upper Maudlin Road, Bristol, BS2 8HW, UK. caroline.norris@bristol.ac.uk.
authors.forename: Caroline
authors.initials: C
authors.lastname: Norris
authors.affiliation: Charité - Universitätsmedizin Berlin, Berlin, Germany. nicolle.kraenkel@charite.de.
authors.forename: Nicolle
authors.initials: N
authors.lastname: Kränkel
authors.affiliation: IRCCS MultiMedica, Milan, Italy. gaia.spinetti@multimedica.it.
authors.forename: Gaia
authors.initials: G
authors.lastname: Spinetti
authors.affiliation: Bristol Heart Institute, School of Clinical Sciences, University of Bristol, Upper Maudlin Road, Bristol, BS2 8HW, UK. costanza.emanueli@bristol.ac.uk.
authors.forename: Costanza
authors.initials: C
authors.lastname: Emanueli
authors.affiliation: Bristol Heart Institute, School of Clinical Sciences, University of Bristol, Upper Maudlin Road, Bristol, BS2 8HW, UK. Paolo.Madeddu@bristol.ac.uk.
authors.forename: Paolo
authors.initials: P
authors.lastname: Madeddu
mesh_terms: D000071916:AC133 Antigen; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D018952:Antigens, CD34 / Q000378:metabolism; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects*; D002465:Cell Movement / Q000187:drug effects; D054377:Chemokine CXCL12 / Q000494:pharmacology*; D016207:Cytokines / Q000032:analysis; D004195:Disease Models, Animal; D004452:Echocardiography; D006023:Glycoproteins / Q000378:metabolism; D006439:Hemodynamics; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000032:analysis; D008297:Male; D051379:Mice; D008875:Middle Aged; D009000:Monocytes / Q000166:cytology / Q000378:metabolism / Q000637:transplantation*; D017202:Myocardial Ischemia / Q000473:pathology / Q000628:therapy*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism; D010455:Peptides / Q000378:metabolism; D012259:Ribonuclease, Pancreatic / Q000235:genetics / Q000378:metabolism*
chemical_list: D000071916:AC133 Antigen; D015703:Antigens, CD; D018952:Antigens, CD34; D054377:Chemokine CXCL12; D016207:Cytokines; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; C000606023:PROM1 protein, human; D010455:Peptides; C000606024:Prom1 protein, mouse; C046366:angiogenin; D012259:Ribonuclease, Pancreatic