title: Conditioned medium from human amniotic mesenchymal stromal cells limits infarct size and enhances angiogenesis.
abstract: The paracrine properties of human amniotic membrane-derived mesenchymal stromal cells (hAMCs) have not been fully elucidated. The goal of the present study was to elucidate whether hAMCs can exert beneficial paracrine effects on infarcted rat hearts, in particular through cardioprotection and angiogenesis. Moreover, we aimed to identify the putative active paracrine mediators. hAMCs were isolated, expanded, and characterized. In vitro, conditioned medium from hAMC (hAMC-CM) exhibited cytoprotective and proangiogenic properties. In vivo, injection of hAMC-CM into infarcted rat hearts limited the infarct size, reduced cardiomyocyte apoptosis and ventricular remodeling, and strongly promoted capillary formation at the infarct border zone. Gene array analysis led to the identification of 32 genes encoding for the secreted factors overexpressed by hAMCs. Among these, midkine and secreted protein acidic and rich in cysteine were also upregulated at the protein level. Furthermore, high amounts of several proangiogenic factors were detected in hAMC-CM by cytokine array. Our results strongly support the concept that the administration of hAMC-CM favors the repair process after acute myocardial infarction.
authors.affiliation: Department of Cardiothoracic and Vascular Sciences, Coronary Care Unit and Laboratory of Clinical and Experimental Cardiology, Laboratory of Experimental Cardiology for Cell and Molecular Therapy, Division of Clinical Immunology, Immunohematology, and Transfusion Service, Center for the Study and Cure of Myelofibrosis, Biotechnology Research Laboratories, and Division of Obstetrics and Gynecology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; Department of Molecular Medicine, Unit of Cardiology, University of Pavia, Pavia, Italy; Laboratory of Cardiovascular Genetics, IRCCS Istituto Auxologico Italiano, Milan, Italy; Department of Cardiology, University Medical Center Groningen, Groningen, The Netherlands; Department of Medicine, University of Cape Town, Cape Town, South Africa.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Danieli
authors.affiliation: Department of Cardiothoracic and Vascular Sciences, Coronary Care Unit and Laboratory of Clinical and Experimental Cardiology, Laboratory of Experimental Cardiology for Cell and Molecular Therapy, Division of Clinical Immunology, Immunohematology, and Transfusion Service, Center for the Study and Cure of Myelofibrosis, Biotechnology Research Laboratories, and Division of Obstetrics and Gynecology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; Department of Molecular Medicine, Unit of Cardiology, University of Pavia, Pavia, Italy; Laboratory of Cardiovascular Genetics, IRCCS Istituto Auxologico Italiano, Milan, Italy; Department of Cardiology, University Medical Center Groningen, Groningen, The Netherlands; Department of Medicine, University of Cape Town, Cape Town, South Africa.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Malpasso
authors.affiliation: Department of Cardiothoracic and Vascular Sciences, Coronary Care Unit and Laboratory of Clinical and Experimental Cardiology, Laboratory of Experimental Cardiology for Cell and Molecular Therapy, Division of Clinical Immunology, Immunohematology, and Transfusion Service, Center for the Study and Cure of Myelofibrosis, Biotechnology Research Laboratories, and Division of Obstetrics and Gynecology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; Department of Molecular Medicine, Unit of Cardiology, University of Pavia, Pavia, Italy; Laboratory of Cardiovascular Genetics, IRCCS Istituto Auxologico Italiano, Milan, Italy; Department of Cardiology, University Medical Center Groningen, Groningen, The Netherlands; Department of Medicine, University of Cape Town, Cape Town, South Africa.
authors.forename: Maria Chiara
authors.initials: MC
authors.lastname: Ciuffreda
authors.affiliation: Department of Cardiothoracic and Vascular Sciences, Coronary Care Unit and Laboratory of Clinical and Experimental Cardiology, Laboratory of Experimental Cardiology for Cell and Molecular Therapy, Division of Clinical Immunology, Immunohematology, and Transfusion Service, Center for the Study and Cure of Myelofibrosis, Biotechnology Research Laboratories, and Division of Obstetrics and Gynecology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; Department of Molecular Medicine, Unit of Cardiology, University of Pavia, Pavia, Italy; Laboratory of Cardiovascular Genetics, IRCCS Istituto Auxologico Italiano, Milan, Italy; Department of Cardiology, University Medical Center Groningen, Groningen, The Netherlands; Department of Medicine, University of Cape Town, Cape Town, South Africa.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Cervio
authors.affiliation: Department of Cardiothoracic and Vascular Sciences, Coronary Care Unit and Laboratory of Clinical and Experimental Cardiology, Laboratory of Experimental Cardiology for Cell and Molecular Therapy, Division of Clinical Immunology, Immunohematology, and Transfusion Service, Center for the Study and Cure of Myelofibrosis, Biotechnology Research Laboratories, and Division of Obstetrics and Gynecology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; Department of Molecular Medicine, Unit of Cardiology, University of Pavia, Pavia, Italy; Laboratory of Cardiovascular Genetics, IRCCS Istituto Auxologico Italiano, Milan, Italy; Department of Cardiology, University Medical Center Groningen, Groningen, The Netherlands; Department of Medicine, University of Cape Town, Cape Town, South Africa.
authors.forename: Laura
authors.initials: L
authors.lastname: Calvillo
authors.affiliation: Department of Cardiothoracic and Vascular Sciences, Coronary Care Unit and Laboratory of Clinical and Experimental Cardiology, Laboratory of Experimental Cardiology for Cell and Molecular Therapy, Division of Clinical Immunology, Immunohematology, and Transfusion Service, Center for the Study and Cure of Myelofibrosis, Biotechnology Research Laboratories, and Division of Obstetrics and Gynecology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; Department of Molecular Medicine, Unit of Cardiology, University of Pavia, Pavia, Italy; Laboratory of Cardiovascular Genetics, IRCCS Istituto Auxologico Italiano, Milan, Italy; Department of Cardiology, University Medical Center Groningen, Groningen, The Netherlands; Department of Medicine, University of Cape Town, Cape Town, South Africa.
authors.forename: Francesco
authors.initials: F
authors.lastname: Copes
authors.affiliation: Department of Cardiothoracic and Vascular Sciences, Coronary Care Unit and Laboratory of Clinical and Experimental Cardiology, Laboratory of Experimental Cardiology for Cell and Molecular Therapy, Division of Clinical Immunology, Immunohematology, and Transfusion Service, Center for the Study and Cure of Myelofibrosis, Biotechnology Research Laboratories, and Division of Obstetrics and Gynecology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; Department of Molecular Medicine, Unit of Cardiology, University of Pavia, Pavia, Italy; Laboratory of Cardiovascular Genetics, IRCCS Istituto Auxologico Italiano, Milan, Italy; Department of Cardiology, University Medical Center Groningen, Groningen, The Netherlands; Department of Medicine, University of Cape Town, Cape Town, South Africa.
authors.forename: Federica
authors.initials: F
authors.lastname: Pisano
authors.affiliation: Department of Cardiothoracic and Vascular Sciences, Coronary Care Unit and Laboratory of Clinical and Experimental Cardiology, Laboratory of Experimental Cardiology for Cell and Molecular Therapy, Division of Clinical Immunology, Immunohematology, and Transfusion Service, Center for the Study and Cure of Myelofibrosis, Biotechnology Research Laboratories, and Division of Obstetrics and Gynecology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; Department of Molecular Medicine, Unit of Cardiology, University of Pavia, Pavia, Italy; Laboratory of Cardiovascular Genetics, IRCCS Istituto Auxologico Italiano, Milan, Italy; Department of Cardiology, University Medical Center Groningen, Groningen, The Netherlands; Department of Medicine, University of Cape Town, Cape Town, South Africa.
authors.forename: Manuela
authors.initials: M
authors.lastname: Mura
authors.affiliation: Department of Cardiothoracic and Vascular Sciences, Coronary Care Unit and Laboratory of Clinical and Experimental Cardiology, Laboratory of Experimental Cardiology for Cell and Molecular Therapy, Division of Clinical Immunology, Immunohematology, and Transfusion Service, Center for the Study and Cure of Myelofibrosis, Biotechnology Research Laboratories, and Division of Obstetrics and Gynecology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; Department of Molecular Medicine, Unit of Cardiology, University of Pavia, Pavia, Italy; Laboratory of Cardiovascular Genetics, IRCCS Istituto Auxologico Italiano, Milan, Italy; Department of Cardiology, University Medical Center Groningen, Groningen, The Netherlands; Department of Medicine, University of Cape Town, Cape Town, South Africa.
authors.forename: Lennaert
authors.initials: L
authors.lastname: Kleijn
authors.affiliation: Department of Cardiothoracic and Vascular Sciences, Coronary Care Unit and Laboratory of Clinical and Experimental Cardiology, Laboratory of Experimental Cardiology for Cell and Molecular Therapy, Division of Clinical Immunology, Immunohematology, and Transfusion Service, Center for the Study and Cure of Myelofibrosis, Biotechnology Research Laboratories, and Division of Obstetrics and Gynecology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; Department of Molecular Medicine, Unit of Cardiology, University of Pavia, Pavia, Italy; Laboratory of Cardiovascular Genetics, IRCCS Istituto Auxologico Italiano, Milan, Italy; Department of Cardiology, University Medical Center Groningen, Groningen, The Netherlands; Department of Medicine, University of Cape Town, Cape Town, South Africa.
authors.forename: Rudolf A
authors.initials: RA
authors.lastname: de Boer
authors.affiliation: Department of Cardiothoracic and Vascular Sciences, Coronary Care Unit and Laboratory of Clinical and Experimental Cardiology, Laboratory of Experimental Cardiology for Cell and Molecular Therapy, Division of Clinical Immunology, Immunohematology, and Transfusion Service, Center for the Study and Cure of Myelofibrosis, Biotechnology Research Laboratories, and Division of Obstetrics and Gynecology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; Department of Molecular Medicine, Unit of Cardiology, University of Pavia, Pavia, Italy; Laboratory of Cardiovascular Genetics, IRCCS Istituto Auxologico Italiano, Milan, Italy; Department of Cardiology, University Medical Center Groningen, Groningen, The Netherlands; Department of Medicine, University of Cape Town, Cape Town, South Africa.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Viarengo
authors.affiliation: Department of Cardiothoracic and Vascular Sciences, Coronary Care Unit and Laboratory of Clinical and Experimental Cardiology, Laboratory of Experimental Cardiology for Cell and Molecular Therapy, Division of Clinical Immunology, Immunohematology, and Transfusion Service, Center for the Study and Cure of Myelofibrosis, Biotechnology Research Laboratories, and Division of Obstetrics and Gynecology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; Department of Molecular Medicine, Unit of Cardiology, University of Pavia, Pavia, Italy; Laboratory of Cardiovascular Genetics, IRCCS Istituto Auxologico Italiano, Milan, Italy; Department of Cardiology, University Medical Center Groningen, Groningen, The Netherlands; Department of Medicine, University of Cape Town, Cape Town, South Africa.
authors.forename: Vittorio
authors.initials: V
authors.lastname: Rosti
authors.affiliation: Department of Cardiothoracic and Vascular Sciences, Coronary Care Unit and Laboratory of Clinical and Experimental Cardiology, Laboratory of Experimental Cardiology for Cell and Molecular Therapy, Division of Clinical Immunology, Immunohematology, and Transfusion Service, Center for the Study and Cure of Myelofibrosis, Biotechnology Research Laboratories, and Division of Obstetrics and Gynecology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; Department of Molecular Medicine, Unit of Cardiology, University of Pavia, Pavia, Italy; Laboratory of Cardiovascular Genetics, IRCCS Istituto Auxologico Italiano, Milan, Italy; Department of Cardiology, University Medical Center Groningen, Groningen, The Netherlands; Department of Medicine, University of Cape Town, Cape Town, South Africa.
authors.forename: Arsenio
authors.initials: A
authors.lastname: Spinillo
authors.affiliation: Department of Cardiothoracic and Vascular Sciences, Coronary Care Unit and Laboratory of Clinical and Experimental Cardiology, Laboratory of Experimental Cardiology for Cell and Molecular Therapy, Division of Clinical Immunology, Immunohematology, and Transfusion Service, Center for the Study and Cure of Myelofibrosis, Biotechnology Research Laboratories, and Division of Obstetrics and Gynecology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; Department of Molecular Medicine, Unit of Cardiology, University of Pavia, Pavia, Italy; Laboratory of Cardiovascular Genetics, IRCCS Istituto Auxologico Italiano, Milan, Italy; Department of Cardiology, University Medical Center Groningen, Groningen, The Netherlands; Department of Medicine, University of Cape Town, Cape Town, South Africa.
authors.forename: Marianna
authors.initials: M
authors.lastname: Roccio
authors.affiliation: Department of Cardiothoracic and Vascular Sciences, Coronary Care Unit and Laboratory of Clinical and Experimental Cardiology, Laboratory of Experimental Cardiology for Cell and Molecular Therapy, Division of Clinical Immunology, Immunohematology, and Transfusion Service, Center for the Study and Cure of Myelofibrosis, Biotechnology Research Laboratories, and Division of Obstetrics and Gynecology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; Department of Molecular Medicine, Unit of Cardiology, University of Pavia, Pavia, Italy; Laboratory of Cardiovascular Genetics, IRCCS Istituto Auxologico Italiano, Milan, Italy; Department of Cardiology, University Medical Center Groningen, Groningen, The Netherlands; Department of Medicine, University of Cape Town, Cape Town, South Africa m.gnecchi@unipv.it.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Gnecchi
mesh_terms: D000653:Amniotic Fluid / Q000166:cytology / Q000378:metabolism; D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology; D064987:Cell- and Tissue-Based Therapy; D017077:Culture Media, Conditioned / Q000494:pharmacology; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism*; D009203:Myocardial Infarction / Q000473:pathology / Q000628:therapy*; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D051381:Rats
chemical_list: D002316:Cardiotonic Agents; D017077:Culture Media, Conditioned
keywords: Cardiac; Clinical translation; Fetal stem cells; Placenta
references.citation: Nucleic Acids Res. 2002 Jan 1;30(1):207-10
references.pmid: 11752295
references.citation: Stem Cells. 2004;22(7):1338-45
references.pmid: 15579651
references.citation: Nat Med. 2005 Apr;11(4):367-8
references.pmid: 15812508
references.citation: Arterioscler Thromb Vasc Biol. 2005 Jun;25(6):1168-73
references.pmid: 15831811
references.citation: J Am Coll Cardiol. 2005 Oct 4;46(7):1339-50
references.pmid: 16198853
references.citation: Am J Obstet Gynecol. 2006 Mar;194(3):664-73
references.pmid: 16522395
references.citation: FASEB J. 2006 Apr;20(6):661-9
references.pmid: 16581974
references.citation: Circulation. 2006 Oct 17;114(16):1713-20
references.pmid: 17015789
references.citation: Mol Ther. 2006 Dec;14(6):840-50
references.pmid: 16965940
references.citation: Circ Res. 2008 Nov 21;103(11):1204-19
references.pmid: 19028920
references.citation: J Exp Med. 2009 Jan 16;206(1):113-23
references.pmid: 19103879
references.citation: Am J Physiol Heart Circ Physiol. 2009 Feb;296(2):H462-9
references.pmid: 19060126
references.citation: Stem Cells. 2009 Apr;27(4):971-9
references.pmid: 19353525
references.citation: J Mol Cell Cardiol. 2010 Mar;48(3):544-9
references.pmid: 19577572
references.citation: Cardiovasc Res. 2010 Apr 1;86(1):113-21
references.pmid: 19969622
references.citation: Stem Cell Res. 2010 May;4(3):214-22
references.pmid: 20138817
references.citation: Circ Res. 2010 May 28;106(10):1613-23
references.pmid: 20508201
references.citation: Circ Res. 2010 Oct 1;107(7):913-22
references.pmid: 20671238
references.citation: Stem Cell Res. 2011 May;6(3):206-14
references.pmid: 21419744
references.citation: Circ Res. 2011 Jun 24;109(1):110-9
references.pmid: 21700952
references.citation: Circ Res. 2011 Nov 11;109(11):1302-8
references.pmid: 21980124
references.citation: Vascul Pharmacol. 2012 Aug 19;57(1):48-55
references.pmid: 22521741
references.citation: Eur Heart J. 2012 Oct;33(20):2569-619
references.pmid: 22922416
references.citation: Circulation. 2012 Dec 18;126(25):2962-75
references.pmid: 23136161
references.citation: J Clin Invest. 2013 Jan;123(1):62-70
references.pmid: 23281411
references.citation: Circulation. 2013 Jan 1;127(1):e6-e245
references.pmid: 23239837
references.citation: Lancet. 2013 Jan 12;381(9861):166-75
references.pmid: 23095318
references.citation: Br J Pharmacol. 2014 Feb;171(4):936-44
references.pmid: 24286213
references.citation: Biochim Biophys Acta. 2015 Jan;1852(1):1-11
references.pmid: 25463630
references.citation: Circ Res. 2004 Mar 19;94(5):678-85
references.pmid: 14739163
references.citation: Circulation. 2004 Sep 14;110(11):1398-405
references.pmid: 15337699
references.citation: J Neurosci Res. 2004 Oct 15;78(2):208-14
references.pmid: 15378611
references.citation: Science. 1992 Sep 4;257(5075):1401-3
references.pmid: 1382313
references.citation: Nat Med. 2003 Sep;9(9):1195-201
references.pmid: 12910262