title: Functional and histopathological improvement of the post-infarcted rat heart upon myoblast cell grafting and relaxin therapy.
abstract: Although the myocardium contains progenitor cells potentially capable of regenerating tissue upon lethal ischaemic injury, their actual role in post-infarction heart healing is negligible. Therefore, transplantation of extra-cardiac stem cells is a promising therapeutic approach for post-infarction heart dysfunction. Paracrine cardiotropic factors released by the grafted cells, such as the cardiotropic hormone relaxin (RLX), may beneficially influence remodelling of recipient hearts. The current study was designed to address whether grafting of mouse C2C12 myoblasts, genetically engineered to express green fluorescent protein (C2C12/GFP) or GFP and RLX (C2C12/RLX), are capable of improving long-term heart remodelling in a rat model of surgically induced chronic myocardial infarction. One month after myocardial infarction, rats were treated with either culture medium (controls), or C2C12/GFP cells, or C2C12/RLX cells plus exogenous RLX, or exogenous RLX alone. The therapeutic effects were monitored for 2 further months. Cell transplantation and exogenous RLX improved the main echocardiographic parameters of cardiac function, increased myocardial viability (assessed by positron emission tomography), decreased cardiac sclerosis and myocardial cell apoptosis and increased microvascular density in the post-infarction scar tissue. These effects were maximal upon treatment with C2C12/RLX plus exogenous RLX. These functional and histopathological findings provide further experimental evidence that myoblast cell grafting can improve myocardial performance and survival during post-infarction heart remodelling and dysfunction. Further, this study provides a proof-of-principle to the novel concept that genetically engineered grafted cells can be effectively employed as cell-based vehicles for the local delivery of therapeutic cardiotropic substances, such as RLX, capable of improving adverse heart remodelling.
authors.affiliation: Department of Medical and Surgical Critical Area, Cardiac Surgery Unit, University of Florence, Florence, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Bonacchi
authors.forename: Silvia
authors.initials: S
authors.lastname: Nistri
authors.forename: Cristina
authors.initials: C
authors.lastname: Nanni
authors.forename: Sandro
authors.initials: S
authors.lastname: Gelsomino
authors.forename: Alessandro
authors.initials: A
authors.lastname: Pini
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Cinci
authors.forename: Massimo
authors.initials: M
authors.lastname: Maiani
authors.forename: Sandra
authors.initials: S
authors.lastname: Zecchi-Orlandini
authors.forename: Roberto
authors.initials: R
authors.lastname: Lorusso
authors.forename: Stefano
authors.initials: S
authors.lastname: Fanti
authors.forename: Josh
authors.initials: J
authors.lastname: Silvertown
authors.forename: Daniele
authors.initials: D
authors.lastname: Bani
mesh_terms: D000818:Animals; D002470:Cell Survival; D004452:Echocardiography / Q000379:methods; D005355:Fibrosis / Q000473:pathology; D005786:Gene Expression Regulation; D049452:Green Fluorescent Proteins / Q000378:metabolism; D008297:Male; D051379:Mice; D032446:Myoblasts / Q000378:metabolism*; D009203:Myocardial Infarction / Q000473:pathology*; D009206:Myocardium / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012065:Relaxin / Q000378:metabolism*; D013234:Stem Cells / Q000166:cytology*
chemical_list: D049452:Green Fluorescent Proteins; D012065:Relaxin
references.citation: Endocrinology. 2004 Sep;145(9):4125-33
references.pmid: 15155573
references.citation: Nat Clin Pract Cardiovasc Med. 2006 Mar;3 Suppl 1:S8-13
references.pmid: 16501638
references.citation: J Cardiothorac Surg. 2008 May 20;3:30
references.pmid: 18492279
references.citation: J Cell Mol Med. 2007 Sep-Oct;11(5):1101-4
references.pmid: 17979885
references.citation: Endocrinology. 2007 Apr;148(4):1582-9
references.pmid: 17204550
references.citation: J Mol Med (Berl). 2004 Aug;82(8):539-49
references.pmid: 15175859
references.citation: Int J Cancer. 2006 Jan 1;118(1):62-73
references.pmid: 16049981
references.citation: Semin Cell Dev Biol. 2005 Aug-Oct;16(4-5):575-84
references.pmid: 16095933
references.citation: Eur J Nucl Med Mol Imaging. 2007 Nov;34(11):1819-22
references.pmid: 17351773
references.citation: Transplantation. 2004 Mar 15;77(5):757-9
references.pmid: 15021842
references.citation: Pharmacol Ther. 2006 Oct;112(1):38-56
references.pmid: 16647137
references.citation: Circ Res. 2004 Oct 29;95(9):911-21
references.pmid: 15472116
references.citation: Nat Med. 2005 Apr;11(4):367-8
references.pmid: 15812508
references.citation: Proc Natl Acad Sci U S A. 2007 Aug 28;104(35):14068-73
references.pmid: 17709737
references.citation: Endocr Rev. 2004 Apr;25(2):205-34
references.pmid: 15082520
references.citation: Am J Physiol Heart Circ Physiol. 2002 Jul;283(1):H346-52
references.pmid: 12063308
references.citation: Am J Physiol Heart Circ Physiol. 2006 Jun;290(6):H2196-203
references.pmid: 16473959
references.citation: J Cell Mol Med. 2006 Jul-Sep;10(3):569-76
references.pmid: 16989721
references.citation: J Mol Cell Cardiol. 2002 Feb;34(2):241-9
references.pmid: 11851363
references.citation: Trends Endocrinol Metab. 2003 Jul;14(5):207-13
references.pmid: 12826326
references.citation: Am J Physiol Heart Circ Physiol. 2004 Nov;287(5):H2049-53
references.pmid: 15475530
references.citation: Circ Res. 1998 Jul 13;83(1):1-14
references.pmid: 9670913
references.citation: Cells Tissues Organs. 2008;188(1-2):202-11
references.pmid: 18160823
references.citation: J Thorac Cardiovasc Surg. 2001 May;121(5):871-8
references.pmid: 11326230
references.citation: Br J Pharmacol. 1995 Sep;116(1):1589-94
references.pmid: 8564223
references.citation: Cardiovasc Hematol Agents Med Chem. 2007 Apr;5(2):101-8
references.pmid: 17430134
references.citation: Am J Physiol Regul Integr Comp Physiol. 2004 Aug;287(2):R250-61
references.pmid: 15271674
references.citation: Nat Med. 1998 Aug;4(8):929-33
references.pmid: 9701245
references.citation: Med Clin North Am. 2007 Jul;91(4):751-68; xii-xiii
references.pmid: 17640546
references.citation: J Cell Mol Med. 2007 Sep-Oct;11(5):1087-100
references.pmid: 17979884
references.citation: J Am Coll Cardiol. 2005 Nov 1;46(9):1651-8
references.pmid: 16256864
references.citation: Am J Pathol. 1998 May;152(5):1367-76
references.pmid: 9588905
references.citation: Pharmacol Ther. 2006 Nov;112(2):529-52
references.pmid: 16814863
references.citation: Circulation. 2004 Sep 14;110(11 Suppl 1):II225-30
references.pmid: 15364867
references.citation: Wound Repair Regen. 2000 Sep-Oct;8(5):361-70
references.pmid: 11186125
references.citation: J Mol Cell Cardiol. 2005 Aug;39(2):377-87
references.pmid: 16038708
references.citation: Gen Pharmacol. 1997 Jan;28(1):13-22
references.pmid: 9112071
references.citation: J Thorac Cardiovasc Surg. 2008 Apr;135(4):799-808
references.pmid: 18374759
references.citation: FASEB J. 2005 Sep;19(11):1525-7
references.pmid: 16009702
references.citation: Nat Clin Pract Cardiovasc Med. 2006 Mar;3 Suppl 1:S129-32
references.pmid: 16501619
references.citation: Annu Rev Physiol. 2006;68:29-49
references.pmid: 16460265
references.citation: Exp Biol Med (Maywood). 2006 Jan;231(1):8-19
references.pmid: 16380640
references.citation: J Nucl Med. 2006 Nov;47(11):1837-44
references.pmid: 17079817