Functional and histopathological improvement of the post-infarcted rat heart upon myoblast cell grafting and relaxin therapy.
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.
Bonacchi
Massimo
M
Department of Medical and Surgical Critical Area, Cardiac Surgery Unit, University of Florence, Florence, Italy.
Nistri
Silvia
S
Nanni
Cristina
C
Gelsomino
Sandro
S
Pini
Alessandro
A
Cinci
Lorenzo
L
Maiani
Massimo
M
Zecchi-Orlandini
Sandra
S
Lorusso
Roberto
R
Fanti
Stefano
S
Silvertown
Josh
J
Bani
Daniele
D
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*
D049452:Green Fluorescent Proteins; D012065:Relaxin
Endocrinology. 2004 Sep;145(9):4125-33
15155573
Nat Clin Pract Cardiovasc Med. 2006 Mar;3 Suppl 1:S8-13
16501638
J Cardiothorac Surg. 2008 May 20;3:30
18492279
J Cell Mol Med. 2007 Sep-Oct;11(5):1101-4
17979885
Endocrinology. 2007 Apr;148(4):1582-9
17204550
J Mol Med (Berl). 2004 Aug;82(8):539-49
15175859
Int J Cancer. 2006 Jan 1;118(1):62-73
16049981
Semin Cell Dev Biol. 2005 Aug-Oct;16(4-5):575-84
16095933
Eur J Nucl Med Mol Imaging. 2007 Nov;34(11):1819-22
17351773
Transplantation. 2004 Mar 15;77(5):757-9
15021842
Pharmacol Ther. 2006 Oct;112(1):38-56
16647137
Circ Res. 2004 Oct 29;95(9):911-21
15472116
Nat Med. 2005 Apr;11(4):367-8
15812508
Proc Natl Acad Sci U S A. 2007 Aug 28;104(35):14068-73
17709737
Endocr Rev. 2004 Apr;25(2):205-34
15082520
Am J Physiol Heart Circ Physiol. 2002 Jul;283(1):H346-52
12063308
Am J Physiol Heart Circ Physiol. 2006 Jun;290(6):H2196-203
16473959
J Cell Mol Med. 2006 Jul-Sep;10(3):569-76
16989721
J Mol Cell Cardiol. 2002 Feb;34(2):241-9
11851363
Trends Endocrinol Metab. 2003 Jul;14(5):207-13
12826326
Am J Physiol Heart Circ Physiol. 2004 Nov;287(5):H2049-53
15475530
Circ Res. 1998 Jul 13;83(1):1-14
9670913
Cells Tissues Organs. 2008;188(1-2):202-11
18160823
J Thorac Cardiovasc Surg. 2001 May;121(5):871-8
11326230
Br J Pharmacol. 1995 Sep;116(1):1589-94
8564223
Cardiovasc Hematol Agents Med Chem. 2007 Apr;5(2):101-8
17430134
Am J Physiol Regul Integr Comp Physiol. 2004 Aug;287(2):R250-61
15271674
Nat Med. 1998 Aug;4(8):929-33
9701245
Med Clin North Am. 2007 Jul;91(4):751-68; xii-xiii
17640546
J Cell Mol Med. 2007 Sep-Oct;11(5):1087-100
17979884
J Am Coll Cardiol. 2005 Nov 1;46(9):1651-8
16256864
Am J Pathol. 1998 May;152(5):1367-76
9588905
Pharmacol Ther. 2006 Nov;112(2):529-52
16814863
Circulation. 2004 Sep 14;110(11 Suppl 1):II225-30
15364867
Wound Repair Regen. 2000 Sep-Oct;8(5):361-70
11186125
J Mol Cell Cardiol. 2005 Aug;39(2):377-87
16038708
Gen Pharmacol. 1997 Jan;28(1):13-22
9112071
J Thorac Cardiovasc Surg. 2008 Apr;135(4):799-808
18374759
FASEB J. 2005 Sep;19(11):1525-7
16009702
Nat Clin Pract Cardiovasc Med. 2006 Mar;3 Suppl 1:S129-32
16501619
Annu Rev Physiol. 2006;68:29-49
16460265
Exp Biol Med (Maywood). 2006 Jan;231(1):8-19
16380640
J Nucl Med. 2006 Nov;47(11):1837-44
17079817