title: Paracrine effects of transplanted myoblasts and relaxin on post-infarction heart remodelling.
abstract: In the post-infarcted heart, grafting of precursor cells may partially restore heart function but the improvement is modest and the mechanisms involved remain to be elucidated. Here, we explored this issue by transplanting C2C12 myoblasts, genetically engineered to express enhanced green fluorescent protein (eGFP) or eGFP and the cardiotropic hormone relaxin (RLX) through coronary venous route to swine with experimental chronic myocardial infarction. The rationale was to deliver constant, biologically effective levels of RLX at the site of cell engraftment. One month after engraftment, histological analysis showed that C2C12 myoblasts selectively settled in the ischaemic scar and were located around blood vessels showing an activated endothelium (ICAM-1-,VCAM-positive). C2C12 myoblasts did not trans-differentiate towards a cardiac phenotype, but did induce extracellular matrix remodelling by the secretion of matrix metalloproteases (MMP) and increase microvessel density through the expression of vascular endothelial growth factor (VEGF). Relaxin-producing C2C12 myoblasts displayed greater efficacy to engraft the post-ischaemic scar and to induce extracellular matrix re-modelling and angiogenesis as compared with the control cells. By echocardiography, C2C12-engrafted swine showed improved heart contractility compared with the ungrafted controls, especially those producing RLX. We suggest that the beneficial effects of myoblast grafting on cardiac function are primarily dependent on the paracrine effects of transplanted cells on extracellular matrix remodelling and vascularization. The combined treatment with myoblast transplantation and local RLX production may be helpful in preventing deleterious cardiac remodelling and may hold therapeutic possibility for post-infarcted patients.
authors.affiliation: Department of Anatomy, University of Florence, Florence, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Formigli
authors.forename: Avio-Maria
authors.initials: AM
authors.lastname: Perna
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Meacci
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Cinci
authors.forename: Martina
authors.initials: M
authors.lastname: Margheri
authors.forename: Silvia
authors.initials: S
authors.lastname: Nistri
authors.forename: Alessia
authors.initials: A
authors.lastname: Tani
authors.forename: Josh
authors.initials: J
authors.lastname: Silvertown
authors.forename: Giovanni
authors.initials: G
authors.lastname: Orlandini
authors.forename: Cristina
authors.initials: C
authors.lastname: Porciani
authors.forename: Sandra
authors.initials: S
authors.lastname: Zecchi-Orlandini
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Medin
authors.forename: Daniele
authors.initials: D
authors.lastname: Bani
mesh_terms: D000818:Animals; D017690:Cell Transplantation; D002478:Cells, Cultured; D005109:Extracellular Matrix / Q000378:metabolism; D005786:Gene Expression Regulation; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D032446:Myoblasts / Q000166:cytology / Q000637:transplantation* / Q000648:ultrastructure; D009203:Myocardial Infarction / Q000503:physiopathology*; D009206:Myocardium / Q000201:enzymology / Q000473:pathology / Q000648:ultrastructure; D019899:Paracrine Communication; D012065:Relaxin / Q000097:blood / Q000378:metabolism*; D013552:Swine; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D020257:Ventricular Remodeling / Q000502:physiology*
chemical_list: D042461:Vascular Endothelial Growth Factor A; D012065:Relaxin; D020782:Matrix Metalloproteinases