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Paracrine effects of transplanted myoblasts and relaxin on post-infarction heart remodelling.

Formigli L, Perna AM, Meacci E, Cinci L, Margheri M, Nistri S, Tani A, Silvertown J, Orlandini G, Porciani C, Zecchi-Orlandini S, Medin J, Bani D - J. Cell. Mol. Med. (2007 Sep-Oct)

Bottom Line: 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).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.

View Article: PubMed Central - PubMed

Affiliation: Department of Anatomy, University of Florence, Florence, Italy.

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.

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Myocardial performance index (MPI), ejection fraction (EF), left ventricular end-diastolic and end-systolic diameters (LVEDD, LVESD) evaluated in basal conditions (black bars), 1 month after the induction of myocardial infarction (post-AMI; striped bars) and 1 month after cell transplantation (post-cellular cardiomyoplasty [CCM]; open bars).Myoblast implantation improves cardiac function. C2C12/RLX myoblasts are more effective than C2C12/GFP ones. Significance of differences (one-way ANOVA): MPI: (a) P<0.001 versus basal; (b) P<0.001 versus post-AMI; (c) P<0.01 versus controls; (d) P<0.001 versus controls; (e) P<0.05 versus C2C12/GFP. EF: (a) P<0.01 versus basal; (b) P<0.001 versus post-AMI; (c) P<0.001 versus controls. LVEDD: (a) P<0.05 versus basal; (b) P<0.01 versus basal; (c) P<0.01 versus controls. LVESD: (a) P<0.01 versus basal & post-AMI; (b) P<0.05 versus controls;(c) P<0.001 versus controls.
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fig06: Myocardial performance index (MPI), ejection fraction (EF), left ventricular end-diastolic and end-systolic diameters (LVEDD, LVESD) evaluated in basal conditions (black bars), 1 month after the induction of myocardial infarction (post-AMI; striped bars) and 1 month after cell transplantation (post-cellular cardiomyoplasty [CCM]; open bars).Myoblast implantation improves cardiac function. C2C12/RLX myoblasts are more effective than C2C12/GFP ones. Significance of differences (one-way ANOVA): MPI: (a) P<0.001 versus basal; (b) P<0.001 versus post-AMI; (c) P<0.01 versus controls; (d) P<0.001 versus controls; (e) P<0.05 versus C2C12/GFP. EF: (a) P<0.01 versus basal; (b) P<0.001 versus post-AMI; (c) P<0.001 versus controls. LVEDD: (a) P<0.05 versus basal; (b) P<0.01 versus basal; (c) P<0.01 versus controls. LVESD: (a) P<0.01 versus basal & post-AMI; (b) P<0.05 versus controls;(c) P<0.001 versus controls.

Mentions: We finally investigated whether myoblast grafting could improve the heart contractile performance by Doppler echocardiography. Under basal conditions, the animals of all groups showed similar values of MPI, EF and left ventricular diameters (Fig. 6). One month after myocardial infarction, the post-infarcted area had a comparable extension in all the animal groups and involved anteroseptal mid and apical segments. Paradoxical motion occurred in two animals, whereas akinesia was observed in all the remaining animals. MPI, which is inversely related to ventricular functional impairment, as well as LVEDD and LVESD were markedly increased, whereas EF was significantly decreased compared with the basal values (Fig. 6).One month after cell transplantation, MPI was markedly improved, EF was increased and LVEDD and LVESD were slightly reduced in both the transplanted groups as compared with the controls.


Paracrine effects of transplanted myoblasts and relaxin on post-infarction heart remodelling.

Formigli L, Perna AM, Meacci E, Cinci L, Margheri M, Nistri S, Tani A, Silvertown J, Orlandini G, Porciani C, Zecchi-Orlandini S, Medin J, Bani D - J. Cell. Mol. Med. (2007 Sep-Oct)

Myocardial performance index (MPI), ejection fraction (EF), left ventricular end-diastolic and end-systolic diameters (LVEDD, LVESD) evaluated in basal conditions (black bars), 1 month after the induction of myocardial infarction (post-AMI; striped bars) and 1 month after cell transplantation (post-cellular cardiomyoplasty [CCM]; open bars).Myoblast implantation improves cardiac function. C2C12/RLX myoblasts are more effective than C2C12/GFP ones. Significance of differences (one-way ANOVA): MPI: (a) P<0.001 versus basal; (b) P<0.001 versus post-AMI; (c) P<0.01 versus controls; (d) P<0.001 versus controls; (e) P<0.05 versus C2C12/GFP. EF: (a) P<0.01 versus basal; (b) P<0.001 versus post-AMI; (c) P<0.001 versus controls. LVEDD: (a) P<0.05 versus basal; (b) P<0.01 versus basal; (c) P<0.01 versus controls. LVESD: (a) P<0.01 versus basal & post-AMI; (b) P<0.05 versus controls;(c) P<0.001 versus controls.
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Related In: Results  -  Collection

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fig06: Myocardial performance index (MPI), ejection fraction (EF), left ventricular end-diastolic and end-systolic diameters (LVEDD, LVESD) evaluated in basal conditions (black bars), 1 month after the induction of myocardial infarction (post-AMI; striped bars) and 1 month after cell transplantation (post-cellular cardiomyoplasty [CCM]; open bars).Myoblast implantation improves cardiac function. C2C12/RLX myoblasts are more effective than C2C12/GFP ones. Significance of differences (one-way ANOVA): MPI: (a) P<0.001 versus basal; (b) P<0.001 versus post-AMI; (c) P<0.01 versus controls; (d) P<0.001 versus controls; (e) P<0.05 versus C2C12/GFP. EF: (a) P<0.01 versus basal; (b) P<0.001 versus post-AMI; (c) P<0.001 versus controls. LVEDD: (a) P<0.05 versus basal; (b) P<0.01 versus basal; (c) P<0.01 versus controls. LVESD: (a) P<0.01 versus basal & post-AMI; (b) P<0.05 versus controls;(c) P<0.001 versus controls.
Mentions: We finally investigated whether myoblast grafting could improve the heart contractile performance by Doppler echocardiography. Under basal conditions, the animals of all groups showed similar values of MPI, EF and left ventricular diameters (Fig. 6). One month after myocardial infarction, the post-infarcted area had a comparable extension in all the animal groups and involved anteroseptal mid and apical segments. Paradoxical motion occurred in two animals, whereas akinesia was observed in all the remaining animals. MPI, which is inversely related to ventricular functional impairment, as well as LVEDD and LVESD were markedly increased, whereas EF was significantly decreased compared with the basal values (Fig. 6).One month after cell transplantation, MPI was markedly improved, EF was increased and LVEDD and LVESD were slightly reduced in both the transplanted groups as compared with the controls.

Bottom Line: 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).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.

View Article: PubMed Central - PubMed

Affiliation: Department of Anatomy, University of Florence, Florence, Italy.

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.

Show MeSH
Related in: MedlinePlus