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Improvement of Heart Function After Transplantation of Encapsulated Stem Cells Induced with miR-1/Myocd in Myocardial Infarction Model of Rat.

ABSTRACT: Cardiovascular disease is one of the most common causes of death worldwide. Mesenchymal stem cells (MSCs) are one of the most common sources in cell-based therapies in heart regeneration. There are several methods to differentiate MSCs into cardiac-like cells, such as gene induction. Moreover, using a three-dimensional (3D) culture, such as hydrogels increases efficiency of differentiation. In the current study, mouse adipose-derived MSCs were co-transduced with lentiviruses containing microRNA-1 (miR-1) and Myocardin (Myocd). Then, expression of cardiac markers, such as NK2 homeobox 5(Nkx2-5), GATA binding protein 4 (Gata4), and troponin T type 2 (Tnnt2) was investigated, at both gene and protein levels in two-dimensional (2D) culture and chitosan/collagen hydrogel (CS/CO) as a 3D culture. Additionally, after induction of myocardial infarction (MI) in rats, a patch containing the encapsulated induced cardiomyocytes (iCM/P) was implanted to MI zone. Subsequently, 30 days after MI induction, echocardiography, immunohistochemistry staining, and histological examination were performed to evaluate cardiac function. The results of quantitative real -time polymerase chain reaction (qRT-PCR) and immunocytochemistry showed that co-induction of miR-1 and Myocd in MSCs followed by 3D culture of transduced cells increased expression of cardiac markers. Besides, results of in vivo study implicated that heart function was improved in MI model of rats in iCM/P-treated group. The results suggested that miR-1/Myocd induction combined with encapsulation of transduced cells in CS/CO hydrogel increased efficiency of MSCs differentiation into iCMs and could improve heart function in MI model of rats after implantation.

SUBMITTER: Khazaei S

PROVIDER: S-EPMC8493326 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background: Bone marrow-derived multipotent progenitor cell (MPC) transplantation leads to short term functional and bioenergetic improvement in a porcine model of postinfarction Left Ventricular (LV) remodeling despite a low engraftment rate. However, the long term outcome after MPC transplantation is unknown. Methods and Results: The objectives of this study were to determine the long term functional outcome after MPC transplantation in a porcine model of postinfarction LV remodeling and to elucidate its mechanisms. Myocardial infarction (MI) was created by ligating the first and second diagonal branches of the Left anterior descending artery after open thoracotomy. Intramyocardial injection of 50 million lacZ labeled MPC was performed in the periscar region (Cell, n=7) with 5 equal injections immediately after MI, while in control animals (CONT, n=7; only 6 were profiled by microarray) saline was injected. Outcome was assessed temporally for 4 months with MRI and P-31 MRS. Engraftment was studied on histology and gene chip (Affymetrix) array analysis was used to study differential expression of genes in the two groups at 4 months. MPC treatment resulted in improvement of ejection fraction as early as 10 days after MI (32.2Â±5.5 vs. 43.4Â±5.1 in CONT and Cell respectively, p <0.05). This improvement was seen each month and persisted up to 4 months (35.7Â±5.0 vs. 51.2Â±4.8 in CONT and Cell respectively, p<0.005). PCr/ATP ratio improved with MPC transplantation (1.88Â±0.11 vs. 2.13Â±0.13 in CONT and Cell respectively, p<0.05). Under increased workload with inotropic stimulation, the bioenergetic differences were even more pronounced. There was no significant difference in scar size (scar/LV area*100) at 10 days post infarction (9.7Â±2.3 vs. 8.3Â±1.5 in CONT and Cell respectively). However, at 4 months there was a significant decrease in scar size in the MPC treated animals (8.6Â±2.4 vs. 4.6Â±1.0 in CONT and Cell respectively, p <0.05). No significant engraftment of MPC was observed on histology at 4 months. Gene chip array analysis identified several genes which were differentially expressed in the two groups. MPC transplantation was associated with a downregulation of mitochondrial oxidative enzymes, increased levels of MEF2a (Myocyte Enhancer Factor 2a) and ZFP91 (Zinc finger protein 91). Conclusion: MPC transplantation results in long term improvement in ventricular function and myocardial energetics that is associated with a decreased scar size and differential expression of genes. 13 swine were randomized after myocardial infarction to receive either 50 million stem cells (n=7) or saline only (n=6). The pigs were followed for a total of 4 months after transplantation with MRI occurring at baseline, 10 days, 1 month and then subsequently each month for 4 months. At the end of the study open-chest NMR spectroscopy was performed and then after sacrifice histology and microarray analysis was done on the tissue samples.

Project description:Background: Bone marrow-derived multipotent progenitor cell (MPC) transplantation leads to short term functional and bioenergetic improvement in a porcine model of postinfarction Left Ventricular (LV) remodeling despite a low engraftment rate. However, the long term outcome after MPC transplantation is unknown. Methods and Results: The objectives of this study were to determine the long term functional outcome after MPC transplantation in a porcine model of postinfarction LV remodeling and to elucidate its mechanisms. Myocardial infarction (MI) was created by ligating the first and second diagonal branches of the Left anterior descending artery after open thoracotomy. Intramyocardial injection of 50 million lacZ labeled MPC was performed in the periscar region (Cell, n=7) with 5 equal injections immediately after MI, while in control animals (CONT, n=7; only 6 were profiled by microarray) saline was injected. Outcome was assessed temporally for 4 months with MRI and P-31 MRS. Engraftment was studied on histology and gene chip (Affymetrix) array analysis was used to study differential expression of genes in the two groups at 4 months. MPC treatment resulted in improvement of ejection fraction as early as 10 days after MI (32.2±5.5 vs. 43.4±5.1 in CONT and Cell respectively, p <0.05). This improvement was seen each month and persisted up to 4 months (35.7±5.0 vs. 51.2±4.8 in CONT and Cell respectively, p<0.005). PCr/ATP ratio improved with MPC transplantation (1.88±0.11 vs. 2.13±0.13 in CONT and Cell respectively, p<0.05). Under increased workload with inotropic stimulation, the bioenergetic differences were even more pronounced. There was no significant difference in scar size (scar/LV area*100) at 10 days post infarction (9.7±2.3 vs. 8.3±1.5 in CONT and Cell respectively). However, at 4 months there was a significant decrease in scar size in the MPC treated animals (8.6±2.4 vs. 4.6±1.0 in CONT and Cell respectively, p <0.05). No significant engraftment of MPC was observed on histology at 4 months. Gene chip array analysis identified several genes which were differentially expressed in the two groups. MPC transplantation was associated with a downregulation of mitochondrial oxidative enzymes, increased levels of MEF2a (Myocyte Enhancer Factor 2a) and ZFP91 (Zinc finger protein 91). Conclusion: MPC transplantation results in long term improvement in ventricular function and myocardial energetics that is associated with a decreased scar size and differential expression of genes.

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Improvement of Heart Function After Transplantation of Encapsulated Stem Cells Induced with miR-1/Myocd in Myocardial Infarction Model of Rat.

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