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Impact of hepatocyte growth factor on skeletal myoblast transplantation late after myocardial infarction.

ABSTRACT: In clinical studies, skeletal myoblast (SKMB) transplantation late after myocardial infarction (MI) has minimal impact on left ventricular (LV) function. This may be related to our previous observation that the extent of SKMB engraftment is minimal in chronic MI when compared to acute MI, which correlates with decreased hepatocyte growth factor (HGF) expression, an important regulator of SKMB function. Here, we investigated delivery of exogenous HGF as a strategy for augmenting SKMB engraftment late after MI. Rats underwent SKMB transplantation 4 weeks after coronary ligation. HGF or vehicle control was delivered intravenously during the subsequent 2 weeks. LV function was assessed by MRI before and 2 weeks after SKMB transplantation. We evaluated HGF delivery, SKMB engraftment, and expression of genes associated with post-MI remodeling. Serum HGF was 6.2 ± 2.4 ng/mL after 2 weeks of HGF infusion (n = 7), but undetectable in controls (n = 7). LV end-diastolic volume and ejection fraction did not improve with HGF treatment (321 ± 27 mm(3), 42% ± 2% vs. 285 ± 33 mm(3), 43% ± 2%, HGF vs. control). MIs were larger in HGF-treated animals (50 ± 7 vs. 30 ± 6 mm(3), P = 0.046), but the volume of engrafted SKMBs or percentage of MIs occupied by SKMBs did not increase with HGF (1.7 ± 0.3 mm(3), 4.7% ± 1.9% vs. 1.4 ± 0.4 mm(3), 5.3% ± 1.6%, HGF vs. control). Expression of genes associated with post-infarction remodeling was not altered by HGF. Delivery of exogenous HGF failed to augment SKMB engraftment and functional recovery in chronic MI. Expression of genes associated with LV remodeling was not altered by HGF. Alternative strategies to enhance engraftment of SKMB must be explored to optimize the clinical efficacy of SKMB transplantation.

SUBMITTER: O'Blenes SB

PROVIDER: S-EPMC3653889 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Impact of hepatocyte growth factor on skeletal myoblast transplantation late after myocardial infarction.

O'Blenes Stacy B SB Li Audrey W AW Bowen Chris C Debay Drew D Althobaiti Mohammed M Clarke James J

Drug target insights 20130506

In clinical studies, skeletal myoblast (SKMB) transplantation late after myocardial infarction (MI) has minimal impact on left ventricular (LV) function. This may be related to our previous observation that the extent of SKMB engraftment is minimal in chronic MI when compared to acute MI, which correlates with decreased hepatocyte growth factor (HGF) expression, an important regulator of SKMB function. Here, we investigated delivery of exogenous HGF as a strategy for augmenting SKMB engraftment ...[more]

PMID: 23700363

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Project description:Subcutaneous pouch is a potential site for islet transplantation. However, insufficient oxygen supply remains challenging. Pretreatment of neovascularization using basic fibroblast growth factor can solve this, but it needs 2× operations. We developed a device that contains rat islets in chitosan gel packed in a bag made of highly biocompatible ethylene vinyl alcohol copolymer porous membrane. This study investigated whether coencapsulation of hepatocyte growth factor (HGF) with islets in the device enables novel method of prevascularization-free primary subcutaneous transplantation.MethodsIn vitro experiments examined slow release of HGF from the chitosan gel and islet-protection effect of HGF against hypoxia. In the latter, rat islets with/without HGF (200 ng/mL) was cultured in 1% oxygen. In in vivo experiment, fabricated device with/without HGF (10 μg/device) containing rat islets was primarily transplanted to streptozotocin-induced diabetic mice subcutaneously.ResultsIn vitro experiments showed sustained release of HGF for 28 d and alleviating effect of HGF on cell death and glucose-responsive insulin release after hypoxic culture. Islet + HGF mice, but not islet-alone mice, showed decreased nonfasting blood glucose and regained body weight after transplantation. In intraperitoneal glucose tolerance test, islet + HGF mice exhibited decreased fasting blood glucose (200 ± 55 mg/dL) and good blood glucose disappearance rate (K value) (0.817 ± 0.101) comparing to normal mice (123 ± 28 mg/dL and 1.074 ± 0.374, respectively). However, in islet-alone mice, fasting blood glucose was high (365 ± 172 mg/dL) and K value was indeterminable. Serum insulin in islet + HGF mice (1.58 ± 0.94 μg/L) was close to normal mice (1.66 ± 0.55 μg/L), whereas those in islet-alone mice (0.279 ± 0.076 μg/L) and diabetic mice (0.165 ± 0.079 μg/L) were low. Immunohistochemical examination showed intact insulin- and glucagon-positive islets in retrieved devices with HGF, but no intact islet was found in the device without HGF.ConclusionsHGF could enhance islet survival in hypoxia and enhance in vivo function of encapsulated islets after primary subcutaneous transplantation.

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.

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Impact of hepatocyte growth factor on skeletal myoblast transplantation late after myocardial infarction.

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Impact of hepatocyte growth factor on skeletal myoblast transplantation late after myocardial infarction.

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