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Human CD34+ cells in experimental myocardial infarction: long-term survival, sustained functional improvement, and mechanism of action.

ABSTRACT: Human CD34(+) cells have been used in clinical trials for treatment of myocardial infarction (MI). However, it is unknown how long the CD34(+) cells persist in hearts, whether the improvement in cardiac function is sustained, or what are the underlying mechanisms.We sought to track the fate of injected human CD34(+) cells in the hearts of severe combined immune deficiency (SCID) mice after experimental MI and to determine the mechanisms of action.We used multimodality molecular imaging to track the fate of injected human CD34(+) cells in the hearts of SCID mice after experimental MI, and used selective antibody blocking to determine the mechanisms of action. Bioluminescence imaging showed that injected CD34(+) cells survived in the hearts for longer than 12 months. The PET signal from the injected cells was detected in the wall of the left ventricle. Cardiac MRI showed that left ventricular ejection fraction was significantly improved in the treated mice compared to the control mice for up to 52 weeks (P<0.05). Furthermore, treatment with anti-alpha4beta1 showed that generation of human-derived cardiomyocytes was inhibited, whereas anti-vascular endothelial growth factor (VEGF) treatment blocked the production of human-derived endothelial cells. However, the improvement in cardiac function was abolished only in the anti-VEGF, but not anti-alpha4beta1, treated group.Angiogenesis and/or paracrine effect, but not myogenesis, is responsible for functional improvement following CD34(+) cells therapy.

SUBMITTER: Wang J

PROVIDER: S-EPMC2908245 | biostudies-literature | 2010 Jun

REPOSITORIES: biostudies-literature

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Human CD34+ cells in experimental myocardial infarction: long-term survival, sustained functional improvement, and mechanism of action.

Wang Jingxiong J Zhang Sui S Rabinovich Brian B Bidaut Luc L Soghomonyan Suren S Alauddin Mian M MM Bankson James A JA Shpall Elizabeth E Willerson James T JT Gelovani Juri G JG Yeh Edward T H ET

Circulation research 20100506 12

<h4>Rationale</h4>Human CD34(+) cells have been used in clinical trials for treatment of myocardial infarction (MI). However, it is unknown how long the CD34(+) cells persist in hearts, whether the improvement in cardiac function is sustained, or what are the underlying mechanisms.<h4>Objective</h4>We sought to track the fate of injected human CD34(+) cells in the hearts of severe combined immune deficiency (SCID) mice after experimental MI and to determine the mechanisms of action.<h4>Methods a ...[more]

PMID: 20448213

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Project description:BACKGROUND:In the months after acute myocardial infarction (MI), risk for acute atherothrombotic events in nonculprit arteries increases several fold. OBJECTIVES:This study investigated whether sustained proinflammatory and prothrombotic endothelial alterations occur in remote vessels after MI. METHODS:Wild-type mice, atherosclerotic mice with double knockout (DKO) of the low-density lipoprotein receptor and Apobec-1, and DKO mice treated with the Nox-inhibitor apocynin were studied at baseline and at 3 and 21 days after closed-chest MI. Ultrasound molecular imaging of P-selectin, vascular cell adhesion molecule (VCAM)-1, von Willebrand factor (VWF) A1-domain, and platelet GPIbα was performed. Intravital microscopy was used to characterize post-MI leukocyte and platelet recruitment in the remote microcirculation after MI. RESULTS:Aortic molecular imaging for P-selectin, VCAM-1, VWF-A1, and platelets was increased several-fold (p < 0.01) 3 days post-MI for both wild-type and DKO mice. At 21 days, these changes resolved in wild-type mice but persisted in DKO mice. Signal for platelet adhesion was abolished 1 h after administration of ADAMTS13, which regulates VWF multimerization. In DKO and wild-type mice, apocynin significantly attenuated the post-MI increase for molecular targets, and platelet depletion significantly reduced P-selectin and VCAM-1 signal. On intravital microscopy, MI resulted in remote vessel leukocyte adhesion and platelet string or net complexes. On histology, high-risk inflammatory features in aortic plaque increased in DKO mice 21 days post-MI, which were completely prevented by apocynin. CONCLUSIONS:Acute MI stimulates a spectrum of changes in remote vessels, including up-regulation of endothelial inflammatory adhesion molecules and platelet-endothelial adhesion from endothelial-associated VWF multimers. These remote arterial alterations persist longer in the presence of hyperlipidemia, are associated with accelerated plaque growth and inflammation, and are attenuated by Nox inhibition.

Project description:The study examined the long-term outcome of cardiac stem cell transplantation in hearts with postinfarction left ventricular (LV) remodeling. Myocardial infarction (MI) was created by ligating the first and second diagonal branches of the left anterior descending coronary artery in miniature swine. Intramyocardial injections of 50 million LacZ-labeled bone marrow-derived multipotent progenitor cells (MPC) were performed in the periscar region (Cell, n = 7) immediately after MI, whereas, in control animals (Cont, n = 7), saline was injected. Functional outcome was assessed monthly for 4 mo with MRI and (31)P-magnetic resonance spectroscopy. Engraftment was studied on histology, and gene chip (Affymetrix) array analysis was used to study differential expression of genes in the two groups. MPC treatment resulted in improvement of ejection fraction as early as 10 days after MI (Cell, 43.4 +/- 5.1% vs. Cont, 32.2 +/- 5.5%; P < 0.05). This improvement was seen each month and persisted to 4 mo (Cell, 51.2 +/- 4.8% vs. Cont, 35.7 +/- 5.0%; P < 0.05). PCr-to-ATP ratio (PCr/ATP) improved with MPC transplantation, which was most pronounced at high cardiac work states (subendocardial PCr/ATP was 1.70 +/- 0.10 vs. 1.34 +/- 0.14, P < 0.05). There was no significant difference in scar size (scar/LV area * 100) at 10 days postinfarction. However, at 4 mo, there was a significant decrease in scar size in the Cell group (Cell, 4.6 +/- 1.0% vs. Cont, 8.6 +/- 2.4%; P < 0.05). No significant engraftment of MPC was observed. MPC transplantation was associated with a downregulation of mitochondrial oxidative enzymes and increased levels of myocyte enhancer factor 2a and zinc finger protein 91. In conclusion, MPC transplantation leads to long-term functional and bioenergetic improvement in a porcine model of postinfarction LV remodeling, despite no significant engraftment of stem cells in the heart. MPC transplantation reduces regional wall stresses and infarct size and mitigates the adverse effects of LV remodeling, as seen by a reduction in LV hypertrophy and LV dilatation, and is associated with differential expression of genes relating to metabolism and apoptosis.

Dataset Information

Human CD34+ cells in experimental myocardial infarction: long-term survival, sustained functional improvement, and mechanism of action.

Publications

Human CD34+ cells in experimental myocardial infarction: long-term survival, sustained functional improvement, and mechanism of action.

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