Long-term functional improvement and gene expression changes after bone marrow-derived multipotent progenitor cell transplantation in myocardial infarction

Jameel, Mohammad Nurulqadr; Li, Qinglu; Mansoor, Abdul; Xiong, Qing; Sarver, Aaron L.; Wang, Xiaohong; Swingen, Cory; Zhang, Jianyi J

doi:10.1152/ajpheart.01100.2009

Cited by 35 publications

(41 citation statements)

References 42 publications

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“…By 1 week post-injection, the transcriptomes of saline and matrix-injected infarcts clustered separately. Similar analyses have also been applied to other experimental therapies for MI including cell transplantation (10–12) and injection of cell-derived products (13); however, to our knowledge, no other biologic-based therapy has been reported to induce a distinct transcription signature at a global level. In this study, the key modulated pathways included inflammation, reduction of apoptosis and cardiac hypertrophy, metabolism, and blood vessel and cardiac development (Central Illustration).…”

Section: Discussionmentioning

confidence: 80%

“…We showed an increase in PGC-1α in cardiomyocytes in matrix-injected animals. In comparison, injections of various bone marrow cells into the infarct myocardium have been associated with decreased expression of genes related to mitochondrial function (10,12). Angiotensin-converting enzyme inhibition using captopril, a common treatment for HF, similarly did not rescue changes in fatty acid metabolism (28).…”

Section: Discussionmentioning

confidence: 99%

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Evidence for Mechanisms Underlying the Functional Benefits of a Myocardial Matrix Hydrogel for Post-MI Treatment

Wassenaar

Gaetani

Garcia

et al. 2016

Journal of the American College of Cardiology

129

117

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BACKGROUND There is increasing need for better therapies to prevent the development of heart failure after myocardial infarction (MI). An injectable hydrogel derived from decellularized porcine ventricular myocardium has been shown to halt the post-infarction progression of negative left ventricular remodeling and decline in cardiac function in both small and large animal models. OBJECTIVES We sought to elucidate the tissue level mechanisms underlying the therapeutic benefits of myocardial matrix injection. METHODS Myocardial matrix or saline was injected into infarcted myocardium 1 week after ischemia-reperfusion in Sprague Dawley rats. Cardiac function was evaluated by magnetic resonance imaging and hemodynamic measurements at 5 weeks post-injection. Whole transcriptome microarrays were performed on ribonucleic acid (RNA) isolated from the infarct at 3 days and 1 week after injection. Quantitative polymerase chain reaction and histological quantification confirmed expression of key genes and their activation in altered pathways. RESULTS Principal component analysis of the transcriptomes showed that samples collected from myocardial matrix-injected infarcts are distinct and cluster separately from saline-injected controls. Pathway analysis indicated that these differences are due to changes in several tissue processes that may contribute to improved cardiac healing post-MI. Matrix-injected infarcted myocardium exhibits an altered inflammatory response, reduced cardiomyocyte apoptosis, enhanced infarct neovascularization, diminished cardiac hypertrophy and fibrosis, altered metabolic enzyme expression, increased cardiac transcription factor expression, and progenitor cell recruitment, along with improvements in global cardiac function and hemodynamics. CONCLUSIONS These results indicate that the myocardial matrix alters several key pathways post-MI creating a pro-regenerative environment, further demonstrating its promise as a potential post-MI therapy.

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Section: Discussionmentioning

confidence: 80%

Section: Discussionmentioning

confidence: 99%

Evidence for Mechanisms Underlying the Functional Benefits of a Myocardial Matrix Hydrogel for Post-MI Treatment

Wassenaar

Gaetani

Garcia

et al. 2016

Journal of the American College of Cardiology

129

117

View full text Add to dashboard Cite

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“…The causation for the lowered OXPHOS enzymatic activity is currently unknown. Jameel et al (12) hypothesized that a reduction in regional wall stress and energetic demands following the cellbased therapy may result in the differential CI subunit gene expression and may contribute to OXPHOS enzymatic alterations. In support, we observed cardiac ANP gene expression to be increased in the MI ϩ MSC mice above that of the MI ϩ PBS and SHAM animals.…”

Section: E170mentioning

confidence: 99%

Mesenchymal stem cell transplantation for the infarcted heart: a role in minimizing abnormalities in cardiac-specific energy metabolism

Hughey¹,

Johnsen

et al. 2012

American Journal of Physiology-Endocrinology and Metabolism

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Hughey CC, Johnsen VL, Ma L, James FD, Young PP, Wasserman DH, Rottman JN, Hittel DS, Shearer J. Mesenchymal stem cell transplantation for the infarcted heart: a role in minimizing abnormalities in cardiac-specific energy metabolism. Am J Physiol Endocrinol Metab 302: E163-E172, 2012. First published October 4, 2011; doi:10.1152/ajpendo.00443.2011.-Intense interest has been focused on cell-based therapy for the infarcted heart given that stem cells have exhibited the ability to reduce infarct size and mitigate cardiac dysfunction. Despite this, it is unknown whether mesenchymal stem cell (MSC) therapy can prevent metabolic remodeling following a myocardial infarction (MI). This study examines the ability of MSCs to rescue the infarcted heart from perturbed substrate uptake in vivo. C57BL/6 mice underwent chronic ligation of the left anterior descending coronary artery to induce a MI. Echocardiography was performed on conscious mice at baseline as well as 7 and 23 days post-MI. Twenty-eight days following the ligation procedure, hyperinsulinemic euglycemic clamps assessed in vivo insulin sensitivity. Isotopic tracer administration evaluated whole body, peripheral tissue, and cardiac-specific glucose and fatty acid utilization. To gain insight into the mechanisms by which MSCs modulate metabolism, mitochondrial function was assessed by high-resolution respirometry using permeabilized cardiac fibers. Data show that MSC transplantation preserves insulin-stimulated fatty acid uptake in the peri-infarct region (4.25 Ϯ 0.64 vs. 2.57 Ϯ 0.34 vs. 3.89 Ϯ 0.54 mol·100 g Ϫ1 ·min Ϫ1 , SHAM vs. MI ϩ PBS vs. MI ϩ MSC; P Ͻ 0.05) and prevents increases in glucose uptake in the remote left ventricle (3.11 Ϯ 0.43 vs. 3.81 Ϯ 0.79 vs. 6.36 Ϯ 1.08 mol·100 g Ϫ1 ·min Ϫ1 , SHAM vs. MI ϩ PBS vs. MI ϩ MSC; P Ͻ 0.05). This was associated with an enhanced efficiency of mitochondrial oxidative phosphorylation with a respiratory control ratio of 3.36 Ϯ 0.18 in MSC-treated cardiac fibers vs. 2.57 Ϯ 0.14 in the infarct-only fibers (P Ͻ 0.05). In conclusion, MSC therapy exhibits the potential to rescue the heart from metabolic aberrations following a MI. Restoration of metabolic flexibility is important given the metabolic demands of the heart and the role of energetics in the progression to heart failure. substrate uptake; mitochondria; hyperinsulinemic euglycemic clamp; skeletal muscle; peroxisome proliferator-activated receptor-␥ coactivator-1␣TO SATISFY THE CONTINUOUS ENERGETIC DEMAND of contractile function, fatty acids (FA) and to a lesser extent glucose are catabolized by mitochondria to synthesize ATP via oxidative phosphorylation (OXPHOS) (28). In response to physiological stressors, the heart must maintain an efficient means of energy provision. This is accomplished by the heart possessing metabolic flexibility, the ability to switch to the most appropriate substrate. Following a myocardial infarction (MI), the heart undergoes energetic alterations in which this adaptability is lost (14). This metabolic remodeling is characterized by a ...

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“…However, the development of MR reporters is limited, and cardiovascular applications have not yet been explored. While MRI has been extensively used to assess the therapeutic efficacy of stem cell treatment with [34] or without stem cell tracking by MRI [35,36], the ability to safely and accurately scan patients with implanted devices, ie, defibrillators, pacemakers, valves, etc., remains a concern. The hurdles that will probably limit universal adoption of MRlabeling techniques for clinical trials are the lack of a high fidelity ECG while scanning and the high cost of MRI.…”

Section: Mrimentioning

confidence: 99%

Emerging Approaches for Cardiovascular Stem Cell Imaging

Kedziorek

Kraitchman

2010

Curr Cardiovasc Imaging Rep

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Stem cell therapies offer potential therapeutic alternatives for coronary artery disease, myocardial infarction, and heart failure. To a lesser extent, stem cell transplantations are used for experimental treatment of congenital heart conditions, atherosclerotic peripheral arterial disease, and other cardiovascular pathologies. The efficacy of stem cell transplants on the aforementioned diseases has been inconsistent, and the specific regenerative mechanisms by which stem cells work are not well understood. Thus, a reliable and efficient method of cell tracking and monitoring would be beneficial. The different imaging strategies and modalities for cell tracking, as well as the latest approaches to cell labeling in this field, are reviewed in the hope that this will foster a better understanding of the best methods to treat cardiovascular diseases with cellular therapeutics.

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Long-term functional improvement and gene expression changes after bone marrow-derived multipotent progenitor cell transplantation in myocardial infarction

Cited by 35 publications

References 42 publications

Evidence for Mechanisms Underlying the Functional Benefits of a Myocardial Matrix Hydrogel for Post-MI Treatment

Evidence for Mechanisms Underlying the Functional Benefits of a Myocardial Matrix Hydrogel for Post-MI Treatment

Mesenchymal stem cell transplantation for the infarcted heart: a role in minimizing abnormalities in cardiac-specific energy metabolism

Emerging Approaches for Cardiovascular Stem Cell Imaging

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