Optical mapping of cryoinjured rat myocardium grafted with mesenchymal stem cells

Costa, Andréa Rodrigues da; Panda, Nikhil; Yong, S. L.; Mayorga, Maritza E.; Pawłowski, G; Fan, KeKe; Penn, Marc S.; Laurita, Kenneth R.

doi:10.1152/ajpheart.00019.2011

Cited by 20 publications

(18 citation statements)

References 33 publications

(60 reference statements)

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“…5). These findings are consistent with our previous studies which suggest MSCs enhance electrical activity when administered following acute MI [10] or cryoinjury [11]. Other laboratories, such as Potapova et al [25], have shown that human MSCs form gap junctions with adjacent cardiac myocytes in situ .…”

Section: Discussionsupporting

confidence: 92%

“…It is possible that MSCs differentiate into cardiac myocytes [30–33]. However, we have recently shown [11] along with others [34] that MSCs only exhibit signs of electronic influence rather than action potential generation [11]. This and other studies [35, 36] suggest it is unlikely that MSCs differentiate into cardiomyocytes that generate action potentials.…”

Section: Discussionmentioning

confidence: 82%

“…For example, mesenchymal stem cells (MSCs) are the subject of ongoing clinical trials [6], and results to date demonstrate that MSCs are safe and improve function [7–9]. Studies from our laboratory suggest that MSCs may enhance impulse propagation in tissue damaged by acute ischemia [10] and cryoinjury [11] by a passive, electrotonic mechanism. Others have shown an association between MSCs and reduced arrhythmia propensity in animals [12] and patients [7] during acute MI, suggesting amelioration of the arrhythmia substrate.…”

Section: Introductionmentioning

confidence: 99%

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Improved conduction and increased cell retention in healed MI using mesenchymal stem cells suspended in alginate hydrogel

Panda

Zuckerman

Mesubi

et al. 2014

J Interv Card Electrophysiol

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Introduction Mesenchymal stem cells (MSCs) have been associated with reduced arrhythmias; however, the mechanism of this action is unknown. In addition, limited retention and survival of MSCs can significantly reduce efficacy. We hypothesized that MSCs can improve impulse conduction and that alginate hydrogel will enhance retention of MSCs in a model of healed myocardial infarction (MI). Methods and results Four weeks after temporary occlusion of the left anterior descending artery (LAD), pigs (n=13) underwent a sternotomy to access the infarct and then were divided into two studies. In study 1, designed to investigate impulse conduction, animals were administered, by border zone injection, 9–15 million MSCs (n=7) or phosphate-buffered saline (PBS) (control MI, n=5). Electrogram width measured in the border zone 2 weeks after injections was significantly decreased with MSCs (−30±8 ms, p<0.008) but not in shams (4±10 ms, p=NS). Optical mapping from border zone tissue demonstrated that conduction velocity was higher in regions with MSCs (0.49±0.03 m/s) compared to regions without MSCs (0.39±0.03 m/s, p<0.03). In study 2, designed to investigate MSC retention, animals were administered an equal number of MSCs suspended in either alginate (2 or 1 % w/v) or PBS (n=6/group) by border zone injection. Greater MSC retention and survival were observed with 2 % alginate compared to PBS or 1 % alginate. Confocal immunofluorescence demonstrated that MSCs survive and are associated with expression of connexin-43 (Cx43) for either PBS (control), 1 %, or 2 % alginate. Conclusions For the first time, we are able to directly associate MSCs with improved impulse conduction and increased retention and survival using an alginate scaffold in a clinically relevant model of healed MI.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 82%

Section: Introductionmentioning

confidence: 99%

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Improved conduction and increased cell retention in healed MI using mesenchymal stem cells suspended in alginate hydrogel

Panda

Zuckerman

Mesubi

et al. 2014

J Interv Card Electrophysiol

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“…27,28 The findings reported herein have multiple implications on the field of cardiovascular gene therapy. Perhaps most importantly our findings suggest that prior plasmid gene transfer studies may have been significantly under dosed.…”

Section: Discussionmentioning

confidence: 89%

SDF-1 in myocardial repair

et al. 2012

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Stem cell therapy for the prevention and treatment of cardiac dysfunction holds significant promise for patients with ischemic heart disease. Excitingly early clinical studies have demonstrated safety and some clinical feasibility, while at the same time studies in the laboratory have investigated mechanisms of action and strategies to optimize the effects of regenerative cardiac therapies. One of the key pathways that has been demonstrated critical in stem cell-based cardiac repair is (stromal cell-derived factor-1) SDF-1:CXCR4. SDF-1:CXCR4 has been shown to affect stem cell homing, cardiac myocyte survival and ventricular remodeling in animal studies of acute myocardial infarction and chronic heart failure. Recently released clinical data suggest that SDF-1 alone is sufficient to induce cardiac repair. Most importantly, studies like those on the SDF-1:CXCR4 axis have suggested mechanisms critical for cardiac regenerative therapies that if clinical investigators continue to ignore will result in poorly designed studies that will continue to yield negative results. Gene Therapy (2012) 19, 583-587; doi:10.1038/gt.2012.32Keywords: acute myocordial infarction; regenerative medicine; stem cells; chemokines INTRODUCTIONOver a decade ago we hypothesized that stem cell-based repair of ischemic tissue is a natural response to tissue injury but that it is clinically inefficient because of the short-lived nature of the molecular signals regulating the process, not a lack of stem cells. At that time it was of great interest to us that stem cells in the blood stream homed to the myocardium in animal models of acute myocardial infarction (AMI), but not in models of chronic ischemic cardiomyopathy. These observations led us to investigate potential regulators of stem cell homing. We eventually identified stromal cell-derived factor-1 (SDF-1, aka CXCL12) as the key regulator of stem cell migration to sites of tissue injury. 1 More recently studies have extended the relevance of the SDF-1:CXCR4 axis by demonstrating its critical importance in cardiogenic specification during development. 2 As that initial observation we have demonstrated that transient engineered-cell-based 3 or plasmid-based 4 overexpression of SDF-1 in ischemic cardiomyopathy improved cardiac function. Furthermore, we have demonstrated that delivery of mesenchymal stem cells engineered to overexpress SDF-1 at the time of AMI leads to improvement in cardiac function. 5 Research by our laboratory and others have demonstrated that mechanism of action of SDF-1 overexpression in AMI and chronic heart failure (CHF) are clearly multifactorial including both systemic and direct trophic effects. [4][5][6] The initiation of endogenous stem cell-based repair appears blunted because of the natural short-term expression of SDF-1 at the time of AMI. 1 Furthermore, there appears to be commonalities associated with the mechanisms of action of SDF-1 in AMI and CHF as well as some distinct differences. We were the first to show that SDF-1 leads to the recruitment of cardiac st...

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“…We measured the area at risk and infarct as described previously (4,18,22). Briefly, mouse hearts were harvested 4 days post-MI, and the area of the LV at risk for ischemic injury was determined by 2% Evans blue staining of the myocardium via a cannula inserted into the proximal ascending aorta.…”

Section: Measurement Of Area At Risk and Infarctmentioning

confidence: 99%

Early upregulation of myocardial CXCR4 expression is critical for dimethyloxalylglycine-induced cardiac improvement in acute myocardial infarction

Mayorga

Kiedrowski

Shamhart

et al. 2016

American Journal of Physiology-Heart and Circulatory Physiology

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Early upregulation of myocardial CXCR4 expression is critical for dimethyloxalylglycine-induced cardiac improvement in acute myocardial infarction. Am J Physiol Heart Circ Physiol 310: H20 -H28, 2016. First published October 30, 2015 doi:10.1152/ajpheart.00449.2015.-The stromal cell-derived factor-1 (SDF-1):CXCR4 is important in myocardial repair. In this study we tested the hypothesis that early upregulation of cardiomyocyte CXCR4 (CM-CXCR4) at a time of high myocardial SDF-1 expression could be a strategy to engage the SDF-1:CXCR4 axis and improve cardiac repair. The effects of the hypoxia inducible factor (HIF) hydroxylase inhibitor dimethyloxalylglycine (DMOG) on CXCR4 expression was tested on H9c2 cells. In mice a myocardial infarction (MI) was produced in CM-CXCR4 null and wild-type controls. Mice were randomized to receive injection of DMOG (DMOG group) or saline (Saline group) into the border zone after MI. Protein and mRNA expression of CM-CXCR4 were quantified. Echocardiography was used to assess cardiac function. During hypoxia, DMOG treatment increased CXCR4 expression of H9c2 cells by 29 and 42% at 15 and 24 h, respectively. In vivo DMOG treatment increased CM-CXCR4 expression at 15 h post-MI in control mice but not in CM-CXCR4 null mice. DMOG resulted in increased ejection fraction in control mice but not in CM-CXCR4 null mice 21 days after MI. Consistent with greater cardiomyocyte survival with DMOG treatment, we observed a significant increase in cardiac myosin-positive area within the infarct zone after DMOG treatment in control mice, but no increase in CM-CXCR4 null mice. Inhibition of cardiomyocyte death in MI through the stabilization of HIF-1␣ requires downstream CM-CXCR4 expression. These data suggest that engagement of the SDF-1:CXCR4 axis through the early upregulation of CM-CXCR4 is a strategy for improving cardiac repair after MI.

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Optical mapping of cryoinjured rat myocardium grafted with mesenchymal stem cells

Abstract: Costa AR, Panda NC, Yong S, Mayorga ME, Pawlowski GP, Fan K, Penn MS, Laurita KR. Optical mapping of cryoinjured rat myocardium grafted with mesenchymal stem cells.

Cited by 20 publications

References 33 publications

Improved conduction and increased cell retention in healed MI using mesenchymal stem cells suspended in alginate hydrogel

Improved conduction and increased cell retention in healed MI using mesenchymal stem cells suspended in alginate hydrogel

SDF-1 in myocardial repair

Early upregulation of myocardial CXCR4 expression is critical for dimethyloxalylglycine-induced cardiac improvement in acute myocardial infarction

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