The Orchestra of Myocardial Regeneration

A glimpse on previous and current literature ignites the recognition of the luxurious era that cardiac science has reached. In particular, the past fifteen years have provided tremendous advancements in the field of myocardial biology with the characterization of cardiac stem cells, reprogramming of somatic cells, microRNA discovery, exosome-protocols and imaging modalities. In addition, conventional and outdated biological processes such as myocyte metabolism, cell cycle, and senescence are revisited with fresh perspectives. This phylogeny represents a foundation that provides a broad range of possibilities and directions that can be pursued. While preceding science evolved around characterization of peculiar topics, perhaps contemporary science postulates an orchestrated approach where molecular biological conglomerates are deciphered and connections are made in a panoramic manner. Similar to a musical composition; molecular biological systems demand comprehensive knowledge of distinct notes or molecules that are then orchestrated in a timely and harmonious fashion. This composition-based demeanor, as symbolized by a portrait of the legendary composer Ludwig van Beethoven, concurrently calls for contemplation of the frame-works and restrictions that are imposed by innate properties of a system. The current thesis is a compilation of assorted topics that may appear heterogeneous at first but are related in the harmony of ‘myocardial regeneration composition’. The perspective of myocardial regeneration consists of two main branches: Myocyte-mediated regeneration and Stem Cell mediated regeneration. Overall, the current work may represent certain controversies and even attempts to challenge particular common beliefs. However, in this era of accelerated phylogeny and the extent of knowledge generated on a daily basis, perhaps new scientists ought to question certain existing criteria and definitions from time to time. After all, a common criteria for a successful composer might be ‘a crystal clear sense of hearing’ and yet, while composing some of his legendary compositions, Ludwig van Beethoven was deaf

MiR-155 inhibits cell migration of human cardiomyocyte progenitor cells (hCMPCs) via targeting of MMP-16

Undesired cell migration after targeted cell transplantation potentially limits beneficial effects for cardiac regeneration. MicroRNAs are known to be involved in several cellular processes, including cell migration. Here, we attempt to reduce human cardiomyocyte progenitor cell (hCMPC) migration via increasing microRNA-155 (miR-155) levels, and investigate the underlying mechanism. Human cardiomyocyte progenitor cells (hCMPCs) were transfected with pre-miR-155, anti-miR-155 or control-miR (ctrl-miR), followed by scratch- and transwell- assays. These functional assays displayed that miR-155 over-expression efficiently inhibited cell migration by 38 ± 3.6% and 59 ± 3.7% respectively. Conditioned medium from miR-155 transfected cells was collected and zymography analysis showed a significant decrease in MMP-2 and MMP-9 activities. The predicted 3′-UTR of MMP-16, an activator of MMP-2 and -9, was cloned into the pMIR-REPORT vector and luciferase assays were performed. Introduction of miR-155 significantly reduced luciferase activity which could be abolished by cotransfection with anti-miR-155 or target site mutagenesis. By using MMP-16 siRNA to reduce MMP-16 levels or by using an MMP-16 blocking antibody, hCMPC migration could be blocked as well. By directly targeting MMP-16, miR-155 efficiently inhibits cell migration via a reduction in MMP-2 and -9 activities. Our study shows that miR-155 might be used to improve local retention of hCMPCs after intramyocardial delivery

Myocardial Disease and Long-Distance Space Travel: Solving the Radiation Problem

Radiation-induced cardiovascular disease is a well-known complication of radiation exposure. Over the last few years, planning for deep space missions has increased interest in the effects of space radiation on the cardiovascular system, as an increasing number of astronauts will be exposed to space radiation for longer periods of time. Research has shown that exposure to different types of particles found in space radiation can lead to the development of diverse cardiovascular disease via fibrotic myocardial remodeling, accelerated atherosclerosis and microvascular damage. Several underlying mechanisms for radiation-induced cardiovascular disease have been identified, but many aspects of the pathophysiology remain unclear. Existing pharmacological compounds have been evaluated to protect the cardiovascular system from space radiation-induced damage, but currently no radioprotective compounds have been approved. This review critically analyzes the effects of space radiation on the cardiovascular system, the underlying mechanisms and potential countermeasures to space radiation-induced cardiovascular disease

MiR-155 inhibits cell migration of human cardiomyocyte progenitor cells (hCMPCs) via targeting of MMP-16

Abstract Undesired cell migration after targeted cell transplantation potentially limits beneficial effects for cardiac regeneration. MicroRNAs are known to be involved in several cellular processes, including cell migration. Here, we attempt to reduce human cardiomyocyte progenitor cell (hCMPC) migration via increasing microRNA-155 (miR-155) levels, and investigate the underlying mechanism. Human cardiomyocyte progenitor cells (hCMPCs) were transfected with pre-miR-155, anti-miR-155 or control-miR (ctrl-miR), followed by scratch-and transwell-assays. These functional assays displayed that miR-155 over-expression efficiently inhibited cell migration by 38 ± 3.6% and 59 ± 3.7% respectively. Conditioned medium from miR-155 transfected cells was collected and zymography analysis showed a significant decrease in MMP-2 and MMP-9 activities. The predicted 3′-UTR of MMP-16, an activator of MMP-2 and -9, was cloned into the pMIR-REPORT vector and luciferase assays were performed. Introduction of miR-155 significantly reduced luciferase activity which could be abolished by cotransfection with anti-miR-155 or target site mutagenesis. By using MMP-16 siRNA to reduce MMP-16 levels or by using an MMP-16 blocking antibody, hCMPC migration could be blocked as well. By directly targeting MMP-16, miR-155 efficiently inhibits cell migration via a reduction in MMP-2 and -9 activities. Our study shows that miR-155 might be used to improve local retention of hCMPCs after intramyocardial delivery

Targeting chronic cardiac remodeling with cardiac progenitor cells in a murine model of ischemia/reperfusion injury

<div><p>Background</p><p>Translational failure for cardiovascular disease is a substantial problem involving both high research costs and an ongoing lack of novel treatment modalities. Despite the progress already made, cell therapy for chronic heart failure in the clinical setting is still hampered by poor translation. We used a murine model of chronic ischemia/reperfusion injury to examine the effect of minimally invasive application of cardiac progenitor cells (CPC) in cardiac remodeling and to improve clinical translation.</p><p>Methods</p><p>28 days after the induction of I/R injury, mice were randomized to receive either CPC (0.5 million) or vehicle by echo-guided intra-myocardial injection. To determine retention, CPC were localized <i>in vivo</i> by bioluminescence imaging (BLI) two days after injection. Cardiac function was assessed by 3D echocardiography and speckle tracking analysis to quantify left ventricular geometry and regional myocardial deformation.</p><p>Results</p><p>BLI demonstrated successful injection of CPC (18/23), which were mainly located along the needle track in the anterior/septal wall. Although CPC treatment did not result in overall restoration of cardiac function, a relative preservation of the left ventricular end-diastolic volume was observed at 4 weeks follow-up compared to vehicle control (+5.3 ± 2.1 μl vs. +10.8 ± 1.5 μl). This difference was reflected in an increased strain rate (+16%) in CPC treated mice.</p><p>Conclusions</p><p>CPC transplantation can be adequately studied in chronic cardiac remodeling using this study set-up and by that provide a translatable murine model facilitating advances in research for new therapeutic approaches to ultimately improve therapy for chronic heart failure.</p></div

Functional outcome measurements by echocardiography at 1 month follow-up demonstrated preservation of the end-diastolic volume.

<p><b>A</b>) LVEDV in the CPC group differed from the control group at experimental day 56 (post-treatment). No significant difference between the groups was observed for (<b>B</b>) LVESV and (<b>C</b>) LVEF. Black lines indicate vehicle treated mice (n = 16) and grey lines indicate mice treated with CPC (n = 13). * p< 0.05.</p

Echo-guided intramyocardial injection resulted in successful delivery of CPC.

<p><b>A)</b> Representative B-mode image of intra-myocardial injection (29 Gy needle) at 4 weeks after the onset of I/R injury. The needle tip (marked by white arrowhead) is located in the anterior wall of the left ventricle. <b>B)</b> BLI images 2 days after intramyocardial injection with CPC demonstrated that 18/23 injections were successful (marked with *). <b>C-D</b>) CPC retained in the tissue up to 28 days after injection, as visualized by immunofluorescent staining for human lamin A/C (green), troponin I (red) and nuclei (blue). CPC were predominantly located along the needle track in the anterior and septal wall, at the level of the papillary muscles. (<b>E</b>) Squares mark H&E slides at the level of traced CPC. The left sided H&E slide corresponds to the CPC tracing slide in ‘C and D’.</p