Intravenous and intramyocardial injection of apoptotic white blood cell suspensions prevents ventricular remodelling by increasing elastin expression in cardiac scar tissue after myocardial infarction

Abstract

Congestive heart failure developing after acute myocardial infarction (AMI) is a major cause of morbidity and mortality. Clinical trials of cell-based therapy after AMI evidenced only a moderate benefit. We could show previously that suspensions of apoptotic peripheral blood mononuclear cells (PBMC) are able to reduce myocardial damage in a rat model of AMI. Here we experimentally examined the biochemical mechanisms involved in preventing ventricular remodelling and preserving cardiac function after AMI. Cell suspensions of apoptotic cells were injected intravenously or intramyocardially after experimental AMI induced by coronary artery ligation in rats. Administration of cell culture medium or viable PBMC served as controls. Immunohistological analysis was performed to analyse the cellular infiltrate in the ischaemic myocardium. Cardiac function was quantified by echocardiography. Planimetry of the infarcted hearts showed a significant reduction of infarction size and an improvement of post AMI remodelling in rats treated with suspensions of apoptotic PBMC (injected either intravenously or intramoycardially). Moreover, these hearts evidenced enhanced homing of macrophages and cells staining positive for c-kit, FLK-1, IGF-I and FGF-2 as compared to controls. A major finding in this study further was that the ratio of elastic and collagenous fibres within the scar tissue was altered in a favourable fashion in rats injected with apoptotic cells. Intravenous or intramyocardial injection of apoptotic cell suspensions results in attenuation of myocardial remodelling after experimental AMI, preserves left ventricular function, increases homing of regenerative cells and alters the composition of cardiac scar tissue. The higher expression of elastic fibres provides passive energy to the cardiac scar tissue and results in prevention of ventricular remodelling.Electronic supplementary materialThe online version of this article (doi:10.1007/s00395-011-0173-0) contains supplementary material, which is available to authorized users.

Assessment of Myocardial Infarction and Postinfarction Scar Remodeling With an Elastin-Specific Magnetic Resonance Agent

“…Previous work by Mizuno et al 4,5 has demonstrated that increased expression of elastin within the myocardial scar using transfected endothelial cells reduces infarct expansion and preserves ventricular function after experimental MI. Lichtenauer et al 14 have shown that increasing the expression of elastin within the infarct scar via intravenous or intramyocardial injection of apoptotic white blood cells attenuates ventricular remodeling in a rat model. Thus, because elastin is a major constituent of the healing heart, we thought to investigate the feasibility of a noninvasive assessment of elastin after MI using molecular MRI.…”

Ultrasound-guided Transthoracic Intramyocardial Injection in Mice

“…Recent cell based therapy trials in myocardial infarction models have described an open thoracotomy approach to the delivery of injectate [12][13][14] . An important factor in the success of a myocardial therapeutic intervention hinges on the choice of delivery route.…”

Therapeutic Potential of Paracrine Factors and Secretome-based Treatment in Spinal Cord Injury

“…Subsequent centrifugation allowed further processing of the cell-free supernatant or secretome, also referred to as conditioned medium. Several pre-clinical models were used to investigate the therapeutic potential of this secretome derived from apoptotic PBMCs (ApoSec, patent number: WO2010/070105, WO2010/079086) [22][23][24][25][26][27][28] . Therapeutic efficacy was shown to be a synergistic effect caused by modulation of multiple molecular pathways, many of which are also known to be involved in secondary cascades after SCI.…”

“…The following findings lead to the idea and initiation of this pre-clinical SCI trial. Firstly, ApoSec was shown to up-regulate pathways associated with cell survival and inhibition of apoptosis in-vitro and in-vivo [26][27][28][29] . Secondly, the secretome of apoptotic PBMCs improves microvascular flow via inhibition of thrombocyte activation and vasodilation and features angiogenic characteristics [24,28] .…”