The integrative aspects of cardiac physiology and their implications for cell-based therapy

Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands.
Annals of the New York Academy of Sciences (Impact Factor: 4.38). 02/2010; 1188(1):7-14. DOI: 10.1111/j.1749-6632.2009.05077.x
Source: PubMed


Cardiac development is characterized by a complex interplay of chemical, mechanical, and electrical forces, which together contribute to the proper formation of the heart muscle. In adult myocardium, cardiomyocytes are elongated, well-coupled by gap junctions, and organized in spatially well-defined muscle fibers. This specific tissue architecture affects electromechanical activation and global cardiac function. Since the adult heart has only limited capacity for repair after injury, a significant loss of myocardial tissue often leads to impaired cardiac function. Recent efforts to transplant autologous cells to counteract this cardiomyocyte loss have resulted in marginal functional improvement and no evidence of myocyte regeneration. In order to achieve durable therapeutic efficiency, the transplanted cells will need to not only be cardiomyogenic, but also functionally integrate with host myocardial tissue and thereby contribute to both structural and functional restoration.

Download full-text


Available from: Sean M Wu, Oct 03, 2015
13 Reads
  • [Show abstract] [Hide abstract]
    ABSTRACT: Transplantation of stem cells into the heart can improve cardiac function after myocardial infarction and in chronic heart failure, but the extent of benefit and of reproducibility of this approach are insufficient. Survival of transplanted cells into myocardium is poor, and new strategies are needed to enhance stem cell differentiation and survival in vivo. In this review, we describe how biomaterials can enhance stem cell function in the heart. Biomaterials can mimic or include naturally occurring extracellular matrix and also instruct stem cell function in different ways. Biomaterials can promote angiogenesis, enhance engraftment and differentiation of stem cells, and accelerate electromechanical integration of transplanted stem cells. Biomaterials can also be used to deliver proteins, genes, or small RNAs together with stem cells. Furthermore, recent evidence indicates that the biophysical environment of stem cells is crucial for their proliferation and differentiation, as well as their electromechanical integration. Many approaches in regenerative medicine will likely ultimately require integration of molecularly designed biomaterials and stem cell biology to develop stable tissue regeneration.
    Circulation Research 09/2011; 109(8):910-22. DOI:10.1161/CIRCRESAHA.111.249052 · 11.02 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: A clear understanding of myocardial development is essential not only for understanding the molecular basis of congenital heart disease and its prevention, but also for successful regeneration after cardiac injury. A recent study used a novel Cre/LoxP-based lineage-tracing approach with a multicolor reporter in zebrafish to examine the fates of populations of developing cardiomyocytes. The results showed that a remarkably few number of clones of cardiomyocytes are involved in the formation of adult zebrafish heart. Furthermore, a striking difference in the mechanism of myocardial compaction was described, involving the creation of a completely new layer of cortical myocardium.
    Circulation Research 02/2013; 112(4):583-5. DOI:10.1161/CIRCRESAHA.113.300964 · 11.02 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background: After intramyocardial injection, mesenchymal stem cells (MSCs) may engraft and influence host myocardium. However, engraftment rate and pattern of distribution are difficult to control in vivo, hampering assessment of potential adverse effects. In this study, the role of the engraftment patterns of MSCs on arrhythmicity in controllable in vitro models is investigated. Methods and results: Cocultures of 4×10(5) neonatal rat cardiomyocytes and 7% or 28% adult human MSCs (hMSCs) in diffuse or clustered distribution patterns were prepared. Electrophysiological effects were studied by optical mapping and patch-clamping. In diffuse cocultures, hMSCs dose-dependently decreased neonatal rat cardiomyocyte excitability, slowed conduction, and prolonged action potential duration until 90% repolarization (APD90). Triggered activity (14% versus 0% in controls) and increased inducibility of re-entry (53% versus 6% in controls) were observed in 28% hMSC cocultures. MSC clusters increased APD90, slowed conduction locally, and increased re-entry inducibility (23%), without increasing triggered activity. Pharmacological heterocellular electric uncoupling increased excitability and conduction velocity to 133% in 28% hMSC cocultures, but did not alter APD90. Transwell experiments showed that hMSCs dose-dependently increased APD90, APD dispersion, inducibility of re-entry and affected specific ion channel protein levels, whereas excitability was unaltered. Incubation with hMSC-derived exosomes did not increase APD in neonatal rat cardiomyocyte cultures. Conclusions: Adult hMSCs affect arrhythmicity of neonatal rat cardiomyocyte cultures by heterocellular coupling leading to depolarization-induced conduction slowing and by direct release of paracrine factors that negatively affect repolarization rate. The extent of these detrimental effects depends on the number and distribution pattern of hMSCs. These results suggest that caution should be urged against potential adverse effects of myocardial hMSC engraftment.
    Circulation Arrhythmia and Electrophysiology 02/2013; 6(2). DOI:10.1161/CIRCEP.111.000215 · 4.51 Impact Factor
Show more