PRECLINICAL STUDY: PRECLINICAL STUDY
Human Adult Bone Marrow Mesenchymal Stem Cells Repair Experimental Conduction Block in Rat Cardiomyocyte Cultures
Saskia L.M.A. Beeres, MD*,
Douwe E. Atsma, MD, PhD*,*,
Arnoud van der Laarse, PhD*,
Daniël A. Pijnappels, MSc*,
John van Tuyn, MSc*, ,
Willem E. Fibbe, MD, PhD ,
Antoine A.F. de Vries, PhD,
Dirk L. Ypey, PhD ,
Ernst E. van der Wall, MD, PhD* and
Martin J. Schalij, MD, PhD*
* Department of Cardiology
Molecular Cell Biology Section Gene Therapy
Hematology
Physiology, Leiden University Medical Center, Leiden, the Netherlands
Manuscript received May 20, 2005;
revised manuscript received July 8, 2005,
accepted July 11, 2005.
* Reprint requests and correspondence: Dr. Douwe E. Atsma, Department of Cardiology, Leiden University Medical Center, P.O. Box 9600, 2300RC Leiden, the Netherlands
(Email: d.e.atsma{at}lumc.nl).
OBJECTIVES: We evaluated whether human adult bone marrow-derived mesenchymal stem cells (hMSCs) could repair an experimentally induced conduction block in cardiomyocyte cultures.
BACKGROUND: Autologous stem cell therapy is a novel treatment option for patients with heart disease. However, detailed electrophysiological characterization of hMSCs is still lacking.
METHODS: Neonatal rat cardiomyocytes were seeded on multi-electrode arrays. After 48 h, abrasion of a 200- to 450-µm–wide channel caused conduction block. Next, we applied adult hMSCs (hMSC group, n = 8), human skeletal myoblasts (myoblast group, n = 7), rat cardiac fibroblasts (fibroblast group, n = 7), or no cells (control group, n = 7) in a channel-crossing pattern. Cross-channel electrical conduction was analyzed after 24 and 48 h. Intracellular action potentials of hMSCs and cardiomyocytes were recorded. Immunostaining for connexins and intercellular dye transfer (calcein) assessed the presence of functional gap junctions.
RESULTS: After creation of conduction block, two asynchronously beating fields of cardiomyocytes were present. Application of hMSCs restored synchronization between the two fields in five of eight cultures after 24 h. Conduction velocity across hMSCs (0.9 ± 0.4 cm/s) was approximately 11-fold slower than across cardiomyocytes (10.4 ± 5.8 cm/s). No resynchronization occurred in the myoblast, fibroblast, or control group. Intracellular action potential recordings indicated that conduction across the channel presumably occurred by electrotonic impulse propagation. Connexin-43 was present along regions of hMSC-to-cardiomyocyte contact, but not along regions of cardiomyocyte-to-myoblast or cardiomyocyte-to-fibroblast contact. Calcein transfer from cardiomyocytes to hMSCs was observed within 24 h after co-culture initiation.
CONCLUSIONS: Human mesenchymal stem cells are able to repair conduction block in cardiomyocyte cultures, probably through connexin-mediated coupling.
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Abbreviations and Acronyms
| | Cx = connexin | | DMEM = Dulbecco's modified eagle medium | | FBS = fetal bovine serum | | hMSC = human mesenchymal stem cell | | LAT = local activation time | | MEA = micro-electrode array | | PBS = phosphate-buffered saline |
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