Effect of Stem Cell Transplantation on the Calcium Signaling in Adult Ventricular Myocytes

Abstract

Bone marrow derived stem cells (MSCs) are often discussed as a potential source for cardiac replacement tissue. Transplantation of undifferentiated cells into cardiac infarct regions has been shown to decrease infarct size and preserve cardiac function but the impact the cells have through paracrine effects or intercellular coupling remains to be determined. To determine how MSCs influence the excitability of cardiac myocytes we established a co-culture between freshly isolated mouse ventricular myocytes and dissociated MSCs. After 3 hrs of co-culture the cells were loaded with the Ca2+ indicator Fluo-4/AM and the Ca2+ handling properties of ventricular myocytes were analyzed at a stimulation frequency of 0.5 Hz. In comparison to control myocytes (ctrl) cardiomyocytes that co-localized with MSCs (co-MSC) exhibited a significantly increased Ca2+-transient amplitude (F/Fo: ctrl: 2.3 ± 0.5, n =8; co-MSC: 3.5 ± 1.2, n=4). In addition, the transient duration at 50% (APD50: ctrl: 457 ± 61 ms to co-MSC: 360 ± 33 ms); and 90% inactivation (APD90: ctrl: 1.31 ± 0.15 s; co-MSC: 1.08 ± 0.16 s) was significantly shortened. We have previously demonstrated that stem cell derived cardiomyocytes and adult myocytes can establish intercellular coupling within 1 hour of co-culture. However, in heterocellular pairs of ventricular myocytes and MSCs no change MSC [Ca2+]i could be determined upon stimulation of the myocyte. The data indicate that MSCs modulate substantially the Ca2+ signaling properties of adult ventricular myocytes and therefore could have as substantial anti-arrhythmic effect upon transplantation. It remains to be determined if intercellular coupling is necessary to establish this effect.