AimsCardiac progenitor cells (CPCs) have been shown to promote cardiac regeneration in vivo. Understanding the function of CPCs is essential for further implementation of these cells in the treatment of cardiac diseases. The present study tested the hypothesis that adult CPC exert paracrine effects that lead to an improvement in the functional characteristics of cardiomyocytes. This study also investigated whether aging (we included patients aged between 4 months and 81 years) has any effect on the paracrine mechanisms of CPC. Methods and resultsThe supernatant of CPC generated both from human and rat hearts-so called 'conditioned cardiosphere medium' improved the contractile behaviour of isolated adult cardiomyocytes in a concentration-dependent manner after incubation for 24 h and increased the SERCA/NCX ratio. The observed positive effects on contractile behaviour were independent of the CPC donors' age. Conditioned cardiosphere media also normalized angiotensin IIinduced contractile dysfunction. Cytokines released by CPC into the media were detected by cytokine arrays. ConclusionThe observed diversity of cytokines released by CPC needs to be further elucidated in detail. Nevertheless, CPC are a promising therapeutic approach in the field of cardiac disease. The methods described allow investigation of the underlying paracrine mechanisms in a standardized in vitro situation.--

Cardiosphere-derived cells (CDCs) were cultured from human, murine, and rat hearts. Diluted supernatant (conditioned-medium) of the cultures improved the contractile behavior of isolated rat cardiomyocytes (CMCs). This effect is mediated by the paracrine release of cytokines. The present study tested the hypothesis, that the cardiovascular state of the donor's heart influences this effect on CMCs and tries to identify the responsible factors. CDCs were cultured from human tissue samples of cardiac surgery and from murine and rat hearts. The supernatants of cultured CDCs from hypertensive humans and rats showed a higher improvement of the contractile behavior of CMCs compared to CDCs of normotensive origin. Subsequently, the cytokine profile of the supernatants was analyzed. Among the cytokines elevated in supernatants originating from hypertensive humans or rats was Interleukin-6. CDCs were also generated from Interleukin-6(-/-) -mice and their wildtype littermates. The supernatant of the cultured Interleukin-6(-/-) -CDCs had no effect on the contractile behavior, whereas the supernatant of the Interleukin-6(+/+) -CDCs showed a positive effect. To confirm the hypothesis that Interleukin-6 contributes to the paracrine effects, CMCs were incubated with Interleukin-6. It improved the contractile function in a concentration dependent way. Finally, the effect of the supernatant of cultured CDCs derived from a hypertensive human sample could be abolished by simultaneous incubation with a specific Interleukin-6 antibody. CDCs release cytokines that improve the contractile behavior of CMCs. This effect is more intense in CDCs from hypertensive donors. Interleukin-6 is involved in this phenomenon.