Purpose: 

Therapy with stem or progenitor cells is a popular method to treat heart failure. Beside the direct replacement of necrotic cells, a better neovascularisation, and an altered remodelling, paracrine effects seem to be important for the improvement of heart function. This study examines the influence of different cytokines released form ex-vivo generated progenitor cells on the contractile function of isolated cardiomyocytes.

Methods: 

Human cardiac progenitor cells were obtained after cardiac surgery and cultivated according to the protocol of Messina et al. The conditioned media of these cells were used to examine contractile function of isolated adult cardiomyocytes. Additionally the released cytokines were detected using a cytokine array (RayBiotech®). For each experiment the respective pure media were used as control. Out of 507 detectable cytokines 29 became actively released which was examined in 5 different progenitor cell preparations. Out of these 29 different cytokines the influence of 14 different cytokines on contractile function of isolated rat cardiomyocytes were examined. Additionally the SERCA/NCX ratio and the phosphorylation of p38 MAP-kinase were examined by western blotting after stimulation with IL-8.

Results: 

Conditioned media obtained from 15 different progenitor cell preparations increased contractile function of isolated cardiomyocytes significantly (between 6 and 39 % of increase in fractional shortening compared to the respective pure media). The SERCA/NCX ratio increased with a significant correlation to the respective fractional shortenings. Out of the examined cytokines SIGIRR, VEGF, GDF-15, IL-6, and IL-8 (10 ng/ml and 100 ng/ml) increased fractional shortening of isolated cardiomyocytes 24 h after stimulation significantly. The cytokines IFN, TACI, G-CSF, TGFbeta, IL-1beta, and MCP-1 even decrease contractile function and the cytokines APRIL and GRO had no effect on contractile function at all. In concondance to that conditioned media received from hearts of IL 6-/- mice had no effect on contractile function of myocytes. Single IL-8 incubation for 24 h increased SERCA/NCX ratio in isolated myocytes by 39 % significantly. After incubation of cardiomyocytes with IL-8 for 5 min the phosphorylation degree of p38 MAP-kinase increased significantly as well (+52%±12%, p<0.05 vs. control).

Conclusion: 

Ex-vivo generated cardiac progenitor cells release various cytokines from which some increase contractile function and other do not or even worsen contractile function. This result is in common with the fact that only highly diluted conditioned media (1:10000) increase contractile function. The negative effect of some cytokines on contractile function seems to dominate in the higher concentrated conditioned media. Which cytokines are responsible for the examined effects and which role IL-6 and IL-8 play is a matter of current studies