Impact of heart failure on the behavior of human neonatal stem cells in vitro

Abstract

jats:titleAbstract</jats:title> jats:sec jats:titleBackground</jats:title> jats:pClinical cardiac cell therapy using autologous somatic stem cells is restricted by age and disease-associated impairment of stem cell function. Juvenile cells possibly represent a more potent alternative, but the impact of patient-related variables on such cell products is unknown. We therefore evaluated the behavior of neonatal cord blood mesenchymal stem cells (CB-MSC) in the presence of serum from patients with advanced heart failure (HF).</jats:p> </jats:sec> jats:sec jats:titleMethods</jats:title> jats:pHuman serum was obtained from patients with severe HF (n = 21) and from healthy volunteers (n = 12). To confirm the systemic quality of HF in the sera, TNF-α and IL-6 were quantified. CB-MSC from healthy neonates were cultivated for up to 14 days in medium supplemented with 10% protein-normalized human HF or control serum or fetal calf serum (FCS).</jats:p> </jats:sec> jats:sec jats:titleResults</jats:title> jats:pAll HF sera contained increased cytokine concentrations (IL-6, TNF-α). When exposed to HF serum, CB-MSC maintained basic MSC properties as confirmed by immunophenotyping and differentiation assays, but clonogenic cells were reduced in number and gave rise to substantially smaller colonies in the CFU-F assay. Cell cycle analysis pointed towards G1 arrest. CB-MSC metabolic activity and proliferation were significantly impaired for up to 3 days as measured by MTS turnover, BrdU incorporation and DAPI + nuclei counting. On day 5, however, CB-MSC growth kinetics approached control serum levels, though protein expression of cell cycle inhibitors (p21, p27), and apoptosis marker Caspase 3 remained elevated. Signal transduction included the stress and cytokine-induced JNK and ERK1/2 MAP kinase pathways.</jats:p> </jats:sec> jats:sec jats:titleConclusions</jats:title> jats:pHeart failure temporarily inhibits clonality and proliferation of “healthy” juvenile MSC jats:italicin vitro</jats:italic>. Further studies should address the jats:italicin vivo</jats:italic> and clinical relevance of this finding.</jats:p> </jats:sec>