Alteration of Notch signaling and functionality of adipose tissue derived mesenchymal stem cells in heart failure.

Aim: Circulating mesenchymal cells increase in heart failure (HF) patients and could be used therapeutically. Our aim was to investigate whether HF affects adipose tissue derived mesenchymal cell (adMSC) isolation, functional characteristics and Notch pathway. Methods and results: We compared 25 patients with different degrees of HF (11 NYHA classes I and II and 14 NYHA III and IV) with 10 age and gender matched controls. 100% adMSC cultures were obtained from controls, while only 72.7% and 35.7% from patients with mild or severe HF (p b 0.0001). adMSC from HF patients showed higher markers of senescence (p16 positive cells: 14 ± 2.3% in controls and 35.6 ± 5.6% (p b 0.05) and 69 ± 14.7% (p b 0.01) in mild or severe HF; γ-H2AX positive cells: 3.7 ± 1.2%, 19.4 ± 4.1% (p b 0.05) and 23.7 ± 3.4% (p b 0.05) respectively), lower proliferation index (Ki67 positive cells: 21.5 ± 4.9%, 13.2 ± 2.8% and 13.7 ± 3.2%, respectively), reduced pluripotency-associated genes (Oct4 positive cells: 86.7 ± 4.9%, 55 ± 12% (p b 0.05) and 43.3 ± 8.7% (p b 0.05), respectively; NANOG positive cells: 89.8 ± 3.7%, 39.6 ± 14.4% (p b 0.01) and 47 ± 8.1%, respectively), and decreased differentiation markers (α-sarcomeric actin positive cells: 79.8 ± 4.6%, 49 ± 18.1% and 47 ± 12.1% (p b 0.05) and CD31-positive endothelial cells: 24.5 ± 2.9%, 0.5 ± 0.5% (p b 0.001) and 2.3 ± 2.3% (p b 0.001), respectively). AdMSC from HF patients also showed reduced Notch transcriptional activity (lowered expression of Hey 1 and Hey 2 mRNAs). Stimulation with TNF-α of adMSC isolated from controls affected the transcription of several compo- nents of the Notch pathway (reduction of Notch 4 and Hes 1 mRNAs and increase of Notch 2 and Hey 1 mRNAs). Conclusions: In HF yield and functionality of adMSC are impaired and their Notch signaling is downregulated.