Aim: Circulating mesenchymal cells increase in heart failure (HF) patients and could be used therapeutically. Our aimwas to investigatewhether HF affects adipose tissue derivedmesenchymal cell (adMSC) isolation, functional characteristics and Notch pathway. Methods and results:We compared 25 patientswith different degrees ofHF (11NYHA 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% frompatients with mild or severe HF (p b 0.0001). adMSC fromHF 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 fromHF patients also showed reducedNotch transcriptional activity (lowered expression of Hey 1 andHey 2 mRNAs). Stimulation with TNF-α of adMSC isolated from controls affected the transcription of several components 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.
Alteration of Notch signaling and functionality of adipose tissue derived mesenchymal stem cells in heart failure
FORTINI, Cinzia;AQUILA, Giorgio;RIZZO, Paola;RIBERTI, Carlo;FERRARI, Roberto
2014
Abstract
Aim: Circulating mesenchymal cells increase in heart failure (HF) patients and could be used therapeutically. Our aimwas to investigatewhether HF affects adipose tissue derivedmesenchymal cell (adMSC) isolation, functional characteristics and Notch pathway. Methods and results:We compared 25 patientswith different degrees ofHF (11NYHA 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% frompatients with mild or severe HF (p b 0.0001). adMSC fromHF 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 fromHF patients also showed reducedNotch transcriptional activity (lowered expression of Hey 1 andHey 2 mRNAs). Stimulation with TNF-α of adMSC isolated from controls affected the transcription of several components 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.I documenti in SFERA sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
