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


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<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<0.05) and 69±14.7% (p<0.01) in mild or severe HF; γ-H2AX positive cells: 3.7±1.2%, 19.4±4.1% (p<0.05) and 23.7±3.4% (p<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<0.05) and 43.3±8.7% (p<0.05), respectively; NANOG positive cells: 89.8±3.7%, 39.6±14.4% (p<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<0.05) and CD31-positive endothelial cells: 24.5±2.9%, 0.5±0.5% (p<0.001) and 2.3±2.3% (p<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 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.
Department of Cardiology and LTTA Center, University Hospital of Ferrara, Ferrara, Italy.
C
C
Fortini
Department of Medical and Biological Science, University of Udine, Udine, Italy.
D
D
Cesselli
Department of Medical and Biological Science, University of Udine, Udine, Italy.
A P
AP
Beltrami
Maria Cecilia Hospital, GVM Care & Research, E.S. Health Science Foundation, Cotignola, Italy.
N
N
Bergamin
Department of Medical and Biological Science, University of Udine, Udine, Italy.
A
A
Caragnano
Plastic Surgery of University Hospital of Ferrara, Ferrara, Italy.
L
L
Moretti
Department of Cardiology and LTTA Center, University Hospital of Ferrara, Ferrara, Italy.
F
F
Cecaro
Department of Cardiology and LTTA Center, University Hospital of Ferrara, Ferrara, Italy.
G
G
Aquila
Maria Cecilia Hospital, GVM Care & Research, E.S. Health Science Foundation, Cotignola, Italy.
P
P
Rizzo
Plastic Surgery of University Hospital of Ferrara, Ferrara, Italy.
C
C
Riberti
Maria Cecilia Hospital, GVM Care & Research, E.S. Health Science Foundation, Cotignola, Italy.
L
L
Tavazzi
Department of Cardiology and LTTA Center, University Hospital of Ferrara, Ferrara, Italy.
A
A
Fucili
Department of Medical and Biological Science, University of Udine, Udine, Italy.
C A
CA
Beltrami
Department of Cardiology and LTTA Center, University Hospital of Ferrara, Ferrara, Italy,; Maria Cecilia Hospital, GVM Care & Research, E.S. Health Science Foundation, Cotignola, Italy. Electronic address: fri@unife.it.
R
R
Ferrari
D000273:Adipose Tissue / Q000166:cytology*; D000368:Aged; D005260:Female; D006333:Heart Failure / Q000473:pathology*; D006801:Humans; D008297:Male; D059630:Mesenchymal Stem Cells / Q000502:physiology*; D008875:Middle Aged; D051880:Receptors, Notch / Q000502:physiology*; D015398:Signal Transduction
D051880:Receptors, Notch
Heart failure; Notch pathway; Stem cells