title: Disturbed angiogenic activity of adipose-derived stromal cells obtained from patients with coronary artery disease and diabetes mellitus type 2.
abstract: BACKGROUND
  Multipotent mesenchymal stem/stromal cells (MSC) including adipose-derived stromal cells (ADSC) have been successfully applied for cardiovascular diseases treatment. Their regenerative potential is considered due to the multipotency, paracrine activity and immunologic privilege. However, therapeutic efficacy of autologous MSC for myocardial ischemia therapy is modest. We analyzed if ADSC properties are attenuated in patients with chronic diseases such as coronary artery disease (CAD) and diabetes mellitus type 2 (T2DM).
  
  
  RESULTS
  ADSC were isolated from subcutaneous fat tissue of patients without established cardiovascular diseases and metabolic disorders (control group, n = 19), patients with CAD only (n = 32) and patients with CAD and T2DM (n = 28). ADSC phenotype (flow cytometry) was CD90(+)/CD73(+)/CD105(+)/CD45(-)/CD31(-) and they were capable of adipogenic and osteogenic differentiation. ADSC morphology and immunophenotype were similar for all patients, but ADSC from patients with CAD and T2DM had higher proliferation activity and shorter telomeres compared to control patients. ADSC conditioned media stimulated capillary-like tubes formation by endothelial cells (EA.hy926), but this effect significantly decreased for patients with CAD (p = 0.03) and with CAD + T2DM (p = 0.017) compared to the control group. Surprisingly we revealed significantly higher secretion of some pro-angiogenic factors (ELISA) by ADSC: vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) for patients with CAD and HGF and placental growth factor (PlGF) for patients with CAD + T2DM. Among angiogenesis inhibitors such as thrombospondin-1, endostatin and plasminogen activator inhibitor-1 (PAI-1) level of PAI-1 in ADSC conditioned media was significantly higher for patients with CAD and CAD + T2DM compared to the control group (p < 0.01). Inhibition of PAI-1 in ADSC conditioned media by neutralizing antibodies partially restored ADSC angiogenic activity (p = 0.017).
  
  
  CONCLUSIONS
  ADSC angiogenic activity is significantly declined in patients with CAD and T2DM, which could restrict the effectiveness of autologous ADSC cell therapy in these cohorts of patients. This impairment might be due to the disturbance in coordinated network of pro- and anti-angiogenic growth factors secreted by ADSC. Changes in ADSC secretome differ between patients with CAD and T2DM and further investigation are necessary to reveal the MSC-involved mechanisms of cardiovascular and metabolic diseases and develop novel approaches to their correction using the methods of regenerative medicine.
authors.affiliation: Russian Cardiology Research and Production Complex, Moscow, Russian Federation. n.dzhoyashvili@gmail.com.|Faculty of Medicine, Lomonosov Moscow State University, Lomonosovsky av. 31/5, Moscow, 119192, Russian Federation. n.dzhoyashvili@gmail.com.
authors.forename: Nina A
authors.initials: NA
authors.lastname: Dzhoyashvili
authors.affiliation: Faculty of Medicine, Lomonosov Moscow State University, Lomonosovsky av. 31/5, Moscow, 119192, Russian Federation. efimenkoan@gmail.com.
authors.forename: Anastasia Yu
authors.initials: AY
authors.lastname: Efimenko
authors.affiliation: Faculty of Medicine, Lomonosov Moscow State University, Lomonosovsky av. 31/5, Moscow, 119192, Russian Federation. t_kochegur@mail.ru.
authors.forename: Tatiana N
authors.initials: TN
authors.lastname: Kochegura
authors.affiliation: Faculty of Medicine, Lomonosov Moscow State University, Lomonosovsky av. 31/5, Moscow, 119192, Russian Federation. n_i_kalinina@mail.ru.
authors.forename: Natalia I
authors.initials: NI
authors.lastname: Kalinina
authors.affiliation: Faculty of Medicine, Lomonosov Moscow State University, Lomonosovsky av. 31/5, Moscow, 119192, Russian Federation. KoptelovaN@gmail.com.
authors.forename: Natalia V
authors.initials: NV
authors.lastname: Koptelova
authors.affiliation: Institute of Diabetes Mellitus, Endocrinology Research Centre, Moscow, Russian Federation. sukhareva@mail.ru.
authors.forename: Olga Yu
authors.initials: OY
authors.lastname: Sukhareva
authors.affiliation: Institute of Diabetes Mellitus, Endocrinology Research Centre, Moscow, Russian Federation. nephro@endocrincentr.ru.
authors.forename: Marina V
authors.initials: MV
authors.lastname: Shestakova
authors.affiliation: Russian Cardiology Research and Production Complex, Moscow, Russian Federation. akchurin@cardio.ru.
authors.forename: Renat S
authors.initials: RS
authors.lastname: Akchurin
authors.affiliation: Russian Cardiology Research and Production Complex, Moscow, Russian Federation. tkachuk@fbm.msu.ru.|Faculty of Medicine, Lomonosov Moscow State University, Lomonosovsky av. 31/5, Moscow, 119192, Russian Federation. tkachuk@fbm.msu.ru.
authors.forename: Vsevolod A
authors.initials: VA
authors.lastname: Tkachuk
authors.affiliation: Russian Cardiology Research and Production Complex, Moscow, Russian Federation. yeparfyon@mail.ru.|Faculty of Medicine, Lomonosov Moscow State University, Lomonosovsky av. 31/5, Moscow, 119192, Russian Federation. yeparfyon@mail.ru.
authors.forename: Yelena V
authors.initials: YV
authors.lastname: Parfyonova
mesh_terms: D000273:Adipose Tissue / Q000473:pathology*; D000328:Adult; D000368:Aged; D003324:Coronary Artery Disease / Q000150:complications / Q000473:pathology*; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000473:pathology*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009389:Neovascularization, Pathologic; D017154:Stromal Cells / Q000473:pathology*