angiogenin and Myocardial-Ischemia

Topics: Angiogenesis Inducing Agents; Animals; Arteriosclerosis Obliterans; Brain Ischemia; Humans; Myocardial Ischemia; Neovascularization, Physiologic; Ribonuclease, Pancreatic

Topics: Angiogenesis Inducing Agents; Biomarkers; Coronary Disease; Humans; Myocardial Ischemia; Prognosis; Ribonuclease, Pancreatic; Ribonucleases; Risk Assessment

Topics: Animals; Humans; Liver Neoplasms; Myocardial Ischemia; Neovascularization, Physiologic; Proteins; Ribonuclease, Pancreatic

Chemokine-directed migration is crucial for homing of regenerative cells to the infarcted heart and correlates with outcomes of cell therapy trials. Hence, transplantation of chemokine-responsive bone marrow cells may be ideal for treatment of myocardial ischemia. To verify the therapeutic activity of bone marrow mononuclear cells (BM-MNCs) selected by in vitro migration towards the chemokine stromal cell-derived factor-1 (SDF-1) in a mouse model of myocardial infarction (MI), we used BM-MNCs from patients with previous large MI recruited in the TransACT-1&2 cell therapy trials.. Unfractioned BM-MNCs, SDF-1-responsive, and SDF-1-nonresponsive BM-MNCs isolated by patients recruited in the TransACT-1&2 cell therapy trials were tested in Matrigel assay to evaluate angiogenic potential. Secretome and antigenic profile were characterized by flow cytometry. Angiogenin expression was measured by RT-PCR. Cells groups were also intramyocardially injected in an in vivo model of MI (8-week-old immune deficient CD1-FOXN1(nu/nu) mice). Echocardiography and hemodynamic measurements were performed before and at 14 days post-MI. Arterioles and capillaries density, infiltration of inflammatory cells, interstitial fibrosis, and cardiomyocyte proliferation and apoptosis were assessed by immunohistochemistry.. In vitro migration enriched for monocytes, while CD34(+) and CD133(+) cells and T lymphocytes remained mainly confined in the non-migrated fraction. Unfractioned total BM-MNCs promoted angiogenesis on Matrigel more efficiently than migrated or non-migrated cells. In mice with induced MI, intramyocardial injection of unfractionated or migrated BM-MNCs was more effective in preserving cardiac contractility and pressure indexes than vehicle or non-migrated BM-MNCs. Moreover, unfractioned BM-MNCs enhanced neovascularization, whereas the migrated fraction was unique in reducing the infarct size and interstitial fibrosis. In vitro studies on isolated cardiomyocytes suggest participation of angiogenin, a secreted ribonuclease that inhibits protein translation under stress conditions, in promotion of cardiomyocyte survival by migrated BM-MNCs.. Transplantation of bone marrow cells helps post-MI healing through distinct actions on vascular cells and cardiomyocytes. In addition, the SDF-1-responsive fraction is enriched with angiogenin-expressing monocytes, which may improve cardiac recovery through activation of cardiomyocyte response to stress. Identification of factors linking migratory and therapeutic outcomes could help refine regenerative approaches.

Topics: AC133 Antigen; Animals; Antigens, CD; Antigens, CD34; Bone Marrow Cells; Cell Movement; Chemokine CXCL12; Cytokines; Disease Models, Animal; Echocardiography; Glycoproteins; Hemodynamics; Humans; Intercellular Signaling Peptides and Proteins; Male; Mice; Middle Aged; Monocytes; Myocardial Ischemia; Myocytes, Cardiac; Peptides; Ribonuclease, Pancreatic

Accumulated evidence suggests that myogenesis and angiogenesis induced by implanted cells play important roles in restoring cardiac function after a myocardial infarction. The current study investigated the effects of transplanted autologous mesenchymal stem cells overexpressing angiogenin on myocardial perfusion and cardiac function in the porcine chronic ischemic model.. Chronic ischemia was generated in Yorkshire pigs by placing an ameroid constrictor around the left circumflex artery. Four weeks after occlusion, the animals were randomly separated into 4 groups: pigs in the MSC(AdAng) or MSC(AdNull) groups were implanted with 6 x 10(8) mesenchymal stem cells infected with adenovirus containing angiogenin gene or null adenovirus, respectively; pigs in the AdAng or AdNull groups were injected intramyocardially with adenovirus (5 x 10(9) plaque forming unit/pig) containing angiogenin gene or null adenovirus, respectively. Four weeks after implantation, mesenchymal stem cells prelabeled with DiI were observed within the implanted area in both cell transplantation groups.. Angiogenin protein levels were significantly greater in the MSC(AdAng) and AdAng groups than in the other 2 groups and were associated with greater neovessel formation than in the other 2 groups. Mesenchymal stem cell transplantation decreased scar size and increased scar thickness. Both the AdAng and MSC(AdNull) groups experienced improved cardiac function compared with that seen in the AdNull group. However, a synergistic effect of mesenchymal stem cells and angiogenin was observed in the MSC(AdAng) group because myocardial perfusion and cardiac function increased significantly (P < .05 for all groups) in this group compared with all the others.. Transplantation of autologous mesenchymal stem cells transfected with the angiogenin gene revealed a synergistic effect on the improvement of heart perfusion and function after ameroid occlusion.

Topics: Animals; Cells, Cultured; Chronic Disease; Disease Models, Animal; Gene Expression Regulation; Mesenchymal Stem Cells; Myocardial Ischemia; Ribonuclease, Pancreatic; Stem Cell Transplantation; Swine

To investigate the effect of transfection of 5-aza cytidine (5-aza) induced BMSCs that were transfected with Ad. ANG ex vivo into infarcted myocardium.. Lewis rat BMSCs were cultured in vitro and incubated together with 5-aza (3 micro mol/l) for 24 hours, and the induced BMSCs were transfected with Ad. ANG with a infection multiple of 50. ELISA method was applied to assay the expression and secretion of ANG in the medium. Then such BMSCs expressing ANG were transplanted into the ischemic myocardium of 14 Lewis rats whose left descending branch of coronary artery had been ligated 4 weeks ago (Group I). Eight rats with infarcted myocardium were transplanted with such BMSCs too (group II). Another eight rats received only Ad. ANG injection (group III). Twelve rats receiving serum-free medium injection were used as controls (Group IV). Four weeks after the ligation of LDA (for group I) and 4 weeks after the beginning of experiment (for all groups), the parameters of heart function, such as ejection fraction (EF) and end-diastole volume of left heart (EDLV), were examined by echocardiography. Four weeks after the beginning of experiment, the rats were killed, and the survival and differentiation of transplanted BMSCs and angiogenesis were observed by immunohistochemistry and transmission electron micrography.. One day after the beginning of experiment, the concentration of ANG in the supernatant of medium was 162 +/- 10 pg/ml, significantly higher than that in the supernatant of medium in control group (86 +/- 5 pg/ml, P < 0.01). The concentration of ANG gradually increased and reached its peak at the 4th to 7th day; ANG could still be assayed 15 days later. 4 weeks after the transplantation, most of the 5-aza-induced BMSCs in group I and group II had differentiated into cardiomyogenic cells in the transplanted area. The EF value was 0.42 +/- 0.114 weeks after ligation of LAD, and was 0.69 +/- 0.034 weeks after the transplantation in group I. The EF value was 0.46 +/- 0.06 at the beginning of experiment and was 0.64 +/- 0.144 weeks after the transplantation in group II. The improvement of EF in Group I was significantly than that in other 3 groups (P < 0.05 or P < 0.01). The number of new vessels in group I was 36.3/high-power field (HPF), significantly higher than those in the other three groups (10.5/HPF in Group II, 23.1/HPF in Group III, and 0.9/HPF in Group IV).. Induced by 5-aza, BMSCs differentiate into cardiomyogenic cells in infracted myocardium. ANG-expressing BMSCs transplantation is one of the safe and beneficial new strategies for repairing damaged myocardium and enhancing angiogenesis in ischemic myocardium.

Topics: Animals; Azacitidine; Bone Marrow Cells; Cell Differentiation; Hematopoietic Stem Cell Transplantation; Male; Myocardial Ischemia; Myocardium; Rats; Rats, Inbred Lew; Ribonuclease, Pancreatic; Stromal Cells; Transfection