TY - JOUR
T1 - Impact of anti-apoptotic and anti-oxidative effects of bone marrow mesenchymal stem cells with transient overexpression of heme oxygenase-1 on myocardial ischemia
AU - Tsubokawa, Toshinari
AU - Yagi, Kunimasa
AU - Nakanishi, Chiaki
AU - Zuka, Masahiko
AU - Nohara, Atsushi
AU - Ino, Hidekazu
AU - Fujino, Noboru
AU - Konno, Tetsuo
AU - Kawashiri, Masa Aki
AU - Ishibashi-Ueda, Hatsue
AU - Nagaya, Noritoshi
AU - Yamagishi, Masakazu
PY - 2010/5
Y1 - 2010/5
N2 - Although mesenchymal stem cells (MSCs) have therapeutic potential for tissue injury, intolerance and poor cell viability limit their reparative capability. Therefore, we examined the impact of bone marrow-derived MSCs, in which heme oxygenase-1 (HO-1) was transiently overexpressed, on the repair of an ischemic myocardial injury. When MSCs and HO-1-overexpressed MSCs (MSC HO-1) were exposed to serum deprivation/hypoxia or H 2O2-induced oxidative stress, MSCHO-1 exhibited increased resistance to cell apoptosis compared with MSCs (17 ± 1 vs. 30 ± 2%, P < 0.05) and were markedly resistant to cell death (2 ± 1 vs. 32 ± 2%, P < 0.05). Under these conditions, vascular endothelial growth factor (VEGF) production was 2.1-fold greater in MS CHO-1 than in MSCs. Pretreatment of MSCs and MSCHO-1 with phosphatidylinositol 3-kinase (PI 3-kinase)/ protein kinase B (Akt) pathway inhibitors such as LY-294002 (50 μM) or wortmannin (100 nM) significantly decreased VEGF production. In a rat infarction model with MSCs or MSC HO-1 (5×106±0.1×106 cells/rat) transplantation, the number of TdT-mediated dUTP nick end-labeling-positive cells was significantly lower in the MSCHO-1 group than in the MSC group (12.1 ± 1.0 cells/field vs. 26.5 ± 2.6, P < 0.05) on the 4th day after cell transplantation. On the 28th day, increased capillary density associated with decreased infarction size was observed in the MSCHO-1 group (1,415 ± 47/mm2 with 21.6 ± 2.3%) compared with those in the MSCs group (1,215 ± 43/mm2 with 28.2 ± 2.3%, P < 0.05), although infarction size relative to area at risk was not different in each group at 24 h after transplantation. These results demonstrate that MSCHO-1 exhibit markedly enhanced antiapoptotic and anti-oxidative capabilities compared with MSCs, thus contributing to improved repair of ischemic myocardial injury through cell survival and VEGF production associated with the PI 3-kinase/ Akt pathway.
AB - Although mesenchymal stem cells (MSCs) have therapeutic potential for tissue injury, intolerance and poor cell viability limit their reparative capability. Therefore, we examined the impact of bone marrow-derived MSCs, in which heme oxygenase-1 (HO-1) was transiently overexpressed, on the repair of an ischemic myocardial injury. When MSCs and HO-1-overexpressed MSCs (MSC HO-1) were exposed to serum deprivation/hypoxia or H 2O2-induced oxidative stress, MSCHO-1 exhibited increased resistance to cell apoptosis compared with MSCs (17 ± 1 vs. 30 ± 2%, P < 0.05) and were markedly resistant to cell death (2 ± 1 vs. 32 ± 2%, P < 0.05). Under these conditions, vascular endothelial growth factor (VEGF) production was 2.1-fold greater in MS CHO-1 than in MSCs. Pretreatment of MSCs and MSCHO-1 with phosphatidylinositol 3-kinase (PI 3-kinase)/ protein kinase B (Akt) pathway inhibitors such as LY-294002 (50 μM) or wortmannin (100 nM) significantly decreased VEGF production. In a rat infarction model with MSCs or MSC HO-1 (5×106±0.1×106 cells/rat) transplantation, the number of TdT-mediated dUTP nick end-labeling-positive cells was significantly lower in the MSCHO-1 group than in the MSC group (12.1 ± 1.0 cells/field vs. 26.5 ± 2.6, P < 0.05) on the 4th day after cell transplantation. On the 28th day, increased capillary density associated with decreased infarction size was observed in the MSCHO-1 group (1,415 ± 47/mm2 with 21.6 ± 2.3%) compared with those in the MSCs group (1,215 ± 43/mm2 with 28.2 ± 2.3%, P < 0.05), although infarction size relative to area at risk was not different in each group at 24 h after transplantation. These results demonstrate that MSCHO-1 exhibit markedly enhanced antiapoptotic and anti-oxidative capabilities compared with MSCs, thus contributing to improved repair of ischemic myocardial injury through cell survival and VEGF production associated with the PI 3-kinase/ Akt pathway.
KW - Apoptosis
KW - Cell transplantation
KW - Heme oxygenase-1
KW - Mesenchymal stem cells
KW - Myocardial ischemia
UR - http://www.scopus.com/inward/record.url?scp=77951868977&partnerID=8YFLogxK
U2 - 10.1152/ajpheart.01330.2008
DO - 10.1152/ajpheart.01330.2008
M3 - 学術論文
C2 - 20154257
AN - SCOPUS:77951868977
SN - 0363-6135
VL - 298
SP - H1320-H1329
JO - American Journal of Physiology - Heart and Circulatory Physiology
JF - American Journal of Physiology - Heart and Circulatory Physiology
IS - 5
ER -