Division of Cardiovascular Medicine, Kanazawa University Graduate School of Medicine, Takara-machi 13-1, Kanazawa, Ishikawa, Japan.
Am J Physiol Heart Circ Physiol. 2010 May;298(5):H1320-9. doi: 10.1152/ajpheart.01330.2008. Epub 2010 Feb 12.
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(2)O(2)-induced oxidative stress, MSC(HO-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 MSC(HO-1) than in MSCs. Pretreatment of MSCs and MSC(HO-1) with phosphatidylinositol 3-kinase (PI 3-kinase)/protein kinase B (Akt) pathway inhibitors such as LY-294002 (50 muM) or wortmannin (100 nM) significantly decreased VEGF production. In a rat infarction model with MSCs or MSC(HO-1) (5 x 10(6) +/- 0.1 x 10(6) cells/rat) transplantation, the number of TdT-mediated dUTP nick end-labeling-positive cells was significantly lower in the MSC(HO-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 MSC(HO-1) group (1,415 +/- 47/mm(2) with 21.6 +/- 2.3%) compared with those in the MSCs group (1,215 +/- 43/mm(2) 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 MSC(HO-1) exhibit markedly enhanced anti-apoptotic 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.
虽然间充质干细胞（MSCs）在组织损伤方面具有治疗潜力，但细胞不耐受和低存活率限制了它们的修复能力。因此，我们研究了短暂过表达血红素加氧酶-1（HO-1）的骨髓来源的 MSCs 对缺血性心肌损伤修复的影响。当 MSCs 和过表达 HO-1 的 MSCs（MSC（HO-1））暴露于血清剥夺/缺氧或 H2O2 诱导的氧化应激时，与 MSCs 相比，MSC（HO-1）表现出对细胞凋亡的更高抗性（17 ± 1%对 30 ± 2%，P < 0.05），并且对细胞死亡具有明显的抗性（2 ± 1%对 32 ± 2%，P < 0.05）。在这些条件下，MSC（HO-1）中血管内皮生长因子（VEGF）的产生是 MSCs 的 2.1 倍。用磷脂酰肌醇 3-激酶（PI 3-kinase）/蛋白激酶 B（Akt）途径抑制剂如 LY-294002（50 μM）或wortmannin（100 nM）预处理 MSCs 和 MSC（HO-1）可显著降低 VEGF 的产生。在 MSCs 或 MSC（HO-1）（5×106 ± 0.1×106 细胞/大鼠）移植的大鼠梗死模型中，与 MSC 组相比，移植后第 4 天 MSC（HO-1）组的末端转移酶介导的 dUTP 缺口末端标记阳性细胞数明显减少（12.1 ± 1.0 个/视野对 26.5 ± 2.6，P < 0.05）。在第 28 天，与 MSCs 组相比，MSC（HO-1）组观察到与梗死面积减少相关的毛细血管密度增加（1415 ± 47/mm2，21.6 ± 2.3%）（1215 ± 43/mm2，28.2 ± 2.3%，P < 0.05），尽管在移植后 24 小时，每组的梗死面积相对于危险区域没有差异。这些结果表明，与 MSCs 相比，MSC（HO-1）表现出明显增强的抗凋亡和抗氧化能力，从而通过与 PI 3-kinase/Akt 途径相关的细胞存活和 VEGF 产生来改善缺血性心肌损伤的修复。
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