Cell Transplantation for the Treatment of Acute Myocardial Infarction Using Vascular Endothelial Growth Factor-Expressing Mesenchymal Stem Cells

使用表达血管内皮生长因子的间充质干细胞进行细胞移植治疗急性心肌梗死

• 批准号: 14570685
• 负责人: YOSHIYAMA Minoru
• 金额: $ 2.56万
• 依托单位: Osaka City University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14570685/
• 关键词: Myocatrdial infarction; Remodeling; Cell therapy; Stem cell; Heart failure; signal transduction; Cell Therapy; Myocardial infarction

Vascular endothelial growth factor (VEGF) may be a therapeutic reagent for ischemic region by inducing angiogenesis. Mesenchymal stem cells (MSCs) have multiple differentiated potential including cardiomyocytes. Therefore, we hypothesized that transplantation of VEGF-expressing MSCs could effectively treat myocardial infarction by providing VEGF-induced cardioprotection, followed by angiogenesis in ischemic myocardium combined with the functional benefits of MSCs-derived cells. Bone marrow mononuclear cells of Lewis rats were cultured with low glucose DMEM for MSCs outgrowth. MSCs were transfected with adenovirus expressing human VEGF_<165> and/or beta-galactosidase (lac Z). Six million of VEGF and lac Z transfected MSCs (VEGF group, n=8), lac Z transfected MSCs (Cont group, n=7), or medium only (M group, n=10) were injected into infarcted myocardium of syngeneic rat after left coronary artery occlusion for one hour. At one week after the injection, lac Z-expression cells were immunohi … More stochemically detected in VEGF group and Cont group. Moreover, positive finding against VEGF polyclonal antibody was increased in VEGF group than in Cont group. At four weeks, infarct size (VEGF; 26.3, Cont; 31.4, M; 38.0 %, P<0.05) was significantly reduced in VEGE group, compared with M group. By echocardiography assessment, left ventricular end-diastolic dimension was significantly lower in the VEGF group, compared with M group (VEGF; 9.9, Cont; 10.2, M; 10.8 mm, p<0.01). Left ventricular fractional shortening (VEGF; 20.0, Cont; 17.7, M; 10.7 %, P<0.05) and ejection fraction (VEGF; 48.3, Cont; 43.6, M; 28.6 %, P<0.05) were significantly higher in VEGF group and Cont group. By light microscopy, increased number of capillaries was observed in infarcted area of VEGF group. Under electoron microscopy, many spindle-shaped interstitial cells and small cells containing myofilaments were observed adjacent to the infarcted area both in VEGF group and Cont group. Furthermore, the spindle-shaped cells were often making point-to-point contact each other and arranged helically around a lumen in VEGF group. In conclusion, this combined strategy of cell transplantation with gene therapy could be important for the treatment of acute myocardial infarction. Less

血管内皮生长因子（VEGF）可能通过诱导血管新生而成为缺血区的治疗剂。间充质干细胞（Mesenchymal stem cells，MSCs）具有向心肌细胞等多种细胞分化的潜能。因此，我们假设移植表达VEGF的MSC可以通过提供VEGF诱导的心脏保护作用，然后通过缺血心肌中的血管生成结合MSC衍生细胞的功能益处来有效治疗心肌梗死。取刘易斯大鼠骨髓单个核细胞，用低糖DMEM培养，观察MSCs的生长情况。用表达人VEGF和<165>/或β-半乳糖苷酶（lacZ）的腺病毒转染MSC。将600万VEGF和lac Z转染的MSCs（VEGF组，n=8）、lac Z转染的MSCs（Cont组，n=7）或仅培养基（M组，n=10）注射到同系大鼠左冠状动脉闭塞1h后的梗死心肌内。在注射后一周，lac Z表达细胞免疫组化显示， ...更多信息 VEGF组和Cont组进行化学计量学检测。VEGF组抗VEGF多克隆抗体阳性率明显高于对照组。4周时，VEGE组梗死面积（VEGF; 26.3，Cont; 31.4，M; 38.0%，P&lt;0.05）较M组显著减小。通过超声心动图评估，与M组相比，VEGF组的左心室舒张末期内径显著降低（VEGF; 9.9，Cont; 10.2，M; 10.8 mm，p&lt;0.01）。VEGF组和Cont组左室短轴缩短率（VEGF; 20.0，Cont; 17.7，M; 10.7%，P&lt;0.05）和射血分数（VEGF; 48.3，Cont; 43.6，M; 28.6%，P&lt;0.05）均显著升高。光镜下VEGF组梗死区毛细血管增多。电镜下，VEGF组和Cont组梗死灶旁可见大量梭形间质细胞和含肌丝的小细胞。VEGF组细胞呈梭形，多为点到点接触，呈螺旋状排列于管腔周围。总之，细胞移植与基因治疗相结合的策略对于急性心肌梗死的治疗具有重要意义。少

项目成果

Omura T, Yoshiyama M, Yoshida K, Nakamura Y, Kim S, Iwao H, Takeuchi K, Yoshikawa J: "Dominant negative mutant of c-Jun inhibits cardiomyocyte hypertrophy induced by endothelin 1 and phenylephrine"Hypertension. 39. 81 (2002)

Omura T、Yoshiyama M、Yoshida K、Nakamura Y、Kim S、Iwao H、Takeuchi K、Yoshikawa J：“c-Jun 的显性阴性突变体抑制内皮素 1 和去氧肾上腺素诱导的心肌细胞肥大”高血压。

Omura T, Yoshiyama M, Kim S, Iwao H, Takeudchi K, Yoshikawa J.: "Dominant Negative Mutant of c-Jun Inhibits Cardiomyocyte Hypertrophy Induced by Endothelin 1 and Phenylephrine"Hypertension. 39. 81-86 (2002)

Omura T、Yoshiyama M、Kim S、Iwao H、Takeudchi K、Yoshikawa J.：“c-Jun 的显性阴性突变体抑制内皮素 1 和去氧肾上腺素诱导的心肌细胞肥大”高血压。

Shirai N, Yamagishi H, Yoshiyama M, Teragaki M, Akioka K, Takeuchi K, Yoshikawa J, Ochi H: "Incremental value of assessment of regional wall motion for detection of multivessel coronary artery disease in exercise (201)Tl gated myocardial perfusion imaging

Shirai N、Yamagishi H、Yoshiyama M、Teragaki M、Akioka K、Takeuchi K、Yoshikawa J、Ochi H：“运动 (201)Tl 门控心肌灌注成像中区域壁运动评估对检测多支冠状动脉疾病的增量价值

Nakamura Y, Yoshiyama M, Omura T, Takeuchi K, Yoshikawa J.: "Beneficial effects of combination of ACE inhibitor and angiotensin II type 1 receptor blocker on cardiac remodeling in rat myocardial infarction"Cardiovasc Res.. 57. 48-54 (2003)

Nakamura Y、Yoshiyama M、Omura T、Takeuchi K、Yoshikawa J.：“ACE抑制剂和血管紧张素II 1型受体阻滞剂联合使用对大鼠心肌梗死心脏重塑的有益作用”Cardiovasc Res.. 57. 48-54 (2003)

Izutani S, Yoshiyama M, Omura T, Yoshida K, Nakamura Y, Kim S, Takeuchi K, Yoshikawa J: "Nipradilol can prevent left ventricular systolic and diastolic dysfunction after myocardial infarction in rats"Circulation Journal. 66. 289 (2002)

Izutani S、Yoshiyama M、Omura T、Yoshida K、Nakamura Y、Kim S、Takeuchi K、Yoshikawa J：“尼普地洛可以预防大鼠心肌梗死后左心室收缩和舒张功能障碍”循环杂志。