Mesenchymal stem cells alone or ex vivo gene modified with endothelial nitric oxide synthase reverse age-associated erectile dysfunction
Mesenchymal stem cells alone or ex vivo gene modified with endothelial nitric oxide synthase reverse age-associated erectile dysfunction
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DOI：
10.1152/ajpheart.00685.2006
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发表时间：
2007-03-01
影响因子：
4.8
通讯作者：
Kadowitz, Philip J.
中科院分区：
文献类型：
--
作者：
Bivalacqua, Trinity J.;Deng, Weiwen;Kadowitz, Philip J.
间充质干细胞（MSC）可用于基于成体干细胞的血管疾病基因治疗。为了检验单独的 MSC 或内皮一氧化氮合酶 (eNOS) 修饰的 MSC 可用于治疗勃起功能障碍 (ED) 的假设，分离同基因大鼠 MSC (rMSC)，离体扩增，用含有 eNOS 的腺病毒转导，并注射到老年大鼠的阴茎中。组织学分析表明，rMSCs海绵体内注射后在体组织中存活至少21天，并且未诱导炎症反应。海绵体内注射经 eNOS 修饰的 rMSC 可改善老年大鼠注射后 7 天和 21 天的勃起反应。勃起功能的增加与 eNOS 蛋白、NOS 活性和 cGMP 水平的增加有关。单独的rMSCs在第21天增加了老年大鼠的勃起功能，但在第7天没有增加，移植的细胞对几种内皮细胞和平滑肌细胞标记物表现出阳性免疫染色。 rMSC 表型的这种变化伴随着阴茎 eNOS 蛋白表达/活性的上调和 cGMP 水平的升高。这些发现表明，腺病毒可用于转导离体扩增的rMSC以表达eNOS，并且eNOS修饰的rMSC改善老年大鼠的勃起功能。海绵体内注射未经修饰的野生型 rMSC 在注射 21 天后通过改善内皮源性 NO/cGMP 信号传导和 rMSC 分化为表达内皮和平滑肌标记物的阴茎细胞的机制改善了勃起功能。这些数据凸显了基于成体干细胞的疗法治疗 ED 的潜在临床用途。
Mesenchymal stem cells (MSCs) can be used in adult stem cell-based gene therapy for vascular diseases. To test the hypothesis that MSCs alone or endothelial nitric oxide synthase (eNOS)-modified MSCs can be used for treatment of erectile dysfunction (ED), syngeneic rat MSCs (rMSCs) were isolated, ex vivo expanded, transduced with adenovirus containing eNOS, and injected into the penis of aged rats. Histological analysis demonstrated that rMSCs survived for at least 21 days in corporal tissue after intracavernous injection, and an inflammatory response was not induced. Intracavernous administration of eNOS-modified rMSCs improved the erectile response in aged rats at 7 and 21 days after injection. The increase in erectile function was associated with increased eNOS protein, NOS activity, and cGMP levels. rMSCs alone increased erectile function of aged rats at day 21, but not at day 7, with the transplanted cells exhibiting positive immunostaining for several endothelial and smooth muscle cell markers. This change in rMSC phenotype was accompanied by upregulation of penile eNOS protein expression/activity and elevated cGMP levels. These findings demonstrate that an adenovirus can be used to transduce ex vivo expanded rMSCs to express eNOS and that eNOS-modified rMSCs improve erectile function in the aged rat. Intracavernous injection of unmodified wildtype rMSCs improved erectile function 21 days after injection through mechanisms involving improved endothelium-derived NO/cGMP signaling and rMSC differentiation into penile cells expressing endothelial and smooth muscle markers. These data highlight the potential clinical use of adult stem cell-based therapy for the treatment of ED.