Myocardial improvement with human embryonic stem cell-derived cardiomyocytes enriched by p38MAPK inhibition.
Myocardial improvement with human embryonic stem cell-derived cardiomyocytes enriched by p38MAPK inhibition.
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DOI：
10.3109/14653249.2011.623690
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发表时间：
2012-02
期刊：
影响因子：
4.5
通讯作者：
Bernstein HS
中科院分区：
文献类型：
--
作者：
Yeghiazarians Y;Gaur M;Zhang Y;Sievers RE;Ritner C;Prasad M;Boyle A;Bernstein HS
我们之前已经证明，抑制 p38 丝裂原激活蛋白激酶 (p38MAPK) 可以指导人胚胎干细胞 (hESC) 衍生的心肌细胞 (hCM) 的分化。我们在小鼠模型中心肌梗塞（MI）后的临床相关时间，使用闭胸超声引导注射，研究了通过抑制 p38MAPK 来心肌内注射 hCM 的治疗益处，hCM 是通过 p38MAPK 抑制而与 hESC 分化的。在小鼠中诱导 MI，并在第 3 天用以下药物治疗动物：(a) hCM，(b) 作为细胞对照的人胎儿成纤维细胞 (hFF)，或 (c) 培养基对照（n = 10 只动物/组）。在 MI 后治疗前以及细胞治疗后第 28 天和 60 天评估左心室射血分数 (LVEF)。第 60 天分析心脏的梗塞面积、血管生成、细胞命运和畸胎瘤形成。与 hFF 和中对照治疗动物相比，第 28 天时，hCM 治疗动物的 LVEF 有所改善（分别为 39.03 ± 1.79% 与 27.89 ± 1.27%，P < 0.05，与 32.90 ± 1.46%，P < 0.05），且持续获益直至第 60 天。 hCM 治疗导致疤痕尺寸显着缩小、毛细血管床面积增加、数量增加与其他两组相比，小动脉减少，原生心肌细胞（CM）凋亡减少，CM 增殖增加。尽管通过免疫组织化学和定量实时聚合酶链反应 (qPCR) 评估，第 60 天注射细胞的保留率非常低，但仍实现了这些益处。 hCM 治疗在第 60 天时并未导致心肌内畸胎瘤形成。这项研究表明，源自 p38MAPK 处理的 hESC 的 hCM 具有令人鼓舞的治疗潜力。
We have shown previously that inhibition of the p38 mitogen-activated protein kinase (p38MAPK) directs the differentiation of human embryonic stem cell (hESC)-derived cardiomyocytes (hCM). We investigated the therapeutic benefits of intramyocardial injection of hCM differentiated from hESC by p38MAPK inhibition using closed-chest ultrasound-guided injection at a clinically relevant time post-myocardial infarction (MI) in a mouse model. MI was induced in mice and the animals treated at day 3 with: (a) hCM, (b) human fetal fibroblasts (hFF) as cell control, or (c) medium control (n = 10 animals/group). Left ventricular ejection fraction (LVEF) was evaluated post-MI prior to therapy, and at days 28 and 60 post-cell therapy. Hearts were analyzed at day 60 for infarct size, angiogenesis, cell fate and teratoma formation. LVEF was improved in the hCM-treated animals compared with both hFF and medium control-treated animals at day 28 (39.03 ± 1.79% versus 27.89 ± 1.27%, P < 0.05, versus 32.90 ± 1.46%, P < 0.05, respectively), with sustained benefit until day 60. hCM therapy resulted in significantly smaller scar size, increased capillary bed area, increased number of arterioles, less native cardiomyocyte (CM) apoptosis, and increased CM proliferation compared with the other two groups. These benefits were achieved despite a very low retention rate of the injected cells at day 60, as assessed by immunohistochemistry and quantitative real-time polymerase chain reaction (qPCR). Therapy with hCM did not result in intramyocardial teratoma formation at day 60. This study demonstrates that hCM derived from p38MAPK-treated hESC have encouraging therapeutic potential.