Department of Pharmacology and Center of Lung and Vascular Biology, University of Illinois College of Medicine, Chicago, Illinois, United States of America.
PLoS One. 2011;6(7):e22550. doi: 10.1371/journal.pone.0022550. Epub 2011 Jul 22.
To study usefulness of bone marrow progenitor cells (BPCs) epigenetically altered by chromatin modifying agents in mediating heart repair after myocardial infarction in mice.
We tested the therapeutic efficacy of bone marrow progenitor cells treated with the clinically-used chromatin modifying agents Trichostatin A (TSA, histone deacetylase inhibitor) and 5Aza-2-deoxycytidine (Aza, DNA methylation inhibitor) in a mouse model of acute myocardial infarction (AMI). Treatment of BPCs with Aza and TSA induced expression of pluripotent genes Oct4, Nanog, Sox2, and thereafter culturing these cells in defined cardiac myocyte-conditioned medium resulted in their differentiation into cardiomyocyte progenitors and subsequently into cardiac myocytes. Their transition was deduced by expression of repertoire of markers: Nkx2.5, GATA4, cardiotroponin T, cardiotroponin I, α-sarcomeric actinin, Mef2c and MHC-α. We observed that the modified BPCs had greater AceH3K9 expression and reduced histone deacetylase1 (HDAC1) and lysine-specific demethylase1 (LSD1) expression compared to untreated BPCs, characteristic of epigenetic changes. Intra-myocardial injection of modified BPCs after AMI in mice significantly improved left ventricular function. These changes were ascribed to differentiation of the injected cells into cardiomyocytes and endothelial cells.
Treatment of BPCs with Aza and TSA converts BPCs into multipotent cells, which can then be differentiated into myocyte progenitors. Transplantation of these modified progenitor cells into infarcted mouse hearts improved left ventricular function secondary to differentiation of cells in the niche into myocytes and endothelial cells.
研究染色质修饰剂改变骨髓祖细胞（BPC）的表观遗传在介导小鼠心肌梗死后心脏修复中的作用。
我们在小鼠急性心肌梗死（AMI）模型中测试了用临床使用的染色质修饰剂曲古抑菌素 A（TSA，组蛋白去乙酰化酶抑制剂）和 5-氮杂-2-脱氧胞苷（Aza，DNA 甲基化抑制剂）处理的骨髓祖细胞的治疗效果。Aza 和 TSA 处理 BPC 可诱导多能基因 Oct4、Nanog、Sox2 的表达，随后将这些细胞在确定的心肌细胞条件培养基中培养可诱导其分化为心肌祖细胞，随后分化为心肌细胞。其转变通过一系列标志物的表达来推断：Nkx2.5、GATA4、心肌肌钙蛋白 T、心肌肌钙蛋白 I、α-横纹肌肌动蛋白、Mef2c 和 MHC-α。我们观察到，与未处理的 BPC 相比，修饰的 BPC 具有更高的 AceH3K9 表达和更低的组蛋白去乙酰化酶 1（HDAC1）和赖氨酸特异性去甲基化酶 1（LSD1）表达，这是表观遗传变化的特征。AMI 后将修饰的 BPC 内注射到小鼠心肌中可显著改善左心室功能。这些变化归因于注射细胞分化为心肌细胞和内皮细胞。
用 Aza 和 TSA 处理 BPC 可将 BPC 转化为多能细胞，然后可将其分化为心肌祖细胞。将这些修饰的祖细胞移植到梗死的小鼠心脏中可改善左心室功能，这是由于细胞在龛位中分化为心肌细胞和内皮细胞所致。
