Hu Jiabiao, Hodgkinson Conrad P, Pratt Richard E, Lee JaeWoo, Sullenger Bruce A, Dzau Victor J
Mandel Center for Heart and Vascular Research, and the Duke Cardiovascular Research Center, Duke University Medical Center, Durham, NC 27710, USA.
Department of Surgery, Duke University, Durham, NC 27710, USA.
Mol Ther Nucleic Acids. 2020 Oct 27;23:55-62. doi: 10.1016/j.omtn.2020.10.034. eCollection 2021 Mar 5.
Reprogramming scar fibroblasts into new heart muscle cells has the potential to restore function to the injured heart. However, the effectiveness of reprogramming is notably low. We have recently demonstrated that the effectiveness of reprogramming fibroblasts into heart muscle cells (cardiomyocytes) is increased by the addition of RNA-sensing receptor ligands. Clinical use of these ligands is problematic due to their ability to induce adverse inflammatory events. To overcome this issue, we sought to determine whether synthetic analogs of natural RNA-sensing receptor ligands, which avoid generating inflammatory insults and are nuclease resistant, would similarly enhance fibroblast reprogramming into cardiomyocytes. Indeed, one such stabilized RNA, ICR2, increased the expression of cardiomyocyte-specific mRNAs in reprogrammed fibroblasts. Moreover, ICR2 enhanced the ability of reprogramming factors to produce cardiomyocytes with mature sarcomeres. Knockdown assays indicated that the effects of ICR2 were mediated by the RNA-sensing receptors Rig-I and TLR3. In addition, ICR2 reduced the effective dose and number of reprogramming factors needed for efficient reprogramming. In summary, the synthetic RNA oligonucleotide ICR2 is a potential therapeutic agent to enhance cardiac reprogramming efficiency.
将瘢痕成纤维细胞重编程为新的心肌细胞有可能恢复受损心脏的功能。然而，重编程的有效性显著较低。我们最近证明，通过添加RNA传感受体配体可提高将成纤维细胞重编程为心肌细胞（ cardiomyocytes ）的有效性。由于这些配体能够引发不良炎症事件，其临床应用存在问题。为克服这一问题，我们试图确定天然RNA传感受体配体的合成类似物是否同样能增强成纤维细胞向心肌细胞的重编程，这些类似物可避免产生炎症损伤且具有核酸酶抗性。事实上，一种这样的稳定化RNA，即ICR2，增加了重编程成纤维细胞中心肌细胞特异性mRNA的表达。此外，ICR2增强了重编程因子产生具有成熟肌节的心肌细胞的能力。敲低实验表明，ICR2的作用是由RNA传感受体Rig-I和TLR3介导的。此外，ICR2降低了高效重编程所需的重编程因子的有效剂量和数量。总之，合成RNA寡核苷酸ICR2是一种提高心脏重编程效率的潜在治疗剂。
