Institute for Bio-Medical Convergence, Department Medicine, Catholic Kwandong University College of Medicine, Gangneung, Republic of Korea; Catholic Kwandong University International St. Mary's Hospital, Metropolitan City, Incheon 404-834, Republic of Korea.
Institute for Bio-Medical Convergence, Department Medicine, Catholic Kwandong University College of Medicine, Gangneung, Republic of Korea; Catholic Kwandong University International St. Mary's Hospital, Metropolitan City, Incheon 404-834, Republic of Korea.
J Mol Cell Cardiol. 2019 Jan;126:118-128. doi: 10.1016/j.yjmcc.2018.11.016. Epub 2018 Nov 27.
Physical microenvironment plays an important role in determining cellular reprogramming. In this study, we first generated directly reprogrammed human dermal fibroblasts (HDFs) into endothelial cells (ECs) mediated by environmental transition-guided cellular reprogramming (e/Entr) using ultrasound and characterized e/Entr. Ultrasound stimulus was introduced to ECs culture media and HDFs and induced into ECs-like cells. We performed microarray, RT-PCR, protein analysis, matrigel plug assay and e/Entr were transplanted into ischemic hindlimb mice model. Here we show that the activation of MAPK signaling pathways and the modulation of histone proteins such as Hp1-α, H3K27me3 and H3K4me3 in e/Entr contribute to the changes in chromatin configuration and reprogramming. Microarray data demonstrated that e/Entr highly expressed genes associated with ECs transcription factors and angiogenesis. In addition, the transplantation of e/Entr into hindlimb ischemia showed a high recovery of blood perfusion, limb salvage and e/Entr contributed to the formation of new vessels. In conclusion, the present study provided the first evidence that ultrasound reprogramming can induce postnatal cells to functional ECs. Therefore, our data suggest that physical stimulus-mediated reprogramming is a highly effective and safe strategy for the novel therapeutic alternatives.
物理微环境在决定细胞重编程中起着重要作用。在这项研究中，我们首次通过环境过渡引导的细胞重编程（e/Entr），使用超声直接将人真皮成纤维细胞（HDF）重编程为内皮细胞（EC），并对 e/Entr 进行了表征。将超声刺激引入 EC 培养基和 HDF 中，并将其诱导为类似 EC 的细胞。我们进行了微阵列、RT-PCR、蛋白质分析、基质胶塞测定和 e/Entr 移植到缺血性后肢小鼠模型中。在这里，我们表明 MAPK 信号通路的激活以及组蛋白蛋白如 Hp1-α、H3K27me3 和 H3K4me3 的调节在 e/Entr 中有助于染色质构象和重编程的变化。微阵列数据表明，e/Entr 高度表达与 ECs 转录因子和血管生成相关的基因。此外，将 e/Entr 移植到后肢缺血模型中显示出高血液灌注恢复、肢体挽救和 e/Entr 有助于新血管的形成。总之，本研究首次提供了证据表明超声重编程可以诱导出生后细胞成为功能性 EC。因此，我们的数据表明，物理刺激介导的重编程是一种高效且安全的新型治疗替代策略。
