Department of Internal Medicine, Catholic Kwandong University College of Medicine, International St. Mary's Hospital, Incheon, Republic of Korea.
Department of Family Medicine, College of Medicine, Dong-A University, Busan, Republic of Korea.
J Tissue Eng Regen Med. 2020 Aug;14(8):1028-1036. doi: 10.1002/term.3073. Epub 2020 Jun 26.
Recently, reprogramming technology has emerged as a fascinating tool to generate specific tissue cells. In this study, we tested the hypothesis that ultrasound-directed cellular reprogramming can generate fibroblasts into hepatogenic cells. We directly induced human dermal fibroblasts (HDFs) into hepatocyte-like cells mediated by environmental transition-guided cellular reprogramming (h/entr) using ultrasound. We confirmed the characteristics of h/entr by the expression levels of hepatocyte specific RNA and proteins. The effects of h/entr on the activation of hepatic stellate cells were analyzed using conditioned medium (CM). h/entr were transplanted into mice with acute liver fibrosis and the therapeutic effects and mechanism of liver fibrosis were determined. h/entr exhibited high levels of hepatocyte specific genes, hepatogenic (hepatocyte growth factor [HGF], colony-stimulating factor 3 [CSF-3]) and anti-inflammatory (interleukin 10 [IL-10]) factors. h/entr CM suppressed the activation of hepatic stellate cells in vitro. Transplantation of h/entr significantly delayed liver fibrosis and improved liver function. Transplantation of h/entr accelerates liver regeneration, and human albumin expressing h/entr and human Alu gene were detected in the mouse livers. This report suggests that directly induced h/entr could be one of the highly effective therapeutic options for the treatment of liver cirrhotic disease.
最近，重编程技术作为一种生成特定组织细胞的工具引起了人们的关注。在本研究中，我们检验了这样一个假设，即超声定向细胞重编程可以将成纤维细胞诱导为肝样细胞。我们使用超声直接将人真皮成纤维细胞（HDF）通过环境转换介导的细胞重编程（h/entr）诱导为肝样细胞。我们通过肝细胞特异性 RNA 和蛋白质的表达水平来验证 h/entr 的特征。通过条件培养基（CM）分析 h/entr 对肝星状细胞激活的影响。将 h/entr 移植到急性肝纤维化小鼠中，确定肝纤维化的治疗效果和机制。h/entr 表现出高水平的肝细胞特异性基因、肝生成（肝细胞生长因子 [HGF]、集落刺激因子 3 [CSF-3]）和抗炎（白细胞介素 10 [IL-10]）因子。h/entr CM 体外抑制肝星状细胞的激活。h/entr 的移植显著延缓了肝纤维化并改善了肝功能。h/entr 的移植加速了肝再生，并且在小鼠肝脏中检测到表达人白蛋白的 h/entr 和人 Alu 基因。本报告表明，直接诱导的 h/entr 可能是治疗肝硬化疾病的一种有效治疗选择。
