阻抑长链非编码RNA-HOTAIR以诱导肌成纤维细胞重分化对肝纤维化的防治意义

肝脏间质细胞失去分化表型，转化为肌成纤维细胞(myofibroblast, MFB)是肝纤维化过程的关键事件。既往的干预措施局限于抑制MFB生成，加速其清除，无法诱导MFB重新向成熟表型分化，因而难以实现阻断乃至逆转肝纤维化的目标。我们近期发现，长链非编码RNA（long non-coding RNA, lnRNA）-HOTAIR在MFB中特异性高表达，并通过同源异型盒基因座的染色质重塑，导致分化相关基因的表达缺失。为此，本研究拟以siRNA实现HOTAIR的基因沉默，从而逆转染色质重塑，恢复促分化基因活性，在此基础上消除MFB的过度增殖、细胞外基质合成/分泌、迁移、趋化等去分化表型，恢复脂质代谢、胆汁分泌等成熟细胞功能。此外借助慢病毒载体进行体内HOTAIR"敲减"，观察诱导MFB重分化对肝纤维化的防治效应。

Myofibroblast (MFB), which plays the critical part in hepatic fibrogenesis, is derived from mesenchymal cells by phenotypic de-differentiation. Although various procedures, such as inhibiting the generation of MFB and eradicating the existing ones, have been employed, the difficulties in MFB redifferentiation still make it a hard task to prevent and reverse the liver fibrosis. Recently, one of the long non-coding RNAs, HOTAIR, is verified to highly express in MFB. Its effects on chromatin remodeling induce the gene depression in HOX loci, and then the de-differentiation phenotype. We, therefore, attempt to restore the chromatin structure by HOTAIR knockdown. The activation of redifferentiation genes, being obtained as a result, will help to abolish the dedifferentiation-related functions (excessive proliferation, extracellular matrix production/secretion, motility and chemotaxis) and acquire the redifferentiation -related functions (lipid metabolism, bile secreton). In vivo down-regulation of HOTAIR using lentiviral vectors provide another insight into its role on MFB redifferentiation, and fibrosis interference.