Chemically Induced CD24+ hepatocyte-derived liver progenitor-like cells revert chronic hepatic dysfunction

Administration of soluble molecules to induce endogenous adult liver progenitor-like cells may provide a clinically and effectively applicable approach for liver damage repair. Here, we report that HGF in combination with a cocktail of small molecules Y-27632, A-83-01, and CHIR99021 (HACY), which we have previously defined to convert mature hepatocytes (MHs) to liver progenitor-like cells (HepLPCs) in vitro, could induce the replenishment of endogenous HepLPCs and relieve chronic liver dysfunction during persistent injury. The liver progenitor cells surface marker, CD24, was found to be highly expressed in HepLPCs in vitro. Similarly, injection of HACY into mice with carbon tetrachloride (CCL4) treatment also induced conversion of mature hepatocytes to CD24+ progenitor-like cells in vivo, leading to the attenuation of liver fibrosis. Compared to the liver progenitor cells (LPCs) derived from nonparenchymal cells, HACY-induced CD24+ HepLPCs retained an increased hepatic function by RNA sequencing analysis and could promote restoration of liver function by replacing CCL4-impaired liver cells during chronic hepatic damages. And CD24+ liver stem cells could also be observed in human liver fibrosis tissues and expanded in 3D hepatic spheroid in the present of HACY. Together, the results of our study indicated that injection of a cocktail of HACY might be a valuable multiple targets therapy for patients with chronic liver fibrotic pathologies.

通过递送可溶性分子诱导内源性成年肝祖细胞样细胞（liver progenitor-like cells），有望为肝损伤修复提供一条兼具临床可行性与应用价值的可行途径。本研究证实，肝细胞生长因子（Hepatocyte Growth Factor, HGF）与小分子组合Y-27632、A-83-01及CHIR99021联用（下文简称HACY）——该组合此前已被本团队证实可在体外将成熟肝细胞（mature hepatocytes, MHs）转化为肝祖细胞样细胞（HepLPCs）——能够在体内诱导内源性HepLPCs的补充，并缓解持续性损伤期间的慢性肝功能异常。研究发现，体外培养的HepLPCs高表达肝祖细胞表面标志物CD24。同理，向经四氯化碳（carbon tetrachloride, CCL4）造模的小鼠体内注射HACY，同样可在体内将成熟肝细胞转化为CD24阳性的祖细胞样细胞，进而减轻肝纤维化。与源自非实质细胞的肝祖细胞（liver progenitor cells, LPCs）相比，经RNA测序分析证实，HACY诱导产生的CD24阳性HepLPCs保留了更强的肝脏功能活性，且在慢性肝损伤过程中，可通过替换受CCL4损伤的肝细胞促进肝功能恢复。此外，在人类肝纤维化组织中亦可观测到CD24阳性肝干细胞，且在HACY存在的条件下可于三维肝球状体（3D hepatic spheroid）中扩增。综上，本研究结果表明，注射HACY小分子组合或许可为慢性肝纤维化相关病症患者提供一种具有多靶点潜力的治疗方案。

搜集汇总

背景与挑战

背景概述

该数据集聚焦于通过化学诱导方法（使用HGF与Y-27632、A-83-01、CHIR99021的混合物，简称HACY）将成熟肝细胞转化为CD24+肝脏祖细胞样细胞，以逆转慢性肝功能障碍。研究基于小鼠（Mus musculus）模型，涉及四氯化碳（CCL4）诱导的肝损伤，并利用RNA-Seq测序技术分析转录组数据，包含4个样本，总数据量约10.52 GB。数据集的关键信息包括：探索HACY疗法对肝纤维化的缓解作用、CD24作为祖细胞标记物的表达，以及这些细胞在恢复肝功能中的潜在应用价值。