Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
Department of Clinical Laboratory, NHO Nagasaki Medical Center, Nagasaki, Japan.
J Hepatobiliary Pancreat Sci. 2024 Oct;31(10):697-704. doi: 10.1002/jhbp.12046. Epub 2024 Jul 18.
Numerous chemical reprogramming techniques have been reported, rendering them applicable to regenerative medicine research. The aim of our study was to evaluate the therapeutic potential of human CLiP derived from clinical specimens transplanted into a nonalcoholic steatohepatitis (NASH) mouse model of liver fibrosis.
We successfully generated chemically induced liver progenitor (CLiP), which exhibited progenitor-like characteristics, through stimulation with low-molecular-weight compounds. We elucidated their cell differentiation ability and therapeutic effects. However, the therapeutic efficacy of human CLiP generated from clinical samples on liver fibrosis, such as liver cirrhosis, remains unproven.
Following a 4 week period, transplanted human CLiP in the NASH model differentiated into mature hepatocytes and demonstrated suppressive effects on liver injury markers (i.e., aspartate transaminase and alanine transaminase). Although genes related to inflammation and fat deposition did not change in the human CLiP transplantation group, liver fibrosis-related factors (Acta2 and Col1A1) showed suppressive effects on gene expression following transplantation, with approximately a 60% reduction in collagen fibers. Importantly, human CLiP could be efficiently induced from hepatocytes isolated from the cirrhotic liver, underscoring the feasibility of using autologous hepatocytes to produce human CLiP.
Our findings demonstrate the effectiveness of human CLiP transplantation as a viable cellular therapy for liver fibrosis, including NASH liver. These results hold promise for the development of liver antifibrosis therapy utilizing human CLiP within the field of liver regenerative medicine.
已有大量化学重编程技术被报道，使其可适用于再生医学研究。我们的研究旨在评估从临床标本中分离出的人 CLiP 移植到非酒精性脂肪性肝炎（NASH）肝纤维化小鼠模型中的治疗潜力。
我们成功地通过低分子量化合物刺激生成了化学诱导的肝祖细胞（CLiP），其表现出祖细胞样特征。我们阐明了它们的细胞分化能力和治疗效果。然而，从临床样本中生成的人 CLiP 对肝纤维化（如肝硬化）的治疗效果尚未得到证实。
在 NASH 模型中，移植的人 CLiP 在 4 周后分化为成熟的肝细胞，并对肝损伤标志物（如天冬氨酸转氨酶和丙氨酸转氨酶）表现出抑制作用。虽然移植组中与炎症和脂肪沉积相关的基因没有改变，但与肝纤维化相关的因子（Acta2 和 Col1A1）在移植后表现出抑制基因表达的作用，胶原纤维减少约 60%。重要的是，人 CLiP 可以从肝硬化肝脏中分离出的肝细胞中高效诱导，这突出了利用自体肝细胞产生人 CLiP 的可行性。
我们的研究结果表明，人 CLiP 移植作为一种有效的肝纤维化细胞治疗方法是可行的，包括 NASH 肝。这些结果为利用肝再生医学领域中的人 CLiP 开发肝抗纤维化治疗提供了前景。
