Chemical conversion of aged hepatocytes into bipotent liver progenitor cells
Chemical conversion of aged hepatocytes into bipotent liver progenitor cells
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DOI：
10.1111/hepr.13609
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发表时间：
2021-02-22
影响因子：
4.2
通讯作者：
Eguchi, Susumu
中科院分区：
文献类型：
--
作者：
Huang, Yu;Miyamoto, Daisuke;Eguchi, Susumu
目的 在老龄化社会中，了解肝细胞年龄对肝细胞捐赠的影响可能有助于扩大替代细胞来源以缓解肝脏捐赠者短缺的情况。 Y27632、A-83-01 和 CHIR99021 分子的组合已用于将啮齿动物幼年肝细胞重编程为化学诱导肝祖细胞 (CLiP)；然而，它是否也能重新编程衰老的肝细胞尚未阐明。方法分别从老年和年轻供体大鼠中分离原代肝细胞。评估肝脏组织学变化。鉴定了肝细胞中基因表达的差异。分析了 CLiP 转化所证明的肝细胞体外重编程可塑性以及重编程 CLIP 的肝细胞和胆管细胞成熟能力。还研究了肝细胞生长因子（HGF）对细胞增殖的影响。结果组织学结果显示老化肝脏中存在持续的肝脏损伤，包括炎症、纤维化、衰老和导管反应。微阵列分析显示，老年捐赠者肝细胞中的基因表达谱发生了改变，特别是在代谢途径方面。衰老的肝细胞可以转化为表达祖细胞标志物的CLiPs（Aged-CLiPs），但与年轻的肝细胞相比，增殖率相对较低。 Aged-CLiPs 具有肝细胞和胆管细胞成熟能力。 HGF 促进衰老肝细胞中的 CLiP 转化，这部分与 Erk1 和 Akt1 信号传导的激活有关。结论 培养中的 CLiP 转化证明，衰老大鼠肝细胞保留了重编程可塑性。 HGF 促进老化肝细胞的增殖和 CLiP 转化。来自老年供体的肝细胞可用作替代细胞来源，以缓解供体短缺的情况。
Aim In the aging society, understanding the influence of hepatocyte age on hepatocyte donation may inform efforts to expand alternative cell sources to mitigate liver donor shortage. A combination of the molecules Y27632, A-83-01, and CHIR99021 has been used to reprogram rodent young hepatocytes into chemically induced liver progenitor (CLiP) cells; however, whether it could also reprogram aged hepatocytes has not yet been elucidated.Methods Primary hepatocytes were isolated from aged and young donor rats, respectively. Hepatic histological changes were evaluated. Differences in gene expression in hepatocytes were identified. The in vitro reprogramming plasticity of hepatocytes as evidenced by CLiP conversion and the hepatocyte and cholangiocyte maturation capacity of reprogrammed CLIPs were analyzed. The effect of hepatocyte growth factor (HGF) on cell propagation was also investigated.Results The histological findings revealed ongoing liver damage with inflammation, fibrosis, senescence, and ductular reaction in aged livers. Microarray analysis showed altered gene expression profiles in hepatocytes from aged donors, especially with regard to metabolic pathways. Aged hepatocytes could be converted into CLiPs (Aged-CLiPs) expressing progenitor cell markers, but with a relatively low proliferative rate compared with young hepatocytes. Aged-CLiPs possessed both hepatocyte and cholangiocyte maturation capacity. HGF facilitated CLiP conversion in aged hepatocytes, which was partly related to the activation of Erk1 and Akt1 signaling.Conclusions Aged rat hepatocytes have retained reprogramming plasticity as evidenced by CLiP conversion in culture. HGF promoted proliferation and CLiP conversion in aged hepatocytes. Hepatocytes from aged donors may be used as an alternative cell source to mitigate donor shortage.