Biomedical Research Center, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Republic of Korea.
Department of Hematology and Oncology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Republic of Korea.
PLoS One. 2023 Aug 8;18(8):e0289798. doi: 10.1371/journal.pone.0289798. eCollection 2023.
Liver transplantation is the most effective treatment option for patients with acute or chronic liver failure. However, the applicability and effectiveness of this modality are often limited by a shortage of donors, surgical complications, high medical costs, and the need for continuing immunosuppressive therapy. An alternative approach is liver cell transplantation. LIGHT (a member of the tumor necrosis factor superfamily) could be a promising candidate for promoting the differentiation of human bone marrow-derived mesenchymal stem cells (hBM-MSCs) into hepatocyte-like cells. In this study, we investigated the effect of LIGHT on hBM-MSC differentiation into hepatocyte-like cells. Our previous results showed that LIGHT receptor lymphotoxin-β receptor (LTβR) is constitutively expressed on the surface of hBM-MSCs. Upon treatment with recombinant human LIGHT (rhLIGHT), the phenotype of hBM-MSCs changed to round or polygonal cells. In addition, the cells exhibited high levels of hepatocyte-specific markers, including albumin, cytokeratin-18 (CK-18), CK-19, cytochrome P450 family 1 subfamily A member 1 (CYP1A1), CYP1A2, CYP3A4, SRY-box transcription factor 17 (SOX17), and forkhead box A2 (FOXA2). These results indicate that rhLIGHT enhances the differentiation of hBM-MSCs into functional hepatocyte-like cells. Furthermore, rhLIGHT-induced hepatocyte-like cells showed a higher ability to store glycogen and uptake indocyanine green compared with control cells, indicating functional progression. Additionally, treatment with rhLIGHT increased the number, viability, and proliferation of cells by inducing the S/G2/M phase and upregulating the expression of various cyclin and cyclin dependent kinase (CDK) proteins. We also found that the hepatogenic differentiation of hBM-MSCs induced by rhLIGHT was mediated by the activation of signal transducer and activator of transcription 3 (STAT3) and STAT5 pathways. Overall, our findings suggest that LIGHT plays an essential role in promoting the hepatogenic differentiation of hBM-MSCs. Hence, LIGHT may be a valuable factor for stem cell therapy.
肝移植是治疗急性或慢性肝功能衰竭患者的最有效治疗方法。然而，这种方法的适用性和有效性通常受到供体短缺、手术并发症、高昂的医疗费用以及持续免疫抑制治疗的需求的限制。另一种方法是肝细胞移植。LIGHT（肿瘤坏死因子超家族的一员）可能是促进人骨髓间充质干细胞（hBM-MSCs）分化为肝样细胞的有前途的候选物。在这项研究中，我们研究了 LIGHT 对 hBM-MSC 分化为肝样细胞的影响。我们之前的结果表明，LIGHT 受体淋巴毒素-β受体（LTβR）在 hBM-MSCs 表面持续表达。在用重组人 LIGHT（rhLIGHT）处理后，hBM-MSCs 的表型变为圆形或多角形细胞。此外，这些细胞表现出高水平的肝细胞特异性标志物，包括白蛋白、细胞角蛋白 18（CK-18）、细胞角蛋白 19（CK-19）、细胞色素 P450 家族 1 亚家族 A 成员 1（CYP1A1）、CYP1A2、CYP3A4、性别决定区 Y 框转录因子 17（SOX17）和叉头框 A2（FOXA2）。这些结果表明，rhLIGHT 增强了 hBM-MSCs 向功能性肝样细胞的分化。此外，与对照细胞相比，rhLIGHT 诱导的肝样细胞具有更高的储存糖原和摄取吲哚菁绿的能力，表明功能进展。此外，rhLIGHT 通过诱导 S/G2/M 期和上调各种细胞周期蛋白和细胞周期蛋白依赖性激酶（CDK）蛋白的表达，增加细胞数量、活力和增殖。我们还发现，rhLIGHT 诱导的 hBM-MSCs 的肝发生分化是通过激活信号转导和转录激活因子 3（STAT3）和 STAT5 途径介导的。总的来说，我们的研究结果表明，LIGHT 在促进 hBM-MSCs 的肝发生分化中起着至关重要的作用。因此，LIGHT 可能是干细胞治疗的有价值的因素。
