Transcriptome Profiling Reveals Distinct Phenotype of Human Bone Marrow Mesenchymal Stem Cell-derived Hepatocyte-like cells
Transcriptome Profiling Reveals Distinct Phenotype of Human Bone Marrow Mesenchymal Stem Cell-derived Hepatocyte-like cells
复制标题
转录组分析揭示人骨髓间充质干细胞衍生的肝细胞样细胞的独特表型
DOI：
10.7150/ijms.36255
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发表时间：
2020-01-01
影响因子：
3.6
通讯作者：
Li, Jun
中科院分区：
文献类型：
--
作者：
Shi, Dongyan;Xin, Jiaojiao;Li, Jun
背景资料：人骨髓间充质干细胞衍生的肝细胞样细胞（hBMSC-HLC）是原代人肝细胞（HH）用于治疗肝病的有希望的替代物。然而，HLC的分子特征仍不清楚。本研究旨在阐明hBMSC-HLCs的转录组特征，为hBMSC-HLCs的临床应用奠定基础。材料和方法：从健康志愿者的骨髓中分离hBMSC并分化为肝细胞。mRNA测序用于hBMSC-HLC的转录组分析，hBMSC和HH作为对照。结果：hBMSC-HLCs呈多角形，有糖原积聚和白蛋白表达。与未分化的hBMSC相比，hBMSC-HLC和HHS中共观察到630个上调和1082个下调的基因。上调的基因主要涉及肝脏代谢和炎症免疫反应。下调的基因主要与干细胞特性（多能分化、细胞周期调控等）有关。对log 2倍数变化> 5的9个上调和9个下调基因进行的确证性qRT-PCR显示了相似的结果。hBMSC在暴发性肝功能衰竭的猪体内转分化证实了5个肝原性基因（TDO 2，HP，SERPINA 3，LBP和SAA 1）的表达类似地上调，在hBMSC移植后7天肝组织中显示出150倍的变化。这5个基因主要参与肝脏代谢和炎症反应。结论：hBMSC-HLCs具有肝脏转录组特征，在体外和体内表达肝脏特异性基因，这可能对未来的临床应用有用。本文鉴定的五种上调基因可能是表征hBMSC-HLC的潜在生物标志物。
Background: Human bone marrow mesenchymal stem cell-derived hepatocyte-like cells (hBMSC-HLCs) are a promising alternative for primary human hepatocytes (HHs) for treating liver disease. However, the molecular characteristics of HLCs remain unclear. Here, we aimed to clarify the transcriptome characteristics of hBMSC-HLCs for future clinical application. Materials and Methods: hBMSCs were isolated from the bone marrow of healthy volunteers and differentiated into hepatocytes. mRNA sequencing was used in the transcriptome profiling of hBMSC-HLCs, with hBMSCs and HHs as controls. Results: hBMSC-HLCs exhibited a polygonal morphology, glycogen accumulation and albumin expression. A total of 630 upregulated and 1082 downregulated genes were observed in hBMSC-HLCs and HHs compared with undifferentiated hBMSCs. The upregulated genes were mainly involved in hepatic metabolism and inflammatory and immune responses. The downregulated genes were mainly associated with stem cell characteristics (multipotent differentiation, cell cycle regulation, etc.). Confirmatory qRT-PCR of 9 upregulated and 9 downregulated genes with log2 fold changes > 5 showed similar results. In vivo transdifferentiation of hBMSCs in pigs with fulminant hepatic failure confirmed the similarly upregulated expression of 5 hepatogenic genes (TDO2, HP, SERPINA3, LBP and SAA1), showing a 150-fold change in liver tissues at 7 days after hBMSC transplantation. These 5 genes mainly contributed to liver metabolism and inflammation. Conclusion: hBMSC-HLCs possess a hepatic transcriptome profile and express hepatic-specific genes in vitro and in vivo, which might be useful for future clinical applications. The five upregulated genes identified herein could be potential biomarkers for the characterization of hBMSC-HLCs.