Decellularized Liver Extracellular Matrix as Promising Tools for Transplantable Bioengineered Liver Promotes Hepatic Lineage Commitments of Induced Pluripotent Stem Cells
Decellularized Liver Extracellular Matrix as Promising Tools for Transplantable Bioengineered Liver Promotes Hepatic Lineage Commitments of Induced Pluripotent Stem Cells
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DOI：
10.1089/ten.tea.2015.0313
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发表时间：
2016-03-01
影响因子：
4.1
通讯作者：
Woo, Heung-Myong
中科院分区：
文献类型：
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作者：
Park, Kyung-Mee;Hussein, Kamal Hany;Woo, Heung-Myong
肝移植是治疗肝功能衰竭的最后手段。然而，由于供体器官的短缺，由去细胞化的全肝支架和诱导多能干细胞（iPSC）衍生的肝细胞（iPSC- heps）生成的生物工程肝脏正在被研究作为治疗肝脏疾病的替代方法。然而，目前还没有iPSC-Heps与肝细胞外基质（ECM）相互作用的报道，也没有iPSC-Heps再细胞化到全肝支架的分析。在这项研究中，我们生产了猪iPSC-Heps，它强烈表达肝脏标志物甲胎蛋白和白蛋白，并表现出肝脏功能，包括糖原储存、脂质积累、低密度脂蛋白摄取和吲哚菁绿代谢。在分化过程中，添加含有肝源性生长因子的猪去细胞化肝脏的ECM可刺激猪iPSC-Heps的白蛋白表达。将iPSC-Heps重新植入去细胞化的肝脏支架中，使用连续灌注系统培养再细胞化的肝脏。将再细胞化肝支架短期移植到大鼠体内，移植物表达肝细胞标记物且未破裂。这些结果为利用干细胞和去细胞支架开发生物工程肝脏提供了基础。
Liver transplantation is the last resort for liver failure patients. However, due to the shortage of donor organs, bioengineered liver generated from decellularized whole liver scaffolds and induced pluripotent stem cell (iPSC)-derived hepatocytes (iPSC-Heps) is being studied as an alternative approach to treat liver disease. Nevertheless, there has been no report on both the interaction of iPSC-Heps with a liver extracellular matrix (ECM) and the analysis of recellularized iPSC-Heps into the whole liver scaffolds. In this study, we produced porcine iPSC-Heps, which strongly expressed the hepatic markers alpha-fetoprotein and albumin and exhibited hepatic functionalities, including glycogen storage, lipid accumulation, low-density lipoprotein uptake, and indocyanine green metabolism. Supplementation of ECM from porcine decellularized liver containing liver-derived growth factors stimulated the albumin expression of porcine iPSC-Heps during differentiation procedures. The iPSC-Heps were reseeded into decellularized liver scaffolds, and the recellularized liver was cultured using a continuous perfusion system. The recellularized liver scaffolds were transplanted into rats for a short term, and the grafts expressed hepatocyte markers and did not rupture. These results provide a foundation for development of bioengineered liver using stem cell and decellularized scaffolds.