Long-Term Superior Performance of a Stem Cell/Hepatocyte Device for the Treatment of Acute Liver Failure
Long-Term Superior Performance of a Stem Cell/Hepatocyte Device for the Treatment of Acute Liver Failure
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DOI：
10.1089/ten.tea.2008.0681
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发表时间：
2009-11-01
影响因子：
4.1
通讯作者：
Yarmush, Martin L.
中科院分区：
文献类型：
--
作者：
Yagi, Hiroshi;Parekkadan, Biju;Yarmush, Martin L.
支持/恢复器官功能的细胞技术是治疗急性肝衰竭（ALF）最有前途的途径之一。最近，间充质干细胞（MSC）被报道为治疗炎症性疾病的新疗法。在这里，我们证明了 MSC 与肝细胞共培养时在 ALF 情况下提供肝脏和抗炎联合治疗的功效。 MSC 在体外显示出与治疗背景相关的多种有益作用，包括 (1) 肝细胞功能支持，(2) 分泌抑制肝细胞凋亡的分子，以及 (3) 在 ALF 诱导的血清中培养的肝细胞调节急性期反应。此外，我们还发现 MSC 分泌组会随着 ALF 大鼠血清暴露而发生动态变化。然后我们进行了肝脏辅助装置 (LAD) 的治疗试验。与其他共培养物和单细胞对照 LAD 相比，含有 MSC 和肝细胞共培养物的 LAD 提供了更大的生存益处。 MSC-肝细胞装置的治疗与肝功能和组织学参数的具体改善以及炎症血清细胞因子水平的降低相关，验证了联合治疗效果。此外，MSC 共培养使装置的总细胞质量减少了一个数量级。这些发现证明了非实质细胞在 LAD 细胞组成中的重要性，并强烈支持将 MSC 整合到基于肝细胞共培养的 LAD 中作为 ALF 的潜在目标治疗。
Cell-based technologies to support/restore organ function represent one of the most promising avenues in the treatment of acute liver failure (ALF). Recently, mesenchymal stem cells (MSCs) have been reported as a new therapeutic for inflammatory conditions. Here, we demonstrate the efficacy of MSCs, when cocultured with hepatocytes, to provide combination hepatic and antiinflammatory therapy in the setting of ALF. MSCs were shown to have multiple beneficial effects in vitro that were relevant in a therapeutic context, including (1) hepatocellular functional support, (2) secretion of molecules that inhibit hepatocyte apoptosis, and (3) modulation of an acute phase response by hepatocytes cultured in ALF-induced serum. In addition, we show that the MSC secretome is dynamically changed in response to serum exposure from ALF rats. We then conducted a therapeutic trial of liver assist devices (LADs). LADs containing cocultures of MSCs and hepatocytes provided a greater survival benefit compared to other coculture and monocellular control LADs. Treatment with MSC-hepatocyte devices was associated with specific improvements in hepatic functional and histological parameters as well as decreasing inflammatory serum cytokine levels, validating a combined therapeutic effect. Moreover, MSC coculture reduced the overall cell mass of the device by an order of magnitude. These findings demonstrate the importance of nonparenchymal cells in the cellular composition of LADs, and strongly support the integration of MSCs into hepatocyte-coculture-based LADs as a potential destination therapy for ALF.