Multifaceted therapeutic benefits of factors derived from stem cells from human exfoliated deciduous teeth for acute liver failure in rats
Multifaceted therapeutic benefits of factors derived from stem cells from human exfoliated deciduous teeth for acute liver failure in rats
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DOI：
10.1002/term.2086
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发表时间：
2017-06-01
影响因子：
3.3
通讯作者：
Yamamoto, Akihito
中科院分区：
文献类型：
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作者：
Matsushita, Yoshihiro;Ishigami, Masatoshi;Yamamoto, Akihito
在急性肝功能衰竭（ALF）中，先天性免疫反应控制不佳导致大规模肝脏破坏，从而引发全身炎症反应、进行性多器官衰竭和最终猝死。虽然肝脏具有固有的组织修复活性，但在ALF期间其再生失败，原位肝移植是唯一的治疗方法。在这里，我们表明，单次静脉注射干细胞从人类脱落的乳牙（SHED）或SHED衍生的无血清条件培养基（SHED-CM）到d-半乳糖胺诱导的ALF大鼠模型显着改善损伤的肝脏和动物的生存率的条件。输注的SHED的植入非常低，SHED和SHED-CM发挥相似的治疗效果，表明SHED通过旁分泌机制逆转ALF。重要的是，SHED-CM减弱了ALF诱导的促炎反应，并产生了抗炎/组织再生环境，这伴随着抗炎M2样肝巨噬细胞的诱导。细胞因子抗体芯片的分泌组分析显示，SHED-CM含有多种组织再生因子，这些因子在抗凋亡/肝细胞保护、血管生成、巨噬细胞分化和肝祖细胞的增殖/分化中具有已知的作用。综上所述，我们的研究结果表明，SHEDs产生的因素，提供多方面的治疗AFL的好处。版权所有（c）2015约翰威利父子有限公司
In acute liver failure (ALF), a poorly controlled innate immune response causes massive hepatic destruction, which elicits a systemic inflammatory response, progressive multiple organ failure and ultimate sudden death. Although the liver has inherent tissue-repairing activities, its regeneration during ALF fails, and orthotopic liver transplantation is the only curative approach. Here we show that a single intravenous administration of stem cells derived from human exfoliated deciduous teeth (SHEDs) or of SHED-derived serum-free conditioned medium (SHED-CM) into the d-galactosamine-induced rat model of ALF markedly improved the condition of the injured liver and the animals' survival rate. The engraftment of infused SHEDs was very low, and both SHEDs and SHED-CM exerted similar levels of therapeutic effect, suggesting that the SHEDs reversed ALF by paracrine mechanisms. Importantly, SHED-CM attenuated the ALF-induced pro-inflammatory response and generated an anti-inflammatory/tissue-regenerating environment, which was accompanied by the induction of anti-inflammatory M2-like hepatic macrophages. Secretome analysis by cytokine antibody array revealed that the SHED-CM contained multiple tissue-regenerating factors with known roles in anti-apoptosis/hepatocyte protection, angiogenesis, macrophage differentiation and the proliferation/differentiation of liver progenitor cells. Taken together, our findings suggest that SHEDs produce factors that provide multifaceted therapeutic benefits for AFL. Copyright (c) 2015 John Wiley & Sons, Ltd.