The bone marrow functionally contributes to liver fibrosis
The bone marrow functionally contributes to liver fibrosis
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DOI：
10.1053/j.gastro.2006.01.036
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发表时间：
2006-05-01
期刊：
影响因子：
29.4
通讯作者：
Forbes, Stuart J.
中科院分区：
文献类型：
--
作者：
Russo, Francesco P.;Alison, Malcolm R.;Forbes, Stuart J.
背景与目的：骨髓细胞可以转分化为器官实质细胞或与器官实质细胞融合。骨髓治疗在肝硬化小鼠模型中显示出希望，骨髓干细胞治疗器官愈合的临床试验正在进行中。然而，BM可能有助于包括肝脏在内的各种器官中的瘢痕形成肌成纤维细胞。我们已经研究了这一轴的再生和瘢痕形成的小鼠模型中的肝硬化，包括评估的时间和功能的贡献BM来源的肌成纤维细胞。方法：对雌性小鼠进行致死性照射，并接受雄性骨髓移植。四氯化碳或硫代乙酰胺用于诱导肝硬化。通过Y染色体原位杂交追踪BM衍生的细胞。使用2种转基因小鼠的骨髓移植来检测肝内胶原蛋白的产生。结果如下：在硬化肝脏中，BM对实质再生的贡献很小（0.6%）;相比之下，BM对肝星状细胞（68%）和肌成纤维细胞（70%）群体的贡献显著。在2个独立的试验中发现这些BM衍生的细胞对I型胶原蛋白转录具有活性，并且可以影响对器官损伤的纤维化反应。这些BM衍生的肌成纤维细胞不是通过BM衍生的细胞和固有肝细胞之间的细胞融合发生的，而是主要来源于BM的间充质干细胞。结论：骨髓在肝纤维化中起重要作用，是治疗肝纤维化的潜在靶点。骨髓细胞治疗肝再生的临床试验应警惕增强器官纤维化的可能性。
Background & Aims: Bone marrow (BM) cells may transdifferentiate into or fuse with organ parenchymal cells. BM therapy shows promise in murine models of cirrhosis, and clinical trials of bone marrow stem cell therapy for organ healing are underway. However, the BM may contribute to scar-forming myofibroblasts in various organs including the liver. We have studied this axis of regeneration and scarring in murine models of cirrhosis, including an assessment of the temporal and functional contribution of the BM-derived myofibroblasts. Methods: Female mice were lethally irradiated and received male BM transplants. Carbon tetrachloride or thioacetamide was used to induce cirrhosis. BM-derived cells were tracked through in situ hybridization for the Y chromosome. BM transplants from 2 strains of transgenic mice were used to detect intrahepatic collagen production. Results: In the cirrhotic liver, the contribution of BM to parenchymal regeneration was minor (0.6%); by contrast, the BM contributed significantly to hepatic stellate cell (68%) and myofibroblast (70%) populations. These BM-derived cells were found to be active for collagen type I transcription in 2 independent assays and could influence the fibrotic response to organ injury. These BM-derived myofibroblasts did not occur through cell fusion between BM-derived cells and indigenous hepatic cells but, instead, originated largely from the BM's mesenchymal stem cells. Conclusions: The BM contributes functionally and significantly to liver fibrosis and is a potential therapeutic target in liver fibrosis. Clinical trials of BM cell therapy for liver regeneration should be vigilant for the possibility of enhanced organ fibrosis.