Development of therapeutic transplantation of human bone marrow mesenchymal cells into injured liver.

自体骨髓细胞移植是一种很有前途的肝病治疗方法。多能性骨髓干细胞可分化为肝细胞，但将其移植到受损肝脏的治疗效果尚未见报道，我们建立了体外培养体系，在生长因子刺激下，小鼠骨髓细胞转分化为肝系细胞。骨髓细胞向肝系细胞的转化被认为是没有融合的转分化，因为在本研究中骨髓细胞没有与肝细胞共培养。值得注意的是，成纤维细胞生长因子具有诱导BM细胞转分化为肝谱系细胞的能力。这种转化与包括肝细胞核因子和加塔蛋白家族的转录因子的诱导有关。特异性细胞消融是分析细胞体内功能的有用方法。我们已经开发了一种简单而敏感的转基因小鼠条件性细胞清除方法，称为“毒素受体介导的细胞敲除”。“我们使用肝细胞特异性启动子在转基因小鼠中表达白喉毒素（DT）受体，并发现注射DT会引起暴发性肝炎。我们可以将从GFP转基因小鼠中获得的成熟肝细胞移植到这些DT转基因小鼠中。将GFP转基因小鼠的各种干细胞或祖细胞移植到毒素敏感的转基因小鼠中，可以跟踪DT给药后再生细胞的发育。

The autologous transplantation of bone marrow cells is a promising treatment for liver disease. Pluripotent bone marrow stem cells can differentiate into hepatocytes, but few reports address the therapeutic effects of transplanting these stem cells into damaged liver in vivo.We previously reported that in vitro culture system was established, in which mouse bone marrow cells were trans-differentiated into hepatic lineage cells in response to growth factor stimulation. This conversion of BM cells to hepatic lineage cells is thought to be the tran-differentiation without fusion, because bone marrow cells were not co-cultured with hepatocytes in this study. It is noteworthy that fibroblast growth factors have the ability to induce the transdifferentiation of BM cells into hepatic lineage cells. This conversion is associated with the induction of transcription factors including hepatocyte nuclear factors and the GATA family of proteins.Specific cell ablation is a useful method for analyzing the in vivo function of cells. We have developed a simple and sensitive method for conditional cell ablation in transgenic mice, called "toxin receptor-mediated cell knockout." We expressed the diphtheria toxin (DT) receptor in transgenic mice using a hepatocyte-specific promoter and found that injection of DT caused fulminant hepatitis. We could transplant mature hepatocytes, obtained from GFP-transgenic mice, into these DT transgenic mice. Transplanting various kinds of stem cells or progenitor cells from GFP-transgenic mice into toxin-sensitive transgenic mice should allow one to follow the development of regenerated cells administration of DT.