干细胞研究大师Nature子刊介绍重要发现

　　

生物通报道：来自斯坦福大学医学院的研究人员发表了题为“Generation of oligodendroglial cells by direct lineage conversion”的文章，直接将鼠的皮肤细胞变为功能性的脑细胞，这与另外一项发表于Cell Stem Cell杂志上的成果一道迎来了髓鞘类疾病新治疗方法的曙光。

领导这一研究的是干细胞转分化（transdifferentiation）研究领域的大师：Marius Wernig，他领导的研究组在将体细胞诱导转变成另外一种细胞研究方面获得了许多重要的成果。

转分化是指一种类型的分化细胞转变成另一种类型的分化细胞的技术，如水母横纹肌细胞经转分化可形成神经细胞、平滑肌细胞、上皮细胞，甚至可形成刺细胞。2010年Wernig研究组在啮齿类动物皮肤细胞中实现了将皮肤细胞转换成神经元这一转换，2011年他们在Nature上发表的文章宣告了人类皮肤细胞的成功转换。

而在最新这项研究中，研究人员成功的将皮肤细胞直接转化成了少突胶质细胞（Oligodendrocyte）前体细胞，少突胶质细胞是大脑和脊髓中髓鞘细胞的来源，在多发性硬化病患、脑瘫病患和罕见的脑白质营养不良症病患体内，髓鞘细胞受到了破坏而且无法被取代。

研究人员利用三个天然出现的蛋白的层次，获得了大量的诱导少突胶质前体细胞（iOPCs）。而且更重要的是，研究人员发现在将这些细胞移植进入大鼠和小鼠体内后，能在神经周围产生新的髓磷脂包层。这表明，这种细胞能分化成正常的髓鞘细胞，未来也许能用于治疗人类的髓磷脂失调等疾病。

文章的第一作者杨南（Nan Yang，音译）也指出了这种方法的另外一种优势，“利用病患来源的皮肤细胞，我们能生成与病人天然OPSs遗传上一致的OPCs，这能避免免疫排斥问题。”

这一方法证明当三个基因（Ascl1,Brn2和Myt1l）同时转入到小鼠皮肤细胞后，在不到一周的时间内，就有大约20%的细胞被诱导成了神经细胞。这些细胞不光看上去像神经元，而且还表达神经元所特有的蛋白，并且能互相或者与正常小鼠的大脑皮层细胞形成神经突触并传导信号。由此确认了转化的细胞具有完全的成熟神经细胞的功能。

下一步研究人员计划在人体细胞中进行深入的研究，如果成功的话，那么这种方法将为髓鞘疾病和脊髓损伤的治疗打开新的一扇窗。

上一篇文章： 两篇Nature，Cell子刊文章获得iPS重要突破

（生物通：张迪）

原文摘要：

Human iPSC-Derived Oligodendrocyte Progenitor Cells Can Myelinate and Rescue a Mouse Model of Congenital Hypomyelination

Neonatal engraftment by oligodendrocyte progenitor cells (OPCs) permits the myelination of the congenitally dysmyelinated brain. To establish a potential autologous source of these cells, we developed a strategy by which to differentiate human induced pluripotent stem cells (hiPSCs) into OPCs. From three hiPSC lines, as well as from human embryonic stem cells (hESCs), we generated highly enriched OLIG2+/PDGFRα+/NKX2.2+/SOX10+ human OPCs, which could be further purified using fluorescence-activated cell sorting. hiPSC OPCs efficiently differentiated into both myelinogenic oligodendrocytes and astrocytes, in vitro and in vivo. Neonatally engrafted hiPSC OPCs robustly myelinated the brains of myelin-deficient shiverer mice and substantially increased their survival. The speed and efficiency of myelination by hiPSC OPCs was higher than that previously observed using fetal-tissue-derived OPCs, and no tumors from these grafts were noted as long as 9 months after transplant. These results suggest the potential utility of hiPSC-derived OPCs in treating disorders of myelin loss.

Generation of oligodendroglial cells by direct lineage conversion

Transplantation of oligodendrocyte precursor cells (OPCs) is a promising potential therapeutic strategy for diseases affecting myelin. However, the derivation of engraftable OPCs from human pluripotent stem cells has proven difficult and primary OPCs are not readily available. Here we report the generation of induced OPCs (iOPCs) by direct lineage conversion. Forced expression of the three transcription factors Sox10, Olig2 and Zfp536 was sufficient to reprogram mouse and rat fibroblasts into iOPCs with morphologies and gene expression signatures resembling primary OPCs. More importantly, iOPCs gave rise to mature oligodendrocytes that could ensheath multiple host axons when co-cultured with primary dorsal root ganglion cells and formed myelin after transplantation into shiverer mice. We propose direct lineage reprogramming as a viable alternative approach for the generation of OPCs for use in disease modeling and regenerative medicine.