Dopaminergic Neurons Derived from Human Induced Pluripotent Stem Cells Survive and Integrate into 6-OHDA-Lesioned Rats
Dopaminergic Neurons Derived from Human Induced Pluripotent Stem Cells Survive and Integrate into 6-OHDA-Lesioned Rats
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DOI：
10.1089/scd.2009.0319
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发表时间：
2010-07-01
影响因子：
4
通讯作者：
Iacovitti, Lorraine
中科院分区：
文献类型：
--
作者：
Cai, Jingli;Yang, Ming;Iacovitti, Lorraine
细胞替代疗法可能是治疗帕金森病（PD）的重要策略，帕金森病是由中脑多巴胺神经元（mDA）变性引起的。这种方法的成功在很大程度上依赖于发现大脑中能够发挥mDA能功能的丰富细胞来源。由于可用的人类胎儿组织的缺乏，人们越来越多地关注可再生干细胞。人类诱导多能干细胞（hiPS）在这方面提供了很大的希望。如果hiPS细胞可以分化成真正的mDA神经元，hiPS可以提供一个潜在的自体来源的移植组织时，从PD患者产生，一个明显的优势超过人类胚胎干细胞（hES）。在这里，我们报告说，mDA神经元可以来自市售的hiPS细胞系，IMR 90克隆4，使用我们实验室建立的修改的hES分化方案。这些细胞表达所有标记物（Lmx 1a、Aldh 1a 1、TH、TrkB），遵循与H9 hES细胞相同的mDA谱系途径，并且具有相似的DA和DOPAC表达水平。此外，当将hiPS mDA祖细胞移植到6-OHDA损伤的PD大鼠中时，它们长期存活，并且许多发育成真正的mDA神经元。尽管它们分化并整合到大脑中，但许多Nestin+肿瘤样细胞仍保留在移植部位。我们的数据表明，与hES细胞一样，选择适当的mDA谱系细胞群并在移植前消除活跃分裂的hiPS细胞对于PD患者未来hiPS细胞替代疗法的成功至关重要。
Cell replacement therapy could be an important treatment strategy for Parkinson's disease (PD), which is caused by the degeneration of dopamine neurons in the midbrain (mDA). The success of this approach greatly relies on the discovery of an abundant source of cells capable of mDAergic function in the brain. With the paucity of available human fetal tissue, efforts have increasingly focused on renewable stem cells. Human induced pluripotent stem (hiPS) cells offer great promise in this regard. If hiPS cells can be differentiated into authentic mDA neuron, hiPS could provide a potential autologous source of transplant tissue when generated from PD patients, a clear advantage over human embryonic stem (hES) cells. Here, we report that mDA neurons can be derived from a commercially available hiPS cell line, IMR90 clone 4, using a modified hES differentiation protocol established in our lab. These cells express all the markers (Lmx1a, Aldh1a1, TH, TrkB), follow the same mDA lineage pathway as H9 hES cells, and have similar expression levels of DA and DOPAC. Moreover, when hiPS mDA progenitor cells are transplanted into 6-OHDA-lesioned PD rats, they survive long term and many develop into bona fide mDA neurons. Despite their differentiation and integration into the brain, many Nestin+ tumor-like cells remain at the site of the graft. Our data suggest that as with hES cells, selecting the appropriate population of mDA lineage cells and eliminating actively dividing hiPS cells before transplantation will be critical for the future success of hiPS cell replacement therapy in PD patients.