Abstract：
The differentiation of human pluripotent stem cells into ventral mesencephalic dopaminergic (DA) fate is relevant for the treatment of Parkinson\'s disease. Shortcuts to obtaining DA cells through direct reprogramming often include forced expression of the transcription factor LMX1A. Although reprogramming with LMX1A can generate tyrosine hydroxylase (TH)-positive cells, their regional identity remains elusive. Using an in vitro model of early human neural tube patterning, we report that forced LMX1A expression induced a ventral-to-dorsal fate shift along the entire neuroaxis with the emergence of roof plate fates despite the presence of ventralizing molecules. The LMX1A-expressing progenitors gave rise to grafts containing roof plate-derived choroid plexus cysts as well as ectopically induced TH-positive neurons of a forebrain identity. Early activation of LMX1A prior to floor plate specification was necessary for the dorsalizing effect. Our work suggests using caution in employing LMX1A for the induction of DA fate, as this factor may generate roof plate rather than midbrain fates.
摘要：
人多能干细胞分化为腹侧中脑多巴胺能（DA）命运与帕金森病的治疗有关。通过直接重编程获得DA细胞的捷径通常包括转录因子LMX1A的强制表达。尽管用LMX1A重编程可以产生酪氨酸羟化酶（TH）阳性细胞，他们的区域身份仍然难以捉摸。使用早期人类神经管图案化的体外模型，我们报道,尽管存在腹侧分子,但LMX1A的强制表达诱导了沿整个神经轴的腹侧到背侧的命运转变,并出现了顶板命运.表达LMX1A的祖细胞产生了包含顶板衍生的脉络丛囊肿以及异位诱导的前脑TH阳性神经元的移植物。在地板规格之前早期激活LMX1A对于背化效果是必要的。我们的工作建议谨慎使用LMX1A诱导DA命运，因为这个因素可能会产生顶板而不是中脑的命运。
