WNT-C59，一种小分子WNT抑制剂，可有效诱导包括人类多能干细胞的皮质运动神经元在内的前皮质。,STEM CELLS Translational Medicine

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WNT-C59，一种小分子WNT抑制剂，可有效诱导包括人类多能干细胞的皮质运动神经元在内的前皮质。
STEM CELLS Translational Medicine ( IF 5.4 ) Pub Date : 2016-03-03 , DOI: 10.5966/sctm.2015-0261
Makoto Motono ₁ , Yoshihiko Ioroi ₂ , Takenori Ogura ₂ , Jun Takahashi ₃

Affiliation

从多能干细胞（PSC）以可控的，确定的方式概括人类神经发育，对研究人类神经发育，电路形成和功能以及构建神经系统疾病的体外模型具有巨大的潜力。通常通过重组蛋白DKK1抑制Wnt信号，对于诱导皮层神经元很重要。在这里，我们报告了一种使用小分子WNT抑制剂WNT-C59（C59）的新型分化方法，以有效诱导人前皮质。我们比较了两种类型的小分子C59和XAV939（XAV），它们是DKK1的替代物，可在无血清类胚体样聚集培养物中诱导来自PSC的皮质神经元。DKK1和XAV仅抑制Wnt信号的经典途径，而C59抑制经典和非经典途径。C59有效诱导CTIP2⁺ / COUP-TF1 ^-细胞，这是将细胞的特性前皮质中发现。另外，当移植到成年小鼠的皮质中时，C59诱导的细胞显示出丰富的轴突纤维向脊髓延伸。这些结果提高了C59有助于运动神经元疾病或损伤的细胞替代治疗的可能性。

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WNT-C59, a Small-Molecule WNT Inhibitor, Efficiently Induces Anterior Cortex That Includes Cortical Motor Neurons From Human Pluripotent Stem Cells.

The recapitulation of human neural development in a controlled, defined manner from pluripotent stem cells (PSCs) has considerable potential for studies of human neural development, circuit formation and function, and the construction of in vitro models of neurological diseases. The inhibition of Wnt signaling, often by the recombinant protein DKK1, is important for the induction of cortical neurons. Here, we report a novel differentiation method using a small‐molecule WNT inhibitor, WNT‐C59 (C59), to efficiently induce human anterior cortex. We compared two types of small molecules, C59 and XAV939 (XAV), as substitutes for DKK1 to induce cortical neurons from PSCs in serum‐free embryoid body‐like aggregate culture. DKK1 and XAV inhibited only the canonical pathway of Wnt signaling, whereas C59 inhibited both the canonical and noncanonical pathways. C59 efficiently induced CTIP2⁺/COUP‐TF1⁻ cells, which are characteristic of the cells found in the anterior cortex. In addition, when grafted into the cortex of adult mice, the C59‐induced cells showed abundant axonal fiber extension toward the spinal cord. These results raise the possibility of C59 contributing to cell replacement therapy for motor neuron diseases or insults.

更新日期：2016-03-03

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