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通过下调 GLYPICAN-4 增强人诱导多能干细胞向中脑多巴胺能神经元谱系的分化。

Enhanced differentiation of human induced pluripotent stem cells toward the midbrain dopaminergic neuron lineage through GLYPICAN-4 downregulation.

机构信息

Aix Marseille Univ, CNRS, Developmental Biology Institute of Marseille (IBDM), Turing Center for Living Systems, Parc Scientifique de Luminy, NeuroMarseille, Marseille, France.

Lillehei Heart Institute and Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota, USA.

出版信息

Stem Cells Transl Med. 2021 May;10(5):725-742. doi: 10.1002/sctm.20-0177. Epub 2021 Feb 2.

DOI:10.1002/sctm.20-0177
PMID:33528918
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8046045/
Abstract

Enhancing the differentiation potential of human induced pluripotent stem cells (hiPSC) into disease-relevant cell types is instrumental for their widespread application in medicine. Here, we show that hiPSCs downregulated for the signaling modulator GLYPICAN-4 (GPC4) acquire a new biological state characterized by increased hiPSC differentiation capabilities toward ventral midbrain dopaminergic (VMDA) neuron progenitors. This biological trait emerges both in vitro, upon exposing cells to VMDA neuronal differentiation signals, and in vivo, even when transplanting hiPSCs at the extreme conditions of floor-plate stage in rat brains. Moreover, it is compatible with the overall neuronal maturation process toward acquisition of substantia nigra neuron identity. HiPSCs with downregulated GPC4 also retain self-renewal and pluripotency in stemness conditions, in vitro, while losing tumorigenesis in vivo as assessed by flank xenografts. In conclusion, our results highlight GPC4 downregulation as a powerful approach to enhance generation of VMDA neurons. Outcomes may contribute to establish hiPSC lines suitable for translational applications.

摘要

增强人类诱导多能干细胞（hiPSC）向疾病相关细胞类型的分化潜能对于它们在医学中的广泛应用至关重要。在这里，我们表明，下调信号调节剂 GLYPICAN-4（GPC4）的 hiPSC 获得了一种新的生物学状态，其特征是向腹侧中脑神经前体细胞（VMDA）神经元祖细胞的 hiPSC 分化能力增强。这种生物学特性不仅在体外暴露于 VMDA 神经元分化信号时出现，而且在体内，甚至在将 hiPSC 移植到大鼠大脑基板阶段的极端条件下时也出现。此外，它与获得黑质神经元身份的整体神经元成熟过程兼容。在体外干性条件下，下调 GPC4 的 hiPSC 也保留自我更新和多能性，而体内通过侧翼异种移植评估则失去致瘤性。总之，我们的结果强调下调 GPC4 是增强 VMDA 神经元生成的一种有效方法。研究结果可能有助于建立适合转化应用的 hiPSC 系。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/45b6/8046045/a10747029ba6/SCT3-10-725-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/45b6/8046045/12124dfe753c/SCT3-10-725-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/45b6/8046045/0c8a7512d10b/SCT3-10-725-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/45b6/8046045/8d1b08c4560b/SCT3-10-725-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/45b6/8046045/da4273e5bf84/SCT3-10-725-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/45b6/8046045/bdfb9679159f/SCT3-10-725-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/45b6/8046045/97187a56e562/SCT3-10-725-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/45b6/8046045/a10747029ba6/SCT3-10-725-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/45b6/8046045/12124dfe753c/SCT3-10-725-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/45b6/8046045/0c8a7512d10b/SCT3-10-725-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/45b6/8046045/8d1b08c4560b/SCT3-10-725-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/45b6/8046045/da4273e5bf84/SCT3-10-725-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/45b6/8046045/bdfb9679159f/SCT3-10-725-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/45b6/8046045/97187a56e562/SCT3-10-725-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/45b6/8046045/a10747029ba6/SCT3-10-725-g004.jpg

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