Human retinal ganglion cell neurons generated by synchronous BMP inhibition and transcription factor mediated reprogramming.
Human retinal ganglion cell neurons generated by synchronous BMP inhibition and transcription factor mediated reprogramming.
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通过同步BMP抑制和转录因子介导的重编程产生人视网膜神经节细胞神经元。
DOI：
10.1038/s41536-023-00327-x
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发表时间：
2023-09-29
影响因子：
7.2
通讯作者：
Wahlin, Karl J.
中科院分区：
文献类型：
--
作者：
Agarwal, Devansh;Dash, Nicholas;Mazo, Kevin W.;Chopra, Manan;Avila, Maria P.;Patel, Amit;Wong, Ryan M.;Jia, Cairang;Do, Hope;Cheng, Jie;Chiang, Colette;Jurlina, Shawna L.;Roshan, Mona;Perry, Michael W.;Rho, Jong M.;Broyer, Risa;Lee, Cassidy D.;Weinreb, Robert N.;Gavrilovici, Cezar;Oesch, Nicholas W.;Welsbie, Derek S.;Wahlin, Karl J.
在包括青光眼在内的视神经疾病中，视网膜神经节细胞(RGC)死亡。细胞移植和内源性再生为视网膜修复提供了策略，然而，成功所需的发育程序还不完全清楚。为了解决这个问题，我们探索了用转录因子(TF)调节RGC发育的细胞重新编程，将其整合到人多能干细胞(PSCs)中作为诱导基因盒。当先锋因子NEUROG2与RGC表达的转录因子(ATOH7、IsL1和POU4F2)相结合时，观察到了一定的转化，当通过BMP抑制预模式时，RGC样诱导神经元(RGC-ins)在不到一周的时间内被高效地产生。这些细胞的转录特征使人联想到视网膜节细胞，并表现出电生理特性，包括AMPA介导的突触传递。此外，我们还证明了DLK/LZK和GCK-IV的小分子抑制剂可以阻断两种药理学轴突损伤模型中的神经元死亡。因此，将发育模式与RGC特异的转录因子相结合，为细胞替代和神经保护的策略提供了宝贵的见解。
In optic neuropathies, including glaucoma, retinal ganglion cells (RGCs) die. Cell transplantation and endogenous regeneration offer strategies for retinal repair, however, developmental programs required for this to succeed are incompletely understood. To address this, we explored cellular reprogramming with transcription factor (TF) regulators of RGC development which were integrated into human pluripotent stem cells (PSCs) as inducible gene cassettes. When the pioneer factor NEUROG2 was combined with RGC-expressed TFs (ATOH7, ISL1, and POU4F2) some conversion was observed and when pre-patterned by BMP inhibition, RGC-like induced neurons (RGC-iNs) were generated with high efficiency in just under a week. These exhibited transcriptional profiles that were reminiscent of RGCs and exhibited electrophysiological properties, including AMPA-mediated synaptic transmission. Additionally, we demonstrated that small molecule inhibitors of DLK/LZK and GCK-IV can block neuronal death in two pharmacological axon injury models. Combining developmental patterning with RGC-specific TFs thus provided valuable insight into strategies for cell replacement and neuroprotection.
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影响因子：
5.2
作者：
Garita-Hernandez, Marcela;Diaz-Corrales, Francisco;Bhattacharya, Shomi S.
通讯作者：
Bhattacharya, Shomi S.
影响因子：
2.6
作者：
Hocking, Jennifer C.;Hehr, Carrie L.;McFarlane, Sarah
通讯作者：
McFarlane, Sarah
影响因子：
4
作者：
Bae, Daekyeong;Mondragon-Teran, Paul;Veraitch, Farlan S.
通讯作者：
Veraitch, Farlan S.
影响因子：
5.3
作者：
de Melo, Jimmy;Zibetti, Cristina;Blackshaw, Seth
通讯作者：
Blackshaw, Seth
影响因子：
46.9
作者：
Chambers, Stuart M.;Fasano, Christopher A.;Papapetrou, Eirini P.;Tomishima, Mark;Sadelain, Michel;Studer, Lorenz
通讯作者：
Studer, Lorenz