Document detail
ID
doi:10.1186/s13024-021-00510-y...
Author
Li, Qian Feng, Yi Xue, Yingchao Zhan, Xiping Fu, Yi Gui, Gege Zhou, Weiqiang Richard, Jean-Philippe Taga, Arens Li, Pan Mao, Xiaobo Maragakis, Nicholas J. Ying, MingyaoLangue
enEditor
BioMed Central
Category
Biomedicine
Year
2022
listing date
2/10/2022
Keywords
spinal cord motor neuron transcription factor amyotrophic lateral sclerosis synthetic mrna mci-186 neurotrophic factor differentiation neuroprotective efficacy mns ipscs disease treatment mimns gdnf effect neurotoxicity signaling neurotrophic edaravone alsAbstract
Background Spinal cord motor neurons (MNs) from human iPS cells (iPSCs) have wide applications in disease modeling and therapeutic development for amyotrophic lateral sclerosis (ALS) and other MN-associated neurodegenerative diseases.
We need highly efficient MN differentiation strategies for generating iPSC-derived disease models that closely recapitulate the genetic and phenotypic complexity of ALS.
An important application of these models is to understand molecular mechanisms of action of FDA-approved ALS drugs that only show modest clinical efficacy.
Novel mechanistic insights will help us design optimal therapeutic strategies together with predictive biomarkers to achieve better efficacy.
Methods We induce efficient MN differentiation from iPSCs in 4 days using synthetic mRNAs coding two transcription factors (Ngn2 and Olig2) with phosphosite modification.
These MNs after extensive characterization were applied in electrophysiological and neurotoxicity assays as well as transcriptomic analysis, to study the neuroprotective effect and molecular mechanisms of edaravone, an FDA-approved drug for ALS, for improving its clinical efficacy.
Results We generate highly pure and functional mRNA-induced MNs (miMNs) from control and ALS iPSCs, as well as embryonic stem cells.
Edaravone alleviates H_2O_2-induced neurotoxicity and electrophysiological dysfunction in miMNs, demonstrating its neuroprotective effect that was also found in the glutamate-induced miMN neurotoxicity model.
Guided by the transcriptomic analysis, we show a previously unrecognized effect of edaravone to induce the GDNF receptor RET and the GDNF/RET neurotrophic signaling in vitro and in vivo, suggesting a clinically translatable strategy to activate this key neuroprotective signaling.
Notably, edaravone can replace required neurotrophic factors (BDNF and GDNF) to support long-term miMN survival and maturation, further supporting the neurotrophic function of edaravone-activated signaling.
Furthermore, we show that edaravone and GDNF combined treatment more effectively protects miMNs from H_2O_2-induced neurotoxicity than single treatment, suggesting a potential combination strategy for ALS treatment.
Conclusions This study provides methodology to facilitate iPSC differentiation and disease modeling.
Our discoveries will facilitate the development of optimal edaravone-based therapies for ALS and potentially other neurodegenerative diseases.
Graphical abstract
Li, Qian,Feng, Yi,Xue, Yingchao,Zhan, Xiping,Fu, Yi,Gui, Gege,Zhou, Weiqiang,Richard, Jean-Philippe,Taga, Arens,Li, Pan,Mao, Xiaobo,Maragakis, Nicholas J.,Ying, Mingyao, 2022, Edaravone activates the GDNF/RET neurotrophic signaling pathway and protects mRNA-induced motor neurons from iPS cells, BioMed Central
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