Reprogramming astrocytes to motor neurons by activation of endogenous Ngn2 and Isl1

Stem Cell Reports, 2021 · DOI: https://doi.org/10.1016/j.stemcr.2021.05.020 · Published: July 13, 2021

Regenerative Medicine Neurology Genetics

Simple Explanation

This study explores a new approach to generate motor neurons (MNs) from other cell types, like astrocytes and fibroblasts, which could be used to treat neurodegenerative diseases and spinal cord injuries. The researchers used CRISPR activation (CRISPRa) system to activate two genes, Ngn2 and Isl1, inside the cells. This activation process reprogrammed the cells into functional motor neurons. The induced motor neurons (iMNs) showed typical characteristics of MNs, including their shape, electrical activity, and ability to form connections with other neurons.

Study Duration

Not specified

Participants

Mouse spinal astrocytes and embryonic fibroblasts

Evidence Level

Not specified

Key Findings

1
Activation of endogenous Ngn2 and Isl1 via CRISPRa successfully reprogrammed mouse spinal astrocytes and embryonic fibroblasts into motor neurons in vitro.
2
The induced motor neurons (iMNs) exhibited electrophysiological activities and motor neuronal morphology, indicating their functionality.
3
Astrocytes in the spinal cord of adult mice could be converted into motor neurons with high efficiency using this approach.

Research Summary

This study demonstrates that activation of endogenous genes Ngn2 and Isl1 by CRISPRa enabled reprogramming of mouse spinal astrocytes and embryonic ﬁbroblasts to motor neurons. These induced neurons showed motor neuronal morphology and exhibited electrophysiological activities. The activation of endogenous genes is sufﬁcient to induce astrocytes into functional motor neurons in vitro and in vivo.

Practical Implications

Therapeutic Strategy

This direct neuronal reprogramming approach may provide a novel potential therapeutic strategy for treating neurodegenerative diseases and spinal cord injury.

Disease Modeling

The generation of patient-specific MNs can be used in regenerative medicine as well as disease-related studies. This conversion of patients’ endogenous glial cells or ﬁbroblasts to MNs, may also help to establish a cellular model for MN-related diseases.

Drug Development

The directly transformed specific neurons may be valuable for disease modeling and drug identification of late-onset human nervous system diseases.

Study Limitations

1
Possibility that other MN-inducing factors are overlooked.
2
Converting efficiency and accuracy could be further improved by changing the mixture of the TF.
3
Whether the induced neurons can integrate into neural circuits and rescue the functional defects in vivo, remains to be solved.

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