Neurons derived from NeuroD1-expressing astrocytes transition through transit-amplifying intermediates but lack
Fangbing Chen1, Xi Liu2, Xiaowen Zhong3
1Institute of Pediatrics, Children's Hospital of Fudan University, Shanghai 201102, China.
Science Advances
|July 25, 2025
Summary
NeuroD1 can convert glial cells into neurons in the brain after injury, but only during a specific window and the new neurons lack mature electrical properties, limiting functional integration.
Area of Science:
- Neuroscience
- Stem Cell Biology
- Regenerative Medicine
Background:
- In vivo conversion of nonneuronal cells into neurons is a promising strategy for treating central nervous system (CNS) injury or disease.
- Glia-to-neuron trans-differentiation using viral vector-mediated NeuroD1 is a debated approach.
Purpose of the Study:
- To investigate the spatiotemporal dynamics and mechanistic basis of astrocyte-to-neuron conversion in vivo.
- To assess the functional properties of NeuroD1-generated neurons.
Main Methods:
- Development of inducible, lineage-traceable transgenic mice.
- Spatiotemporal lineage-mapping.
- Single-cell transcriptomics.
- Assessment of neuroelectrical properties.
Main Results:
- Astrocyte-to-neuron conversion occurs within a specific time window in the lesion core of injured spinal cord and brain.
- NeuroD1 induces conversion via transit-amplifying OLIG2+ progenitors during the early injury phase, not in late phases or nonreactive astrocytes.
- NeuroD1-generated neuronal-like cells exhibit immature neuroelectrical properties, hindering functional integration.
- Loss-of-function NeuroD1 mutant and SOX2 did not induce astrocyte-to-neuron conversion.
Conclusions:
- NeuroD1-driven glia-to-neuron conversion is restricted spatiotemporally and mechanistically involves transit-amplifying intermediates.
- The functional immaturity of converted neurons poses a significant limitation for neural circuit integration and therapeutic application.
