2. Academic Validation
  3. Neurons derived from NeuroD1-expressing astrocytes transition through transit-amplifying intermediates but lack functional maturity

Neurons derived from NeuroD1-expressing astrocytes transition through transit-amplifying intermediates but lack functional maturity

  • Sci Adv. 2025 Jul 25;11(30):eadw9296. doi: 10.1126/sciadv.adw9296.
Fangbing Chen 1,  Xi Liu 2,  Xiaowen Zhong 3,  Xiaoqing Chen 4,  Eva Nicholson 3,  Kaiyi Liu 1,  Huiyao Chen 5,  Yifeng Lin 1,  Yousheng Shu 6,  Wenhao Zhou 7 8,  Carol J Schuurmans 9,  Q Richard Lu 3
Affiliations

Affiliations

  • 1 Institute of Pediatrics, Children's Hospital of Fudan University, Shanghai 201102, China.
  • 2 Institute for Translational Brain Research, Department of Neurosurgery, Jinshan Hospital, Fudan University, Shanghai 200433, China.
  • 3 Department of Pediatrics, Brain Tumor Center, Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
  • 4 Departments of Neonatology, International Peace Maternity and Children Hospital of China Welfare Institution, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China.
  • 5 Center for Molecular Medicine, Children's Hospital of Fudan University, Shanghai 201102, China.
  • 6 Institute for Translational Brain Research, Department of Neurology, Huashan Hospital, Fudan University, Shanghai 200031, China.
  • 7 Key Laboratory of Birth Defects, Children's Hospital of Fudan University, Shanghai 201102, China.
  • 8 Division of Neonatology and Center for Newborn Care, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 511400, China.
  • 9 Sunnybrook Research Institute, Department of Biochemistry, University of Toronto, Toronto, ON, Canada.
PMID: 40712017 DOI: 10.1126/sciadv.adw9296
Abstract

In vivo conversion of nonneuronal cells into neurons is a proposed strategy to replace neurons lost to CNS injury or disease. Glia-to-neuron trans-differentiation by viral vector-mediated GFAP mini-promoter-driven NeuroD1 remains hotly debated. Developing inducible, lineage-traceable transgenic mice, we find that astrocyte-to-neuron conversion is restricted to a specific time window within the lesion core of injured spinal cord and brain. Spatiotemporal lineage-mapping combined with single-cell transcriptomics reveals that ectopic NeuroD1 induces astrocyte-to-neuron conversion specifically in lesion cores via transit-amplifying OLIG2+ progenitors during early injury phase, but not in late phases or in nonreactive astrocytes. Neither a loss-of-function NeuroD1 mutant nor stemness-reprogramming factor SOX2 induces astrocyte-to-neuron conversion. However, contrary to previous reports, the neuronal-like cells generated by NeuroD1 lack mature neuroelectrical properties, limiting their functional integration into neural circuits. Together, our findings establish a spatiotemporal framework for NeuroD1-driven glia-to-neuron conversion, revealing a mechanistic shift from direct astrocyte conversion toward transit-amplifying intermediates and highlighting the functional immaturity of NeuroD1-converted neurons.

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