Neural Regeneration Research ›› 2026, Vol. 21 ›› Issue (8): 3730-3740.doi: 10.4103/NRR.NRR-D-24-01535

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ID3-depleted human induced pluripotent stem cell–derived neural stem/progenitor cells promote neurorepair

Jia-Di Lin1, 2, Ruba Hammad2, 3, Prateek Kumar4, Pedro Manzitti1, Kexin Wu1, Jamal Alzubi5, 6, Andreas Vlachos7, 8, 9, Toni Cathomen3, 5, Armin Blesch4, Yu-Hsuan Chu1, 2, *, Christian Schachtrup1, 9, *   

  1. 1Institute of Anatomy and Cell Biology, Faculty of Medicine, University of Freiburg, Freiburg, Germany; 
    2Faculty of Biology, University of Freiburg, Freiburg, Germany; 
    3Freiburg iPS Core, Institute for Transfusion Medicine and Gene Therapy, Medical Center - University of Freiburg, Freiburg, Germany; 
    4Department of Neurosciences, Center for Neural Repair, University of California, San Diego, La Jolla, CA, USA and VA San Diego Healthcare System, San Diego, CA, USA; 
    5Center for Chronic Immunodeficiency, Faculty of Medicine, University of Freiburg, Freiburg, Germany; 
    6Department of Haematooncology, Faculty of Medicine, University of Ostrava, Ostrava, Czech Republic; 
    7Department of Neuroanatomy, Institute of Anatomy and Cell Biology, Faculty of Medicine, University of Freiburg, Freiburg, Germany; 
    8BrainLinks–BrainTools Center, University of Freiburg, Freiburg, Germany; 
    9Center for Basics in NeuroModulation, Faculty of Medicine, University of Freiburg, Freiburg, Germany
  • Online:2026-08-18 Published:2026-04-27
  • Contact: Christian Schachtrup, PhD, christian.schachtrup@anat.uni-freiburg.de; Yu-Hsuan Chu, PhD, yu-hsuan.chu@anat.uni-freiburg.de.
  • Supported by:
    This study was supported by a Fill in the Gap fellowship (Medical Faculty Freiburg) (to JDL); a Fritz Thyssen Stiftung grant, a European Stroke Research Foundation (ESRF) grant, a Wings for Life foundation grant and the DFG grants SCHA 1442/8‐1, SCHA 1442/8‐3, and SCHA 1442/9‐1 (to CS).

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Abstract:

Human induced pluripotent stem cell–derived neural stem/progenitor cells are used in cell-replacement and regenerative therapeutic strategies after traumatic central nervous system injury. Traumatic injury alters the host microenvironment, which in turn affects the functionality of transplanted human neural stem/progenitor cells and potentially limits their benefits for neurorepair. However, the underlying mechanisms through which the host environment alters the fate and functionality of transplanted human neural stem/progenitor cells remain poorly understood. Here, we showed that massive deposition of blood-derived fibrinogen in a mouse model of spinal cord injury contributed to an altered lesion environment. Fibrinogen promoted human neural stem/progenitor cell differentiation into reactive astrocytes by activating the BMP receptor signaling pathway and inducing of the transcriptional regulator inhibitor of DNA binding 3. ID3-depleted human neural stem/progenitor cells, generated by CRISPR/Cas9-mediated genome editing, reduced astrocyte formation in response to astrogenic stimuli. Instead, ID3-depleted human neural stem/progenitor cells had a bipolar, immature glial progenitor cell phenotype. These modified cells secreted extracellular vesicles with a distinct miRNA profile that enhanced neurite outgrowth. We conclude that targeting inhibitor of DNA binding 3 in human neural stem/progenitor cells can beneficially modulate their functionality and cell fate in the injured central nervous system toward glial progenitor cells, potentially enhancing their capacity to promote central nervous system repair.

Key words: astrocyte, CRISPR-Cas9, extracellular vesicles, fibrinogen, human iPSC-derived neural stem/progenitor cell, inhibitor of DNA binding 3 (ID3), microRNA, nerve regeneration, neurite outgrowth, spinal cord