Abstract
BackgroundSpinal cord injury (SCI) results in glial scar formation and irreversible neuronal loss, which finally leads to functional impairments and long-term disability. Our previous studies have demonstrated that the ectopic expression of Zfp521 reprograms fibroblasts and astrocytes into induced neural stem cells (iNSCs). However, it remains unclear whether treatment with Zfp521 also affects endogenous astrocytes, thus promoting further functional recovery following SCI.MethodsRat astrocytes were transdifferentiated into neural stem cells in vitro by ZFP521 or Sox2. Then, ZFP521 was applied to the spinal cord injury site of a rat. Transduction, real-time PCR, immunohistofluorescence, and function assessments were performed at 6 weeks post-transduction to evaluate improvement and in vivo lineage reprogramming of astrocytes.ResultsHere, we show that Zfp521 is more efficient in reprogramming cultured astrocytes compared with Sox2. In the injured spinal cord of an adult rat, resident astrocytes can be reprogrammed into neurons through a progenitor stage by Zfp521. Importantly, this treatment improves the functional abilities of the rats as evaluated by the Basso, Beattie, and Bresnahan (BBB) locomotor rating scale and further by calculation of its subscores. There was enhanced locomotor activity in the hind limbs, step length, toe spread, foot length, and paw area. In addition, motor evoked potential recordings demonstrated the functional integrity of the spinal cord.ConclusionsThese results have indicated that the generation of iNSCs or neurons from endogenous astrocytes by in situ reprogramming might be a potential strategy for SCI repair.Graphical abstract
Highlights
Spinal cord injury (SCI) is a devastating condition that leads to severe motor, sensory, and autonomic dysfunction below the point of injury [1]
Motor evoked potential recordings demonstrated the functional integrity of the spinal cord. These results have indicated that the generation of induced neural stem cells (iNSCs) or neurons from endogenous astrocytes by in situ reprogramming might be a potential strategy for SCI repair
Establishment of expandable induced neural stem cells from adult rat astrocytes in vitro Extracted astrocytes expressed astrocyte markers S100β and glial fibrillary acidic protein (Gfap), but not neuronal and/or NSC markers Sox2, Nestin, Doublecortin (Dcx; a microtubule-associated protein that is broadly expressed in neuroblasts and immature neurons), and β-tubulin III (Tuj1; a panneuronal marker) at the RNA and protein levels (Additional file 1: Figure S1)
Summary
Spinal cord injury (SCI) is a devastating condition that leads to severe motor, sensory, and autonomic dysfunction below the point of injury [1]. In order to improve recovery following SCI, different strategies under consideration include providing tissue protection, modulating circuit reorganization, or regulating neural bridging connectivity across lesions (for review see [2, 3]). Our previous studies have demonstrated that the ectopic expression of Zfp521 reprograms fibroblasts and astrocytes into induced neural stem cells (iNSCs) It remains unclear whether treatment with Zfp521 affects endogenous astrocytes, promoting further functional recovery following SCI
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