Livingston Jessica M, Lee Tina T, Enbar Tom, Daniele Emerson, Phillips Clara M, Krassikova Alexandra, Bang K W Annie, Kortebi Ines, Donville Brennan W, Ibragimov Omadyor S, Sachewsky Nadia, Lozano Casasbuenas Daniela, Olfat Arman, Morshead Cindi M
Department of Surgery, Division of Anatomy, 1 King's College Circle, University of Toronto, Toronto, ON M5S 1A8, Canada.
Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, 160 College Street, Toronto, ON M5S 3E1, Canada.
Biomedicines. 2024 Mar 15;12(3):663. doi: 10.3390/biomedicines12030663.
Stroke is the leading cause of adult disability worldwide. The majority of stroke survivors are left with devastating functional impairments for which few treatment options exist. Recently, a number of studies have used ectopic expression of transcription factors that direct neuronal cell fate with the intention of converting astrocytes to neurons in various models of brain injury and disease. While there have been reports that question whether astrocyte-to-neuron conversion occurs in vivo, here, we have asked if ectopic expression of the transcription factor is sufficient to promote improved functional outcomes when delivered in the subacute phase following endothelin-1-induced sensory-motor cortex stroke. We used an adeno-associated virus to deliver from the short GFAP promoter and demonstrated improved functional outcomes as early as 28 days post-stroke and persisting to at least 63 days post-stroke. Using -based cell fate tracking, we showed that functional recovery correlated with the expression of neuronal markers in transduced cells by 28 days post-stroke. By 63 days post-stroke, the reporter-expressing cells comprised ~20% of all the neurons in the perilesional cortex and expressed markers of cortical neuron subtypes. Overall, our findings indicate that ectopic expression of in the stroke-injured brain is sufficient to enhance neural repair.
中风是全球成人残疾的主要原因。大多数中风幸存者都留下了严重的功能障碍，而针对这些障碍的治疗选择很少。最近，一些研究使用了异位表达转录因子来引导神经元细胞命运，目的是在各种脑损伤和疾病模型中将星形胶质细胞转化为神经元。虽然有报道对星形胶质细胞向神经元的转化是否在体内发生提出质疑，但在这里，我们探讨了在内皮素-1诱导的感觉运动皮层中风后的亚急性期递送转录因子的异位表达是否足以促进功能改善。我们使用腺相关病毒从短GFAP启动子递送[转录因子名称缺失]，并证明早在中风后28天就出现了功能改善，并且持续到中风后至少63天。使用基于[追踪方法名称缺失]的细胞命运追踪，我们表明在中风后28天，功能恢复与转导细胞中神经元标记物的表达相关。到中风后63天，表达报告基因的细胞占损伤周围皮层所有神经元的约20%，并表达皮层神经元亚型的标记物。总体而言，我们的研究结果表明，在中风损伤的大脑中异位表达[转录因子名称缺失]足以增强神经修复。
