Allogeneic modified bone marrow-derived mesenchymal stromal/stem cells (hMSC-SB623 cells) are in clinical development for the treatment of chronic motor deficits after traumatic brain injury and cerebral ischemic stroke. However, their exact mechanisms of action remain unclear. Here, we investigated the effects of this cell therapy on cortical network excitability, brain tissue and peripheral blood at a chronic stage after ischemic stroke in a rat model. One month after focal cortical ischemic stroke, hMSC-SB623 cells or the vehicle solution were injected into the peri-stroke cortex. Starting one-week post-treatment, cortical excitability was assessed ex vivo. hMSC-SB623 cell transplants reduced stroke-induced cortical hyperexcitability, restoring cortical excitability to control levels. Histology of brain tissue revealed an increase of factors relevant to neuroregeneration and synaptic and cellular plasticity. Whole-blood RNA sequencing and serum protein analyses showed that intracortical hMSC-SB623 cell transplantation reversed effects of stroke on peripheral blood factors known to be involved in stroke pathophysiology. Our findings demonstrate that intra-cortical transplants of hMSC-SB623 cells correct stroke-induced circuit disruptions even at the chronic stage, suggesting broad utility as a therapeutic for neurological conditions with network hyperexcitability. Additionally, the transplanted cells exert far-reaching immunomodulatory effects whose therapeutic impact remains to be explored.

中文翻译：

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改良的人间充质基质/干细胞在大鼠局灶性缺血性中风后恢复皮质兴奋性。


同种异体修饰骨髓来源的间充质基质/干细胞 （hMSC-SB623 细胞） 正在临床开发中，用于治疗创伤性脑损伤和脑缺血性中风后的慢性运动缺陷。然而，它们的确切作用机制仍不清楚。在这里，我们研究了这种细胞疗法对大鼠模型中缺血性中风后慢性期皮层网络兴奋性、脑组织和外周血的影响。局灶性皮质缺血性卒中后 1 个月，将 hMSC-SB623 细胞或载体溶液注射到卒中周围皮层。从治疗后 1 周开始，体外评估皮质兴奋性。hMSC-SB623 细胞移植降低了中风诱导的皮质过度兴奋，将皮质兴奋恢复到控制水平。脑组织学显示与神经再生、突触和细胞可塑性相关的因素增加。全血 RNA 测序和血清蛋白分析显示，皮质内 hMSC-SB623 细胞移植逆转了中风对已知参与中风病理生理学的外周血因子的影响。我们的研究结果表明，hMSC-SB623 细胞的皮质内移植即使在慢性阶段也能纠正中风诱导的回路中断，这表明作为网络过度兴奋的神经系统疾病的治疗方法具有广泛的用途。此外，移植的细胞发挥了深远的免疫调节作用，其治疗效果仍有待探索。