Klein Barbara, Ciesielska Agnieszka, Losada Patricia Morán, Sato Anna, Shah-Morales Sajita, Ford Jeremy B, Higashikubo Bryan, Tager Dale, Urry Alexander, Bombosch Juliane, Chang Wei-Cheng, Andrews-Zwilling Yaisa, Nejadnik Bijan, Warraich Zuha, Paz Jeanne T
SanBio, Inc., Oakland, CA, USA.
Gladstone Institute of Neurological Disease, San Francisco, CA, USA; University of California, San Francisco, Department of Neurology, and the Kavli Institute for Fundamental Neuroscience, San Francisco, CA, USA.
Mol Ther. 2025 Jan 8;33(1):375-400. doi: 10.1016/j.ymthe.2024.12.006. Epub 2024 Dec 11.
Allogeneic modified bone marrow-derived human 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 after treatment, cortical excitability was assessed ex vivo. hMSC-SB623 cell transplants reduced stroke-induced cortical hyperexcitability, restoring cortical excitability to control levels. The 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 intra-cortical 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 usefulness 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.
异体修饰的骨髓源人间充质基质/干细胞（hMSC-SB623细胞）正在进行临床试验，用于治疗创伤性脑损伤和脑缺血性中风后的慢性运动功能障碍。然而，其确切的作用机制仍不清楚。在此，我们在大鼠缺血性中风模型的慢性期，研究了这种细胞疗法对皮质网络兴奋性、脑组织和外周血的影响。局灶性皮质缺血性中风一个月后，将hMSC-SB623细胞或赋形剂溶液注入中风周围皮质。治疗一周后开始，离体评估皮质兴奋性。hMSC-SB623细胞移植减轻了中风诱导的皮质过度兴奋性，将皮质兴奋性恢复到对照水平。脑组织的组织学检查显示，与神经再生、突触和细胞可塑性相关的因子增加。全血RNA测序和血清蛋白分析表明，皮质内hMSC-SB623细胞移植逆转了中风对外周血中已知参与中风病理生理学的因子的影响。我们的研究结果表明，即使在慢性期，皮质内移植hMSC-SB623细胞也能纠正中风诱导的回路破坏，这表明其作为一种治疗具有网络过度兴奋性的神经疾病的疗法具有广泛的应用前景。此外，移植细胞具有深远的免疫调节作用，其治疗效果仍有待探索。
