Division of Genetics and Development, Krembil Brain Institute, University Health Network, Toronto, Ontario, Canada.
Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
Stem Cells Transl Med. 2023 Sep 15;12(9):603-616. doi: 10.1093/stcltm/szad044.
Traumatic spinal cord injury (SCI) results in the loss of neurons, oligodendrocytes, and astrocytes. Present interventions for SCI include decompressive surgery, anti-inflammatory therapies, and rehabilitation programs. Nonetheless, these approaches do not offer regenerative solutions to replace the lost cells, fiber tracts, and circuits. Neural stem/progenitor cell (NPC) transplantation is a promising strategy that aims to encourage regeneration. However, NPC differentiation remains inconsistent, thus, contributing to suboptimal functional recovery. As such, we have previously engineered oligodendrogenically biased NPCs (oNPCs) and demonstrated their efficacy in a thoracic model of SCI. Since the majority of patients with SCI experience cervical injuries, our objective in the current study was to generate human induced pluripotent stem cell-derived oNPCs (hiPSC-oNPCs) and to characterize these cells in vitro and in vivo, utilizing a clinically relevant rodent model of cervical SCI. Following transplantation, the oNPCs engrafted, migrated to the rostral and caudal regions of the lesion, and demonstrated preferential differentiation toward oligodendrocytes. Histopathological evaluations revealed that oNPC transplantation facilitated tissue preservation while diminishing astrogliosis. Moreover, oNPC transplantation fostered remyelination of the spared tissue. Functional analyses indicated improved forelimb grip strength, gait, and locomotor function in the oNPC-transplanted rats. Importantly, oNPC transplantation did not exacerbate neuropathic pain or induce tumor formation. In conclusion, these findings underscore the therapeutic potential of oNPCs in promoting functional recovery and histopathological improvements in cervical SCI. This evidence warrants further investigation to optimize and advance this promising cell-based therapeutic approach.
外伤性脊髓损伤（SCI）会导致神经元、少突胶质细胞和星形胶质细胞的丧失。目前针对 SCI 的干预措施包括减压手术、抗炎治疗和康复计划。然而，这些方法并不能提供再生解决方案来替代丢失的细胞、纤维束和回路。神经干细胞/祖细胞（NPC）移植是一种有前途的策略，旨在促进再生。然而，NPC 分化仍然不一致，因此导致功能恢复不理想。正因为如此，我们之前已经对少突胶质细胞偏向性的 NPC（oNPC）进行了工程化改造，并在胸段 SCI 模型中证明了它们的疗效。由于大多数 SCI 患者经历颈段损伤，我们在当前研究中的目标是生成人诱导多能干细胞衍生的 oNPC（hiPSC-oNPC），并利用临床上相关的颈段 SCI 啮齿动物模型对这些细胞进行体外和体内特征分析。移植后，oNPC 移植后可植入、迁移到损伤的头侧和尾侧区域，并表现出向少突胶质细胞的优先分化。组织病理学评估显示，oNPC 移植有助于组织保存，同时减少星形胶质细胞增生。此外，oNPC 移植促进了未受影响组织的髓鞘再生。功能分析表明，oNPC 移植的大鼠前肢握力、步态和运动功能得到改善。重要的是，oNPC 移植不会加重神经病理性疼痛或引起肿瘤形成。总之，这些发现强调了 oNPC 在促进颈段 SCI 功能恢复和组织病理学改善方面的治疗潜力。这一证据需要进一步研究，以优化和推进这种有前途的基于细胞的治疗方法。
