Schantz Sarah L, Sneed Sydney E, Fagan Madison M, Golan Morgane E, Cheek Savannah R, Kinder Holly A, Duberstein Kylee J, Kaiser Erin E, West Franklin D
Regenerative Bioscience Center, University of Georgia, Athens, GA 30602, USA.
Biomedical and Health Sciences Institute, University of Georgia, Athens, GA 30602, USA.
Biomedicines. 2024 Jul 25;12(8):1663. doi: 10.3390/biomedicines12081663.
Traumatic brain injury (TBI) is a leading cause of death and disability in pediatric patients and often results in delayed neural development and altered connectivity, leading to lifelong learning, memory, behavior, and motor function deficits. Induced pluripotent stem cell-derived neural stem cells (iNSCs) may serve as a novel multimodal therapeutic as iNSCs possess neuroprotective, regenerative, and cell-replacement capabilities post-TBI. In this study, we evaluated the effects of iNSC treatment on cellular, tissue, and functional recovery in a translational controlled cortical impact TBI piglet model. Five days post-craniectomy (n = 6) or TBI (n = 18), iNSCs (n = 7) or PBS (n = 11) were injected into perilesional brain tissue. Modified Rankin Scale (mRS) neurological evaluation, magnetic resonance imaging, and immunohistochemistry were performed over the 12-week study period. At 12-weeks post-transplantation, iNSCs showed long-term engraftment and differentiation into neurons, astrocytes, and oligodendrocytes. iNSC treatment enhanced endogenous neuroprotective and regenerative activities indicated by decreasing intracerebral immune responses, preserving endogenous neurons, and increasing neuroblast formation. These cellular changes corresponded with decreased hemispheric atrophy, midline shift, and lesion volume as well as the preservation of cerebral blood flow. iNSC treatment increased piglet survival and decreased mRS scores. The results of this study in a predictive pediatric large-animal pig model demonstrate that iNSC treatment is a robust multimodal therapeutic that has significant promise in potentially treating human pediatric TBI patients.
创伤性脑损伤（TBI）是儿科患者死亡和残疾的主要原因，常导致神经发育延迟和连接改变，进而导致终身学习、记忆、行为和运动功能缺陷。诱导多能干细胞衍生的神经干细胞（iNSCs）可能作为一种新型的多模式治疗方法，因为iNSCs在TBI后具有神经保护、再生和细胞替代能力。在本研究中，我们在一个转化性控制皮质撞击TBI仔猪模型中评估了iNSC治疗对细胞、组织和功能恢复的影响。颅骨切除术后5天（n = 6）或TBI后5天（n = 18），将iNSCs（n = 7）或PBS（n = 11）注入损伤周围脑组织。在为期12周的研究期间进行改良Rankin量表（mRS）神经学评估、磁共振成像和免疫组织化学。移植后12周，iNSCs显示出长期植入并分化为神经元、星形胶质细胞和少突胶质细胞。iNSC治疗增强了内源性神经保护和再生活性，表现为脑内免疫反应降低、内源性神经元得以保留以及神经母细胞形成增加。这些细胞变化与半球萎缩、中线移位和病变体积减小以及脑血流量的保留相对应。iNSC治疗提高了仔猪存活率并降低了mRS评分。这项在具有预测性的儿科大型动物猪模型中的研究结果表明，iNSC治疗是一种强大的多模式治疗方法，在潜在治疗人类儿科TBI患者方面具有重大前景。
