Department of Stem Cell Biology and Regenerative Medicine, Beckman Research Institute, City of Hope, 1500 East Duarte Road, Duarte, CA, 91010, USA.
Division of Mathematical Oncology and Computational Systems Biology, Department of Computational and Quantitative Medicine, Beckman Research Institute, City of Hope, Duarte, CA, USA.
Sci Rep. 2023 Oct 19;13(1):17874. doi: 10.1038/s41598-023-44426-7.
Efficacious stem cell-based therapies for traumatic brain injury (TBI) depend on successful delivery, migration, and engraftment of stem cells to induce neuroprotection. L-myc expressing human neural stem cells (LMNSC008) demonstrate an inherent tropism to injury sites after intranasal (IN) administration. We hypothesize that IN delivered LMNSC008 cells migrate to primary and secondary injury sites and modulate biomarkers associated with neuroprotection and tissue regeneration. To test this hypothesis, immunocompetent adult female rats received either controlled cortical impact injury or sham surgery. LMNSC008 cells or a vehicle were administered IN on postoperative days 7, 9, 11, 13, 15, and 17. The distribution and migration of eGFP-expressing LMNSC008 cells were quantified over 1 mm-thick optically cleared (CLARITY) coronal brain sections from TBI and SHAM controls. NSC migration was observed along white matter tracts projecting toward the hippocampus and regions of TBI. ELISA and Nanostring assays revealed a shift in tissue gene expression in LMNSC008 treated rats relative to controls. LMNSC008 treatment reduced expression of genes and pathways involved in inflammatory response, microglial function, and various cytokines and receptors. Our proof-of-concept studies, although preliminary, support the rationale of using intranasal delivery of LMNSC008 cells for functional studies in preclinical models of TBI and provide support for potential translatability in TBI patients.
有效的基于干细胞的创伤性脑损伤 (TBI) 治疗依赖于干细胞的成功传递、迁移和植入，以诱导神经保护。表达 L-myc 的人神经干细胞 (LMNSC008) 在经鼻 (IN) 给药后表现出对损伤部位的固有趋向性。我们假设 IN 递送的 LMNSC008 细胞迁移到原发性和继发性损伤部位，并调节与神经保护和组织再生相关的生物标志物。为了验证这一假设，免疫功能正常的成年雌性大鼠接受了皮质控制冲击损伤或假手术。在术后第 7、9、11、13、15 和 17 天，LMNSC008 细胞或载体通过 IN 给药。在 TBI 和 SHAM 对照的 1mm 厚光学清除 (CLARITY) 冠状脑切片上，定量了表达 eGFP 的 LMNSC008 细胞的分布和迁移。NSC 迁移沿着投射到海马体和 TBI 区域的白质束观察到。ELISA 和 Nanostring 分析显示，与对照组相比，LMNSC008 处理的大鼠组织基因表达发生了变化。LMNSC008 治疗降低了与炎症反应、小胶质细胞功能和各种细胞因子和受体相关的基因和途径的表达。虽然我们的概念验证研究尚属初步，但支持了使用 IN 递送 LMNSC008 细胞进行 TBI 临床前模型功能研究的原理，并为 TBI 患者的潜在转化提供了支持。
