细胞替代疗法中的脑类器官（CO）为中风或脑外伤患者重建神经回路提供了一种可行的方法。成功的移植依赖于移植物的有效植入和神经突延伸。早期研究已经验证了将移植手术推迟 1 周的有效性。在这里，我们假设与损伤后立即相比，创伤性脑损伤后 1 周的脑组织具有更有利的细胞移植环境。我们进行了转录组比较，以区分这两种时间状态之间的基因表达。在受控的体外条件下，重组人颗粒体蛋白前体 (rhPGRN) 在氧化应激增强的条件下提高了源自人诱导多能干细胞衍生 CO (hiPSC-CO) 的分离神经元的存活率。活力的增加归因于 Akt 磷酸化导致的细胞凋亡减少。此外，体内移植实验前的rhPGRN预处理显着提高了hiPSC-CO的植入效率，并促进沿宿主大脑皮质脊髓束的神经突伸长。移植后 3 个月的后续组织学评估显示，在 rhPGRN 治疗组中，移植物来源的大脑下投射神经元（重建神经回路的关键要素）的存在量有所增加。这些结果凸显了 PGRN 作为适合纳入基于 hiPSC-CO 的细胞疗法的神经营养因子的潜力。© 作者 2024。由牛津大学出版社出版。

Cerebral organoids (COs) in cell replacement therapy offer a viable approach to reconstructing neural circuits for individuals suffering from stroke or traumatic brain injuries. Successful transplantation relies on effective engraftment and neurite extension from the grafts. Earlier research has validated the effectiveness of delaying the transplantation procedure by 1 week. Here, we hypothesized that brain tissues 1 week following a traumatic brain injury possess a more favorable environment for cell transplantation when compared to immediately after injury. We performed a transcriptomic comparison to differentiate gene expression between these 2 temporal states. In controlled in vitro conditions, recombinant human progranulin (rhPGRN) bolstered the survival rate of dissociated neurons sourced from human induced pluripotent stem cell-derived COs (hiPSC-COs) under conditions of enhanced oxidative stress. This increase in viability was attributable to a reduction in apoptosis via Akt phosphorylation. In addition, rhPGRN pretreatment before in vivo transplantation experiments augmented the engraftment efficiency of hiPSC-COs considerably and facilitated neurite elongation along the host brain's corticospinal tracts. Subsequent histological assessments at 3 months post-transplantation revealed an elevated presence of graft-derived subcerebral projection neurons-crucial elements for reconstituting neural circuits-in the rhPGRN-treated group. These outcomes highlight the potential of PGRN as a neurotrophic factor suitable for incorporation into hiPSC-CO-based cell therapies.© The Author(s) 2024. Published by Oxford University Press.