Progranulin enhances the engraftment of transplanted human iPS cell-derived cerebral neurons.

IF 5.4 2区 医学 Q1 CELL & TISSUE ENGINEERING Stem Cells Translational Medicine Pub Date : 2024-11-12 DOI:10.1093/stcltm/szae066
Keitaro Yamagami, Bumpei Samata, Daisuke Doi, Ryosuke Tsuchimochi, Tetsuhiro Kikuchi, Naoya Amimoto, Megumi Ikeda, Koji Yoshimoto, Jun Takahashi
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Abstract

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.

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Progranulin能增强移植的人类iPS细胞衍生脑神经元的移植。
细胞替代疗法中的脑组织器官(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。移植的成功有赖于移植物的有效移植和神经元的延伸。早前的研究已经验证了将移植过程延迟一周的有效性。在此,我们假设脑外伤一周后的脑组织与刚受伤时相比,拥有更有利于细胞移植的环境。我们进行了转录组比较,以区分这两种时间状态下的基因表达。在受控体外条件下,重组人原粒细胞素(rhPGRN)提高了来源于人类诱导多能干细胞的COs(hiPSC-COs)的离体神经元在氧化应激增强条件下的存活率。存活率的提高归因于通过Akt磷酸化减少了细胞凋亡。此外,rhPGRN 在体内移植实验前的预处理大大提高了 hiPSC-COs 的移植效率,并促进了神经元沿宿主大脑皮质脊髓束的伸长。随后在移植后 3 个月进行的组织学评估显示,rhPGRN 处理组中移植物衍生的大脑下投射神经元(重建神经回路的关键元素)数量增加。这些结果凸显了 PGRN 作为一种神经营养因子的潜力,适合纳入基于 hiPSC-CO 的细胞疗法。
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来源期刊
Stem Cells Translational Medicine
Stem Cells Translational Medicine CELL & TISSUE ENGINEERING-
CiteScore
12.90
自引率
3.30%
发文量
140
审稿时长
6-12 weeks
期刊介绍: STEM CELLS Translational Medicine is a monthly, peer-reviewed, largely online, open access journal. STEM CELLS Translational Medicine works to advance the utilization of cells for clinical therapy. By bridging stem cell molecular and biological research and helping speed translations of emerging lab discoveries into clinical trials, STEM CELLS Translational Medicine will help move applications of these critical investigations closer to accepted best patient practices and ultimately improve outcomes. The journal encourages original research articles and concise reviews describing laboratory investigations of stem cells, including their characterization and manipulation, and the translation of their clinical aspects of from the bench to patient care. STEM CELLS Translational Medicine covers all aspects of translational cell studies, including bench research, first-in-human case studies, and relevant clinical trials.
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