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人诱导多能干细胞源性神经嵴干细胞移植到小鼠小脑后，供体细胞来源的神经元和旁观者效应可维持 6 个月。

Graft-derived neurons and bystander effects are maintained for six months after human iPSC-derived NESC transplantation in mice's cerebella.

机构信息

Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.

Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal.

出版信息

Sci Rep. 2024 Feb 8;14(1):3236. doi: 10.1038/s41598-024-53542-x.

DOI:10.1038/s41598-024-53542-x
PMID:38332227
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10853537/
Abstract

Machado-Joseph disease (MJD) is a neurodegenerative disorder characterized by widespread neuronal death affecting the cerebellum. Cell therapy can trigger neuronal replacement and neuroprotection through bystander effects providing a therapeutic option for neurodegenerative diseases. Here, human control (CNT) and MJD iPSC-derived neuroepithelial stem cells (NESC) were established and tested for their therapeutic potential. Cells' neuroectodermal phenotype was demonstrated. Brain organoids obtained from the Control NESC showed higher mRNA levels of genes related to stem cells' bystander effects, such as BDNF, NEUROD1, and NOTCH1, as compared with organoids produced from MJD NESC, suggesting that Control NESC have a higher therapeutic potential. Graft-derived glia and neurons, such as cells positive for markers of cerebellar neurons, were detected six months after NESC transplantation in mice cerebella. The graft-derived neurons established excitatory and inhibitory synapses in the host cerebella, although CNT neurons exhibited higher excitatory synapse numbers compared with MJD neurons. Cell grafts, mainly CNT NESC, sustained the bystander effects through modulation of inflammatory interleukins (IL1B and IL10), neurotrophic factors (NGF), and neurogenesis-related proteins (Msi1 and NeuroD1), for six months in the mice cerebella. Altogether this study demonstrates the long-lasting therapeutic potential of human iPSC-derived NESC in the cerebellum.

摘要

马查多-约瑟夫病（MJD）是一种神经退行性疾病，其特征是广泛的神经元死亡，影响小脑。细胞疗法可以通过旁观者效应触发神经元替代和神经保护，为神经退行性疾病提供治疗选择。在这里，建立了人对照（CNT）和 MJD iPSC 衍生的神经上皮干细胞（NESC），并测试了它们的治疗潜力。细胞的神经外胚层表型得到了证明。与源自 MJD NESC 的类器官相比，来自对照 NESC 的脑类器官显示出更高的与干细胞旁观者效应相关的基因的 mRNA 水平，例如 BDNF、NEUROD1 和 NOTCH1，这表明对照 NESC 具有更高的治疗潜力。移植后 6 个月，在小鼠小脑中检测到源自 NESC 的移植物衍生的神经胶质和神经元，例如对小脑神经元标志物呈阳性的细胞。移植的神经元在宿主小脑内建立了兴奋性和抑制性突触，尽管 CNT 神经元的兴奋性突触数量高于 MJD 神经元。细胞移植物，主要是 CNT NESC，通过调节炎症细胞因子（IL1B 和 IL10）、神经营养因子（NGF）和神经发生相关蛋白（Msi1 和 NeuroD1），在小鼠小脑内持续发挥旁观者效应 6 个月。总之，这项研究表明，源自人类 iPSC 的 NESC 在小脑中有持久的治疗潜力。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2e36/10853537/f5dbb75539e2/41598_2024_53542_Fig8_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2e36/10853537/f5dbb75539e2/41598_2024_53542_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2e36/10853537/932d92a0e50d/41598_2024_53542_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2e36/10853537/03a64911fb48/41598_2024_53542_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2e36/10853537/8a59310eecbd/41598_2024_53542_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2e36/10853537/32af7561e8d2/41598_2024_53542_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2e36/10853537/6a5a5fd6c5b1/41598_2024_53542_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2e36/10853537/c7a3db74896a/41598_2024_53542_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2e36/10853537/9cbe2e4a18fa/41598_2024_53542_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2e36/10853537/f5dbb75539e2/41598_2024_53542_Fig8_HTML.jpg

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