Targeting connexin 43 expression via scaffold mediated delivery of antisense oligodeoxynucleotide preserves neurons, enhances axonal extension, reduces astrocyte and microglial activation after spinal cord injury.

IF 6.7 1区 工程技术 Q1 CELL & TISSUE ENGINEERING Journal of Tissue Engineering Pub Date : 2023-01-01 DOI:10.1177/20417314221145789
Jiah Shin Chin, Ulla Milbreta, David L Becker, Sing Yian Chew
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引用次数: 1

Abstract

Injury to the central nervous system (CNS) provokes an inflammatory reaction and secondary damage that result in further tissue damage and destruction of neurons away from the injury site. Upon injury, expression of connexin 43 (Cx43), a gap junction protein, upregulates and is responsible for the spread and amplification of cell death signals through these gap junctions. In this study, we hypothesise that the downregulation of Cx43 by scaffold-mediated controlled delivery of antisense oligodeoxynucleotide (asODN), would minimise secondary injuries and cell death, and thereby support tissue regeneration after nerve injuries. Specifically, using spinal cord injury (SCI) as a proof-of-principle, we utilised a fibre-hydrogel scaffold for sustained delivery of Cx43asODN, while providing synergistic topographical cues to guide axonal ingrowth. Correspondingly, scaffolds loaded with Cx43asODN, in the presence of NT-3, suppressed Cx43 up-regulation after complete transection SCI in rats. These scaffolds facilitated the sustained release of Cx43asODN for up to 25 days. Importantly, asODN treatment preserved neurons around the injury site, promoted axonal extension, decreased glial scarring, and reduced microglial activation after SCI. Our results suggest that implantation of such scaffold-mediated asODN delivery platform could serve as an effective alternative SCI therapeutic approach.

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通过支架介导的反义寡脱氧核苷酸递送靶向连接蛋白43的表达,保护神经元,增强轴突延伸,减少脊髓损伤后星形胶质细胞和小胶质细胞的激活。
中枢神经系统(CNS)损伤引起炎症反应和继发性损伤,导致进一步的组织损伤和远离损伤部位的神经元破坏。损伤后,一种间隙连接蛋白connexin 43 (Cx43)的表达上调,并负责通过这些间隙连接传播和扩增细胞死亡信号。在这项研究中,我们假设通过支架介导的反义寡脱氧核苷酸(asODN)的控制递送下调Cx43,可以最大限度地减少继发性损伤和细胞死亡,从而支持神经损伤后的组织再生。具体来说,利用脊髓损伤(SCI)作为原理证明,我们利用纤维-水凝胶支架持续递送Cx43asODN,同时提供协同的地形线索来引导轴突长进。相应的,在NT-3存在的情况下,负载Cx43asODN的支架可以抑制大鼠完全性脊髓损伤后Cx43的上调。这些支架促进Cx43asODN的持续释放长达25天。重要的是,asODN处理保存了损伤部位周围的神经元,促进了轴突延伸,减少了神经胶质瘢痕,减少了脊髓损伤后的小胶质细胞激活。我们的研究结果表明,植入这种支架介导的asODN传递平台可以作为一种有效的替代SCI治疗方法。
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来源期刊
Journal of Tissue Engineering
Journal of Tissue Engineering Engineering-Biomedical Engineering
CiteScore
11.60
自引率
4.90%
发文量
52
审稿时长
12 weeks
期刊介绍: The Journal of Tissue Engineering (JTE) is a peer-reviewed, open-access journal dedicated to scientific research in the field of tissue engineering and its clinical applications. Our journal encompasses a wide range of interests, from the fundamental aspects of stem cells and progenitor cells, including their expansion to viable numbers, to an in-depth understanding of their differentiation processes. Join us in exploring the latest advancements in tissue engineering and its clinical translation.
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