Shultz Robert B, Wang Zhicheng, Nong Jia, Zhang Zhiling, Zhong Yinghui
School of Biomedical Engineering, Science and Health Systems, Drexel University, 3141 Chestnut Street, Philadelphia, PA 19104, United States of America.
J Neural Eng. 2017 Jun;14(3):036014. doi: 10.1088/1741-2552/aa6450. Epub 2017 Mar 30.
Traumatic spinal cord injury (SCI) causes apoptosis of myelin-forming oligodendrocytes (OLs) and demyelination of surviving axons, resulting in conduction failure. Remyelination of surviving denuded axons provides a promising therapeutic target for spinal cord repair. While cell transplantation has demonstrated efficacy in promoting remyelination and functional recovery, the lack of ideal cell sources presents a major obstacle to clinical application. The adult spinal cord contains oligodendrocyte precursor cells and multipotent neural stem/progenitor cells that have the capacity to differentiate into mature, myelinating OLs. However, endogenous oligodendrogenesis and remyelination processes are limited by the upregulation of remyelination-inhibitory molecules in the post-injury microenvironment. Multiple growth factors/molecules have been shown to promote OL differentiation and myelination.
In this study we screened these therapeutics and found that 3, 3', 5-triiodothyronine (T3) is the most effective in promoting oligodendrogenesis and OL maturation in vitro. However, systemic administration of T3 to achieve therapeutic doses in the injured spinal cord is likely to induce hyperthyroidism, resulting in serious side effects.
In this study we developed a novel hydrogel-based drug delivery system for local delivery of T3 to the injury site without eliciting systemic toxicity.
Using a clinically relevant cervical contusion injury model, we demonstrate that local delivery of T3 at doses comparable to safe human doses promoted new mature OL formation and myelination after SCI.
创伤性脊髓损伤（SCI）导致形成髓鞘的少突胶质细胞（OLs）凋亡以及存活轴突的脱髓鞘，从而导致传导功能障碍。对存活的裸露轴突进行髓鞘再生为脊髓修复提供了一个有前景的治疗靶点。虽然细胞移植已证明在促进髓鞘再生和功能恢复方面有效，但缺乏理想的细胞来源是临床应用的主要障碍。成年脊髓含有少突胶质细胞前体细胞和多能神经干细胞/祖细胞，它们有能力分化为成熟的、形成髓鞘的OLs。然而，内源性少突胶质细胞生成和髓鞘再生过程受到损伤后微环境中髓鞘再生抑制分子上调的限制。多种生长因子/分子已被证明可促进OL分化和髓鞘形成。
在本研究中，我们筛选了这些治疗方法，发现3,3',5-三碘甲状腺原氨酸（T3）在体外促进少突胶质细胞生成和OL成熟方面最有效。然而，全身给予T3以在损伤脊髓中达到治疗剂量可能会诱发甲状腺功能亢进，导致严重的副作用。
在本研究中，我们开发了一种新型的基于水凝胶的药物递送系统，用于将T3局部递送至损伤部位而不引起全身毒性。
使用临床相关的颈椎挫伤损伤模型，我们证明以与人类安全剂量相当的剂量局部递送T3可促进SCI后新的成熟OL形成和髓鞘再生。
