Neural stem cell mediated recovery is enhanced by Chondroitinase ABC pretreatment in chronic cervical spinal cord injury.
Neural stem cell mediated recovery is enhanced by Chondroitinase ABC pretreatment in chronic cervical spinal cord injury.
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DOI：
10.1371/journal.pone.0182339
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Fehlings MG
中科院分区：
文献类型：
--
作者：
Suzuki H;Ahuja CS;Salewski RP;Li L;Satkunendrarajah K;Nagoshi N;Shibata S;Fehlings MG
创伤性脊髓损伤（SCIs）影响着全世界数百万人；他们中的大多数人都处于慢性损伤阶段。不幸的是，目前大多数治疗针对急性/亚急性损伤阶段，因为慢性损伤脊髓的微环境由一个成熟的胶质瘢痕组成，具有抑制性硫酸软骨素蛋白多糖（CSPGs），它是再生的有力屏障。研究表明，CSPGs可以通过鞘内软骨素酶ABC （ChABC）在体内降解，从而为内源性细胞或移植的神经干细胞（NSCs）在损伤亚急性期的再生创造更有利的环境。利用与翻译相关的小鼠颈脊髓损伤夹挫伤模型，我们试图确定ChABC预处理是否可以改变恶劣的慢性微环境，以增强诱导多能干细胞衍生的NSCs （iPS-NSC）的随后再生。在损伤7周后的慢性期，我们通过鞘内渗透泵将ChABC输送一周，然后在脑实质内将iPS-NSC移植到损伤中心的吻侧和尾侧。ChABC减少了慢性损伤瘢痕，显著提高了iPSC-NSC的存活率，并明确分化为所有三种神经胶质谱系。膜片钳分析表明，来源于移植细胞的神经元也与宿主电路形成功能性突触。此外，联合治疗导致关键功能肌群的恢复，包括前肢握力和通过Catwalk评估的前肢/后肢运动指标。这代表了重要的概念验证数据，即慢性损伤的脊髓可以通过ChABC预处理“解锁”，从而产生有利于再生iPS-NSC治疗的微环境。
Traumatic spinal cord injuries (SCIs) affect millions of people worldwide; the majority of whom are in the chronic phase of their injury. Unfortunately, most current treatments target the acute/subacute injury phase as the microenvironment of chronically injured cord consists of a well-established glial scar with inhibitory chondroitin sulfate proteoglycans (CSPGs) which acts as a potent barrier to regeneration. It has been shown that CSPGs can be degraded in vivo by intrathecal Chondroitinase ABC (ChABC) to produce a more permissive environment for regeneration by endogenous cells or transplanted neural stem cells (NSCs) in the subacute phase of injury. Using a translationally-relevant clip-contusion model of cervical spinal cord injury in mice we sought to determine if ChABC pretreatment could modify the harsh chronic microenvironment to enhance subsequent regeneration by induced pluripotent stem cell-derived NSCs (iPS-NSC). Seven weeks after injury—during the chronic phase—we delivered ChABC by intrathecal osmotic pump for one week followed by intraparenchymal iPS-NSC transplant rostral and caudal to the injury epicenter. ChABC administration reduced chronic-injury scar and resulted in significantly improved iPSC-NSC survival with clear differentiation into all three neuroglial lineages. Neurons derived from transplanted cells also formed functional synapses with host circuits on patch clamp analysis. Furthermore, the combined treatment led to recovery in key functional muscle groups including forelimb grip strength and measures of forelimb/hindlimb locomotion assessed by Catwalk. This represents important proof-of-concept data that the chronically injured spinal cord can be ‘unlocked’ by ChABC pretreatment to produce a microenvironment conducive to regenerative iPS-NSC therapy.
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影响因子：
14
作者：
Iwasaki, Motoyuki;Wilcox, Jared T.;Fehlings, Michael G.
通讯作者：
Fehlings, Michael G.
影响因子：
2.8
作者：
Bazley, Faith A.;Hu, Charles;All, Angelo H.
通讯作者：
All, Angelo H.
影响因子：
4.2
作者：
Forgione, Nicole;Karadimas, Spyridon K.;Fehlings, Michael G.
通讯作者：
Fehlings, Michael G.
影响因子：
4.2
作者：
Hamers, FPT;Koopmans, GC;Joosten, EAJ
通讯作者：
Joosten, EAJ
接枝的人IPS细胞衍生的少突胶质细胞前体细胞有助于脊髓损伤后脱髓鞘轴突的稳健再生。
影响因子：
5.9
作者：
Kawabata S;Takano M;Numasawa-Kuroiwa Y;Itakura G;Kobayashi Y;Nishiyama Y;Sugai K;Nishimura S;Iwai H;Isoda M;Shibata S;Kohyama J;Iwanami A;Toyama Y;Matsumoto M;Nakamura M;Okano H
通讯作者：
Okano H