Human hepatocyte growth factor promotes functional recovery in primates after spinal cord injury.
Human hepatocyte growth factor promotes functional recovery in primates after spinal cord injury.
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DOI：
10.1371/journal.pone.0027706
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Nakamura M
中科院分区：
文献类型：
--
作者：
Kitamura K;Fujiyoshi K;Yamane J;Toyota F;Hikishima K;Nomura T;Funakoshi H;Nakamura T;Aoki M;Toyama Y;Okano H;Nakamura M
许多使用神经营养因子的脊髓损伤（SCI）的治疗干预集中于减少继发性损伤、损伤后变性所损伤的区域，以促进功能恢复。肝细胞生长因子（HGF）是成熟肝细胞的一种有效的有丝分裂原和组织损伤炎症反应的介质，最近被强调为中枢神经系统中的一种有效的神经营养因子。我们以前报道，引入外源性肝细胞生长因子到受伤的啮齿动物脊髓使用单纯疱疹病毒1型载体显着减少受损组织的面积，促进功能恢复。然而，该研究没有检查损伤后给予HGF的治疗效果，这是临床应用的最关键问题。为了将这一策略应用于人类治疗，我们在灵长类动物普通绒猴中诱导了挫伤性颈脊髓损伤，然后鞘内注射重组人HGF（rhHGF）。运动功能的评估采用了一个原始的开放领域的评分系统，侧重于手动功能，包括达到和把握性能和手的位置在步行。鞘内注射rhHGF可保护皮质脊髓纤维和有髓区，从而促进功能恢复。在体磁共振成像显示完整的脊髓实质的显着保存。与对照组相比，rhHGF治疗没有引起降钙素基因相关肽阳性纤维的异常生长，表明该治疗没有诱导或加剧异常性疼痛。这是第一个报道rhHGF治疗非人灵长类动物SCI疗效的研究。此外，这是第一次提出一种新的量表，用于评估非人灵长类动物挫伤性颈脊髓损伤后的神经运动表现。
Many therapeutic interventions for spinal cord injury (SCI) using neurotrophic factors have focused on reducing the area damaged by secondary, post-injury degeneration, to promote functional recovery. Hepatocyte growth factor (HGF), which is a potent mitogen for mature hepatocytes and a mediator of the inflammatory responses to tissue injury, was recently highlighted as a potent neurotrophic factor in the central nervous system. We previously reported that introducing exogenous HGF into the injured rodent spinal cord using a herpes simplex virus-1 vector significantly reduces the area of damaged tissue and promotes functional recovery. However, that study did not examine the therapeutic effects of administering HGF after injury, which is the most critical issue for clinical application. To translate this strategy to human treatment, we induced a contusive cervical SCI in the common marmoset, a primate, and then administered recombinant human HGF (rhHGF) intrathecally. Motor function was assessed using an original open field scoring system focusing on manual function, including reach-and-grasp performance and hand placement in walking. The intrathecal rhHGF preserved the corticospinal fibers and myelinated areas, thereby promoting functional recovery. In vivo magnetic resonance imaging showed significant preservation of the intact spinal cord parenchyma. rhHGF-treatment did not give rise to an abnormal outgrowth of calcitonin gene related peptide positive fibers compared to the control group, indicating that this treatment did not induce or exacerbate allodynia. This is the first study to report the efficacy of rhHGF for treating SCI in non-human primates. In addition, this is the first presentation of a novel scale for assessing neurological motor performance in non-human primates after contusive cervical SCI.
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