Human glial-restricted progenitor transplantation into cervical spinal cord of the SOD1 mouse model of ALS.
Human glial-restricted progenitor transplantation into cervical spinal cord of the SOD1 mouse model of ALS.
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DOI：
10.1371/journal.pone.0025968
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Maragakis NJ
中科院分区：
文献类型：
--
作者：
Lepore AC;O'Donnell J;Kim AS;Williams T;Tuteja A;Rao MS;Kelley LL;Campanelli JT;Maragakis NJ
肌萎缩性侧索硬化症（ALS）的细胞异常并不局限于运动神经元。在ALS患者和SOD1G93A啮齿类动物（一种被广泛研究的ALS模型）中都有大量的星形胶质细胞功能障碍的观察结果。本研究通过移植人类神经胶质限制性祖细胞（hGRPs）在该模型中治疗靶向星形胶质细胞替代，hGRPs是源自人类胎儿神经组织的谱系限制性祖细胞。我们之前的研究结果表明，将啮齿动物来源的grp移植到颈脊髓腹侧灰质中（以靶向治疗膈功能）对SOD1G93A大鼠具有治疗效果。这些发现证明了以移植为基础的星形胶质细胞替代治疗ALS的可行性和有效性，也表明靶向多节段细胞输送到颈脊髓是一种有前途的治疗策略，特别是因为它与解决ALS相关的呼吸损害有关。本研究探讨了hGRPs在SOD1G93A小鼠体内的安全性、存活、分布、分化及潜在功效。在SOD1G93A小鼠脊髓中，尽管疾病持续进展，hGRP移植物在灰质和白质中均能稳定存活和迁移，并分化为星形胶质细胞。然而，颈脊髓移植并没有产生运动神经元保护或任何功能结果测量的治疗益处。这项研究提供了这种胶质祖细胞的体内特征，并为了解它们的生存能力、在宿主组织内的整合、向胶质亚型的分化、迁移以及缺乏毒性或肿瘤形成提供了基础。
Cellular abnormalities are not limited to motor neurons in amyotrophic lateral sclerosis (ALS). There are numerous observations of astrocyte dysfunction in both humans with ALS and in SOD1G93A rodents, a widely studied ALS model. The present study therapeutically targeted astrocyte replacement in this model via transplantation of human Glial-Restricted Progenitors (hGRPs), lineage-restricted progenitors derived from human fetal neural tissue. Our previous findings demonstrated that transplantation of rodent-derived GRPs into cervical spinal cord ventral gray matter (in order to target therapy to diaphragmatic function) resulted in therapeutic efficacy in the SOD1G93A rat. Those findings demonstrated the feasibility and efficacy of transplantation-based astrocyte replacement for ALS, and also show that targeted multi-segmental cell delivery to cervical spinal cord is a promising therapeutic strategy, particularly because of its relevance to addressing respiratory compromise associated with ALS. The present study investigated the safety and in vivo survival, distribution, differentiation, and potential efficacy of hGRPs in the SOD1G93A mouse. hGRP transplants robustly survived and migrated in both gray and white matter and differentiated into astrocytes in SOD1G93A mice spinal cord, despite ongoing disease progression. However, cervical spinal cord transplants did not result in motor neuron protection or any therapeutic benefits on functional outcome measures. This study provides an in vivo characterization of this glial progenitor cell and provides a foundation for understanding their capacity for survival, integration within host tissues, differentiation into glial subtypes, migration, and lack of toxicity or tumor formation.
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