Department of Neuroscience, Thomas Jefferson University Medical College, Philadelphia, Pennsylvania, United States of America.
PLoS One. 2011;6(10):e25968. doi: 10.1371/journal.pone.0025968. Epub 2011 Oct 5.
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 SOD1(G93A) 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 SOD1(G93A) 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 SOD1(G93A) mouse. hGRP transplants robustly survived and migrated in both gray and white matter and differentiated into astrocytes in SOD1(G93A) 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.
细胞异常不仅局限于肌萎缩侧索硬化症（ALS）中的运动神经元。在 ALS 患者和 SOD1(G93A)啮齿动物（一种广泛研究的 ALS 模型）中，均观察到星形胶质细胞功能障碍。本研究通过移植人少突胶质前体细胞（hGRPs），一种源自人胎儿神经组织的谱系限制祖细胞，对该模型中的星形胶质细胞进行治疗性替代。我们之前的研究结果表明，将啮齿动物源性 GRPs 移植到颈脊髓腹侧灰质（以靶向膈肌功能的治疗），可在 SOD1(G93A)大鼠中产生治疗效果。这些发现证明了基于移植的星形胶质细胞替代治疗 ALS 的可行性和疗效，也表明针对颈脊髓的多节段细胞递送是一种很有前途的治疗策略，特别是因为它与解决与 ALS 相关的呼吸功能障碍有关。本研究探讨了 hGRP 在 SOD1(G93A)小鼠中的安全性和体内存活、分布、分化以及潜在疗效。尽管疾病仍在进展，但 hGRP 移植在 SOD1(G93A)小鼠脊髓的灰质和白质中均能大量存活和迁移，并分化为星形胶质细胞。然而，颈脊髓移植并未导致运动神经元保护或任何对功能结果测量的治疗益处。本研究对这种神经胶质前体细胞进行了体内特征描述，并为了解其在宿主组织中的存活能力、整合、分化为神经胶质亚型、迁移以及无毒性或肿瘤形成能力提供了基础。
