Human Cortical Neural Stem Cells Expressing Insulin-Like Growth Factor-I: A Novel Cellular Therapy for Alzheimer's Disease.
Human Cortical Neural Stem Cells Expressing Insulin-Like Growth Factor-I: A Novel Cellular Therapy for Alzheimer's Disease.
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DOI：
10.5966/sctm.2015-0103
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发表时间：
2016-03
影响因子：
6
通讯作者：
Feldman EL
中科院分区：
文献类型：
--
作者：
McGinley LM;Sims E;Lunn JS;Kashlan ON;Chen KS;Bruno ES;Pacut CM;Hazel T;Johe K;Sakowski SA;Feldman EL
一个人皮质衍生的神经干细胞（NSC）系修饰表达胰岛素样生长因子-I（IGF-I），HK 532-IGF-I，其特征在于在这份报告中。该细胞系正在研究作为阿尔茨海默病（AD）的细胞疗法。HK 532-IGF-I细胞优先分化为γ-氨基丁酸能神经元，这是AD中失调的一种亚型;产生增加的血管内皮生长因子水平;并在体外显示出增加的神经保护能力。HK 532-IGF-I细胞在小鼠AD模型中海马周围移植后存活，并在靶向脑区表现出长期持久性。阿尔茨海默病（Alzheimer's disease，AD）是最常见的与年龄相关的神经退行性疾病，也是痴呆的主要原因。目前的治疗未能改变潜在的疾病病理，并且在开发有效的药物治疗方面几乎没有取得进展。细胞疗法通过多种机制影响疾病，与传统的单靶点方法相比，提供了更高的疗效。在肌萎缩侧索硬化症中，我们已经证明移植的脊髓神经干细胞（NSC）整合到脊髓中，与宿主形成突触，改善炎症，并减少疾病相关的病理。我们目前的目标是开发一种类似的“同类最佳”的AD细胞疗法。在这里，我们描述了一种新的人皮质衍生的神经干细胞系修饰表达胰岛素样生长因子-I（IGF-I），HK 532-IGF-I。由于IGF-I促进体内神经发生和突触发生，这种增强的NSC系提供了额外的环境富集，增强的神经保护和治疗复杂AD病理的多方面方法。我们发现自分泌IGF-I的产生并不影响细胞分泌组或正常的细胞功能，包括增殖、迁移或祖细胞状态的维持。然而，HK 532-IGF-I细胞优先分化为γ-氨基丁酸能神经元，这是AD中失调的一种亚型;产生增加的血管内皮生长因子水平;并在体外显示出增加的神经保护能力。我们还证明了HK 532-IGF-I细胞在小鼠AD模型中海马周围移植后存活，并在靶向脑区表现出长期持久性。总之，我们相信，将细胞和IGF-I疗法的益处结合起来将为患者提供最佳的治疗益处，我们的研究结果支持将HK 532-IGF-I细胞进一步临床前开发为AD的疾病修饰干预。阿尔茨海默病（AD）是一种常见的疾病，目前尚无有效的治疗方法。目前的药物治疗暂时减缓痴呆症状，但最终未能改变疾病进程。鉴于AD的患病率和人口日益老龄化，替代治疗策略是必要的。细胞疗法通过多种机制影响疾病，与传统的单靶点药物发现方法相比，提供了更高的疗效。这项研究描述了一种新的增强型人类干细胞系，该细胞系产生更多的有益于疾病环境的生长因子。研究结果支持进一步开发一种潜在安全和临床可转化的AD患者细胞疗法。
A human cortex-derived neural stem cell (NSC) line modified to express insulin-like growth factor-I (IGF-I), HK532-IGF-I, is characterized in this report. The cell line is under study as a cellular therapy for Alzheimer’s disease (AD). HK532-IGF-I cells preferentially differentiated into gamma-aminobutyric acid-ergic neurons, a subtype dysregulated in AD; produced increased vascular endothelial growth factor levels; and displayed an increased neuroprotective capacity in vitro. HK532-IGF-I cells survived peri-hippocampal transplantation in a murine AD model and exhibited long-term persistence in targeted brain areas. Alzheimer’s disease (AD) is the most prevalent age-related neurodegenerative disorder and a leading cause of dementia. Current treatment fails to modify underlying disease pathologies and very little progress has been made to develop effective drug treatments. Cellular therapies impact disease by multiple mechanisms, providing increased efficacy compared with traditional single-target approaches. In amyotrophic lateral sclerosis, we have shown that transplanted spinal neural stem cells (NSCs) integrate into the spinal cord, form synapses with the host, improve inflammation, and reduce disease-associated pathologies. Our current goal is to develop a similar “best in class” cellular therapy for AD. Here, we characterize a novel human cortex-derived NSC line modified to express insulin-like growth factor-I (IGF-I), HK532-IGF-I. Because IGF-I promotes neurogenesis and synaptogenesis in vivo, this enhanced NSC line offers additional environmental enrichment, enhanced neuroprotection, and a multifaceted approach to treating complex AD pathologies. We show that autocrine IGF-I production does not impact the cell secretome or normal cellular functions, including proliferation, migration, or maintenance of progenitor status. However, HK532-IGF-I cells preferentially differentiate into gamma-aminobutyric acid-ergic neurons, a subtype dysregulated in AD; produce increased vascular endothelial growth factor levels; and display an increased neuroprotective capacity in vitro. We also demonstrate that HK532-IGF-I cells survive peri-hippocampal transplantation in a murine AD model and exhibit long-term persistence in targeted brain areas. In conclusion, we believe that harnessing the benefits of cellular and IGF-I therapies together will provide the optimal therapeutic benefit to patients, and our findings support further preclinical development of HK532-IGF-I cells into a disease-modifying intervention for AD. There is no cure for Alzheimer’s disease (AD) and no means of prevention. Current drug treatments temporarily slow dementia symptoms but ultimately fail to alter disease course. Given the prevalence of AD and an increasingly aging population, alternative therapeutic strategies are necessary. Cellular therapies impact disease by multiple mechanisms, providing increased efficacy compared with traditional, single-target drug discovery approaches. This study describes a novel enhanced human stem cell line that produces increased amounts of growth factors beneficial to the disease environment. Findings support further development into a potentially safe and clinically translatable cellular therapy for patients with AD.