Human Bone Marrow Derived Neural Stem Cell Therapy

人骨髓源性神经干细胞疗法

• 批准号: 7140455
• 负责人: John S Yu
• 金额: $ 17.61万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-15 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7140455
• 关键词: astrocytes; biotechnology; bone marrow; cell differentiation; cell migration; clinical research; confocal scanning microscopy; drug delivery systems; gene therapy; glioma; green fluorescent proteins; human embryonic stem cell line; human subject; immunocytochemistry; neoplasm /cancer therapy; neurons; oligodendroglia; polymerase chain reaction; stem cell transplantation; terminal nick end labeling; tissue /cell culture

DESCRIPTION (provided by applicant): The capacity of neural stem cells (NSC) to migrate towards areas of tissue damage within the brain underscores the potential use of these cells as agents for cell replacement and/or drug delivery in the brain. Malignant gliomas consist of infiltrating tumor cells which are largely refractory to currently employed therapies, resulting in inevitable tumor recurrence. We have demonstrated the efficacy of using primary fetal NSC as delivery vehicles for cytotoxic or immunostimulatory agents to treat infiltrating glioma and have demonstrated a mechanism of glioma tropism. We also described a rapid culture process whereby multipotent neural precursors, phenotypically and morphologically distinct from bone marrow stromal cells can be generated from unfractionated adult bone marrow. These bone marrow derived neural progenitors (BM-NSC) are morphologically and phenotypically indistinguishable from fetal NSC and could differentiate into neurons, astrocytes, and oligodendroglia. BM-NSC demonstrated tumor tropic behavior in vivo and when inoculated into the hippocampus, engrafted and assumed neuronal phenotype. These findings indicate that adult bone marrow may serve as a viable source of neural precursor cells to treat glioma and neurodegeneration. We now aim to translate these findings toward the development of human BM-NSC to treat malignant glioma. We will test the hypotheses that: 1) Neurospheres isolated from adult whole bone marrow contain neural stem cells with the capacity to self-renew and differentiate into neurons, astrocytes, and oligodendrocytes. 2) Human BM-NSC differentiation into A2B5+, GFAP+ astrocytic precursors will promote migration toward glioma, while terminal differentiation into neurons will promote engraftment after intracranial transplantation. 3) Human BM-NSC is safe and effective in an experimental rodent glioma model.

描述（由申请人提供）： 神经干细胞（NSC）迁移到大脑内组织损伤区域的能力强调了这些细胞作为大脑中细胞置换和/或药物递送的药物的潜在用途。恶性神经胶质瘤由浸润的肿瘤细胞组成，这些细胞在很大程度上对当前使用的疗法难治性，导致不可避免的肿瘤复发。我们已经证明了将原代胎儿NSC用作递送车的疗效，用于治疗渗透性神经胶质瘤的细胞毒性或免疫刺激剂，并证明了胶质瘤性胶质瘤的机制。我们还描述了一个快速的培养过程，在这种过程中，在表型和形态上，多能神经前体与骨髓基质细胞不同，可以通过未分离的成年骨髓产生。这些骨髓衍生的神经祖细胞（BM-NSC）在形态和表型上与胎儿NSC无法区分，并且可以分化为神经元，星形胶质细胞和寡头胶质细胞。 BM-NSC在体内表现出肿瘤的热带行为，当将其接种到海马中时，植入并假定的神经元表型。这些发现表明，成年骨髓可以作为治疗神经胶质瘤和神经退行性的神经前体细胞的可行来源。现在，我们旨在将这些发现转化为人类BM-NSC的发展以治疗恶性神经胶质瘤。我们将测试以下假设： 1）从成年的全骨髓中分离出的神经球包含具有自我更新和分化为神经元，星形胶质细胞和少突胶质细胞的能力的神经干细胞。 2）人类BM-NSC分化为A2B5+，GFAP+星形胶质细胞前体将促进向神经胶质瘤迁移，而末端分化为神经元将在颅内移植后促进植入。 3）在实验性啮齿动物神经胶质瘤模型中，人类BM-NSC是安全有效的。