Bone marrow derived neural stem cell therapy for glioma

骨髓源性神经干细胞治疗神经胶质瘤

• 批准号: 6807513
• 负责人: John S Yu
• 金额: $ 32.47万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6807513
• 关键词: apoptosis; astrocytes; athymic mouse; bone marrow; cell differentiation; cell membrane; cell migration; cell proliferation; chemokine receptor; chemotaxis; genetically modified animals; glioma; hepatocyte growth factor; interleukin 1; laboratory rat; neoplasm /cancer therapy; nerve stem cell; platelet derived growth factor; receptor expression; tissue tropism; transforming growth factors

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 murine 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 progenitor cells to treat glioma and neurodegeneration. We now aim to test the hypotheses that: 1) Bone marrow derived NSC (BM-NSC) migration toward glioma is dependent on CXCR4 expression on the plasma membrane of BM-NSC. 2) 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) Overexpression of Shh or Gli-1 will promote BM-NSC proliferation, while Nurr1 will promote neuronal fate and Delta-like ligand 1 will promote astrocytic fate. 4) Promoting BM-NSC proliferation and astrocytic fate will (i) lead to increased migration to glioma and (ii) increase tumor control and prolong survival in an experimental rodent glioma model.

描述（由申请人提供）：神经干细胞（NSC）向大脑内组织损伤区域迁移的能力强调了这些细胞作为大脑中细胞替代和/或药物递送的试剂的潜在用途。恶性神经胶质瘤由浸润性肿瘤细胞组成，目前使用的疗法对这些细胞基本上无效，导致不可避免的肿瘤复发。我们已经证明了使用原代胎鼠 NSC 作为细胞毒性或免疫刺激剂的递送载体来治疗浸润性神经胶质瘤的功效，并证明了神经胶质瘤的趋向性机制。我们还描述了一种快速培养过程，可以从未分级的成人骨髓中产生表型和形态学上与骨髓基质细胞不同的多能神经前体细胞。这些骨髓源性神经祖细胞 (BM-NSC) 在形态和表型上与胎儿 NSC 没有区别，并且可以分化为神经元、星形胶质细胞和少突胶质细胞。 BM-NSC 在体内表现出亲肿瘤行为，并且当接种到海马体、移植并呈现神经元表型时。这些发现表明，成人骨髓可能作为神经祖细胞的可行来源来治疗神经胶质瘤和神经退行性疾病。我们现在的目标是测试以下假设：1) 骨髓源性 NSC (BM-NSC) 向神经胶质瘤的迁移依赖于 BM-NSC 质膜上的 CXCR4 表达。 2）BM-NSC分化为A2B5+、GFAP+星形胶质细胞前体将促进向胶质瘤迁移，而终末分化为神经元将促进颅内移植后的植入。 3）Shh或Gli-1的过度表达将促进BM-NSC增殖，而Nurr1将促进神经元命运，Delta样配体1将促进星形胶质细胞命运。 4) 促进 BM-NSC 增殖和星形胶质细胞命运将 (i) 导致向神经胶质瘤的迁移增加，以及 (ii) 在实验性啮齿动物神经胶质瘤模型中增强肿瘤控制并延长生存期。