Bone marrow derived neural stem cell therapy for glioma

描述（由申请人提供）：神经干细胞（NSC）向脑内组织损伤区域迁移的能力强调了这些细胞作为脑中细胞替代和/或药物递送试剂的潜在用途。恶性神经胶质瘤由浸润性肿瘤细胞组成，其在很大程度上对目前采用的疗法是难治的，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胶质瘤的功效，并且已经证明了胶质瘤嗜性的机制。我们还描述了一种快速培养方法，即多能神经前体细胞，表型和形态学上不同于骨髓基质细胞，可以从普通成人骨髓产生。这些骨髓源性神经祖细胞（BM-NSC）在形态学和表型上与胎儿NSC无法区分，并且可以分化为神经元、星形胶质细胞和少突胶质细胞。BM-NSC在体内表现出肿瘤嗜性行为，并且当接种到海马中时，移植并呈现神经元表型。这些发现表明，成人骨髓可能作为一个可行的来源，神经祖细胞治疗胶质瘤和神经变性。我们现在的目的是验证以下假设：1）骨髓源性NSC（BM-NSC）向胶质瘤的迁移依赖于BM-NSC质膜上CXCR 4的表达。2)BM-NSC分化为A2 B5+、GFAP+星形胶质细胞前体将促进向胶质瘤的迁移，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的过表达将促进BM-NSC增殖，而Nurr 1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）导致向胶质瘤的迁移增加和（ii）增加肿瘤控制并延长实验啮齿动物胶质瘤模型中的存活。

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.