Bone marrow derived neural stem cell therapy for glioma

描述(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突显了这些细胞作为细胞替代和/或脑内药物输送的潜在用途。恶性胶质瘤由浸润性肿瘤细胞组成，这些肿瘤细胞对目前采用的治疗方法很难奏效，导致不可避免的肿瘤复发。我们已经证明了利用原代胎鼠神经干细胞作为细胞毒或免疫刺激药物的载体来治疗浸润性胶质瘤的有效性，并证明了胶质瘤的趋向性机制。我们还描述了一种快速培养过程，通过该过程，可以从未分离的成人骨髓中产生表型和形态上与骨髓基质细胞不同的多潜能神经前体细胞。这些骨髓源性神经前体细胞(BM-NSC)在形态和表型上与胎儿NSC难以区分，可分化为神经元、星形胶质细胞和少突胶质细胞。BM-NSC在体内表现出趋瘤行为，当接种到海马区时，植入并呈现神经元表型。这些发现表明，成人骨髓可能成为治疗神经胶质瘤和神经退行性变的神经前体细胞的可行来源。1)骨髓来源的神经干细胞(BM-NSC)向胶质瘤的迁移依赖于BM-NSC质膜上CXCR4的表达。2)BM-NSC分化为A2B5+、GFAP+星形胶质细胞前体细胞可促进向胶质瘤的迁移，向神经元的终末分化可促进脑移植后的植入。3)Shh或Gli-1过表达促进BM-NSC增殖，Nurr1促进神经元命运，Delta样配体1促进星形胶质细胞命运。4)促进BM-NSC的增殖和星形胶质细胞的命运将(I)增加向胶质瘤的迁移和(Ii)在实验性鼠脑胶质瘤模型中增强肿瘤控制和延长生存期。

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.