Bone marrow derived neural stem cell therapy for glioma

描述（由申请人提供）：神经干细胞（NSC）向大脑组织损伤区域迁移的能力强调了这些细胞作为大脑细胞替代和/或药物递送剂的潜在用途。恶性胶质瘤由浸润性肿瘤细胞组成，目前的治疗方法在很大程度上是难治性的，导致肿瘤不可避免地复发。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治疗浸润性胶质瘤的载体的有效性，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，即从未分离的成人骨髓中产生多能神经前体，在表型和形态上与骨髓基质细胞不同。这些骨髓来源的神经祖细胞（BM-NSC）在形态和表型上与胎儿的NSC难以区分，可以分化为神经元、星形胶质细胞和少突胶质细胞。BM-NSC在体内表现出致瘤性行为，当接种到海马体后，植入并呈现神经元表型。这些发现表明，成人骨髓可能作为神经祖细胞治疗胶质瘤和神经变性的可行来源。我们现在的目标是验证以下假设：1)骨髓源性NSC （BM-NSC）向胶质瘤的迁移依赖于骨髓源性NSC质膜上CXCR4的表达。2) BM-NSC分化为A2B5+、GFAP+星形胶质细胞前体，促进向胶质瘤的迁移，末梢分化为神经元，促进颅内移植后的植入。3)过表达Shh或gli1会促进BM-NSC的增殖，Nurr1会促进神经元的命运，delta样配体1会促进星形细胞的命运。4)在实验性啮齿动物胶质瘤模型中，促进BM-NSC增殖和星形细胞命运将(i)导致向胶质瘤的迁移增加，（ii）增加肿瘤控制并延长生存期。

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.