Human Bone Marrow Derived Neural Stem Cell Therapy

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，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儿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，神经前体细胞治疗神经胶质瘤和神经变性。我们现在的目标是将这些发现转化为人类BM-NSC治疗恶性胶质瘤的发展。我们将检验以下假设： 1)从成人全骨髓中分离的神经球含有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)人BM-NSC在实验啮齿动物胶质瘤模型中是安全有效的。

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.