Zigova T, Pencea V, Betarbet R, Wiegand S J, Alexander C, Bakay R A, Luskin M B
Department of Cell Biology, Emory University School of Medicine, Atlanta, GA 30322, USA.
Cell Transplant. 1998 Mar-Apr;7(2):137-56. doi: 10.1177/096368979800700209.
We have investigated the suitability of a recently identified and characterized population of neuronal progenitor cells for their potential use in the replacement of degenerating or damaged neurons in the mammalian brain. The unique population of neuronal progenitor cells is situated in a well-delineated region of the anterior part of the neonatal subventricular zone (referred to as SVZa). This region can be separated from the remaining proliferative, gliogenic, subventricular zone encircling the lateral ventricles of the forebrain. Because the neurons arising from the highly enriched neurogenic progenitor cell population of the SVZa ordinarily migrate considerable distances and ultimately express the neurotransmitters GABA and dopamine, we have examined whether they could serve as an alternative source of tissue for neural transplantation. SVZa cells from postnatal day 0-2 rats, prelabeled by intraperitoneal injections of the cell proliferation marker BrdU, were implanted into the striatum of adult rats approximately 1 mo after unilateral denervation by 6-OHDA. To examine the spatio-temporal distribution and phenotype of the transplanted SVZa cells, the experimental recipients were perfused at short (less than 1 wk), intermediate (2-3 wk) and long (5 mo) postimplantation times. The host brains were sectioned and stained with an antibody to BrdU and one of several cell-type specific markers to determine the phenotypic characteristics of the transplanted SVZa cells. To identify neurons we used the neuron-specific antibody TuJ1, or antimembrane-associated protein 2 (MAP-2), and anti-GFAP was used to identify astrocytic glia. At all studied intervals the majority of the surviving SVZa cells exhibited a neuronal phenotype. Moreover, morphologically they could be distinguished from the cells of the host striatum because they resembled the intrinsic granule cells of the olfactory bulb, their usual fate. At longer times, a greater number of the transplanted SVZa cells had migrated from their site of implantation, often towards an outlying blood vessel, and the density of cells within the core of the transplant was reduced. Furthermore, there were rarely signs of transplant rejection or a glial scar surrounding the transplant. In the core of the transplant there were low numbers of GFAP-positive cells, indicating that the transplanted SVZa cells, predominantly TuJ1-positive/MAP2-positive, express a neuronal phenotype. Collectively, the propensity of the SVZa cells to express a neuronal phenotype and to survive and integrate in the striatal environment suggest that they may be useful in the reconstruction of the brain following CNS injury or disease.
我们研究了最近鉴定和表征的一群神经祖细胞，探讨其在替代哺乳动物大脑中退化或受损神经元方面的潜在用途。这群独特的神经祖细胞位于新生小鼠脑室下区前部一个界限清晰的区域（称为SVZa）。该区域可与围绕前脑侧脑室的其余增殖性、生成胶质细胞的脑室下区分开。由于源自SVZa高度富集的神经源性祖细胞群体的神经元通常会迁移相当长的距离，并最终表达神经递质GABA和多巴胺，我们研究了它们是否可作为神经移植的另一种组织来源。通过腹腔注射细胞增殖标记物BrdU对出生后0 - 2天大鼠的SVZa细胞进行预标记，在6 - OHDA单侧去神经支配约1个月后，将这些细胞植入成年大鼠的纹状体。为了研究移植的SVZa细胞的时空分布和表型，在植入后短时间（少于1周）、中间时间（2 - 3周）和长时间（5个月）对实验受体进行灌注。将宿主大脑切片，用抗BrdU抗体和几种细胞类型特异性标记物之一进行染色，以确定移植的SVZa细胞的表型特征。为了鉴定神经元，我们使用神经元特异性抗体TuJ1或抗膜相关蛋白2（MAP - 2），并使用抗GFAP来鉴定星形胶质细胞。在所有研究的时间间隔内，大多数存活的SVZa细胞呈现神经元表型。此外，在形态上它们可以与宿主纹状体的细胞区分开来，因为它们类似于嗅球的固有颗粒细胞，这是它们通常的命运。在较长时间时，更多的移植SVZa细胞从植入部位迁移，通常朝向一条外围血管，移植核心内的细胞密度降低。此外，很少有移植排斥的迹象或移植周围的胶质瘢痕。在移植核心中有少量GFAP阳性细胞，表明移植的SVZa细胞主要为TuJ1阳性/MAP2阳性，表达神经元表型。总体而言，SVZa细胞表达神经元表型以及在纹状体环境中存活和整合倾向表明，它们可能在中枢神经系统损伤或疾病后大脑的重建中发挥作用。
