Lindner M D, Winn S R, Baetge E E, Hammang J P, Gentile F T, Doherty E, McDermott P E, Frydel B, Ullman M D, Schallert T
Cyto Therapeutics, Inc., Providence, Rhode Island 02906, USA.
Exp Neurol. 1995 Mar;132(1):62-76. doi: 10.1016/0014-4886(95)90059-4.
Studies in rodents suggest that PC12 cells, encapsulated in semipermeable ultrafiltration membranes and implanted in the striatum, have some potential efficacy for the treatment of age- and 6-OHD-induced sensorimotor impairments (22, 70, 71, 74). The objectives of this study were to: (1) determine if baby hamster kidney cells engineered to secrete glial cell line-derived neurotrophic factor (BHK-GDNF) would survive encapsulation and implantation in a dopamine-depleted rodent striatum, (2) compare polymer-encapsulated PC12 and PC12A cells in terms of their ability to survive and produce catecholamines in vivo in a dopamine-depleted striatum, and (3) determine if BHK-GDNF, PC12, or PC12A cells reduce parkinsonian symptoms in a rodent model of Parkinson's disease. Capsules with BHK-GDNF or PC12 cells contained viable cells after 90 days in vivo, with little evidence of host tissue damage/gliosis. In rats with tyrosine hydroxylase (TH)-positive fibers remaining in the lesioned striatum, there was TH-positive fiber ingrowth into the membranes of the BHK-GDNF capsules. PC12-containing capsules had higher basal release of both dopamine and L-DOPA after 90 days in vivo than before implantation, while basal release of both dopamine and L-DOPA decreased in the PC12A-containing capsules. Both encapsulated PC12 and PC12A cells, but not encapsulated BHK-GDNF cells, decreased apomorphine-induced rotations. Parkinsonian symptoms (akinesia, freezing/bracing, sensorimotor neglect) related to the extent of dopamine depletion were evident even in rats with dopamine depletions of only 25%. Evidence that encapsulated cells may attenuate these parkinsonian symptoms was not detected but most of the rats were more severely depleted of dopamine than Parkinson's patients (less than 2% dopamine remaining in the entire striatum), and these tests were not sensitive to differences between rats with less than 10% dopamine remaining. These results suggest that cell encapsulation technology can safely provide site-specific delivery of dopaminergic agonists or growth factors within the CNS, without requiring suppression of the immune system, and without using fetal tissue. Of the three types of encapsulated cells examined in the present study, PC12 cells seem to offer the most therapeutic potential in rats with severe dopamine depletions.
对啮齿动物的研究表明，封装在半透性超滤膜中并植入纹状体的PC12细胞，在治疗年龄和6 - 羟基多巴胺（6-OHD）诱导的感觉运动障碍方面具有一定的潜在疗效（22, 70, 71, 74）。本研究的目的是：（1）确定经基因工程改造以分泌胶质细胞源性神经营养因子（BHK-GDNF）的幼仓鼠肾细胞在封装并植入多巴胺缺乏的啮齿动物纹状体后是否能存活，（2）比较聚合物封装的PC12和PC12A细胞在多巴胺缺乏的纹状体中体内存活和产生儿茶酚胺的能力，以及（3）确定BHK-GDNF、PC12或PC12A细胞是否能减轻帕金森病啮齿动物模型中的帕金森症状。含有BHK-GDNF或PC12细胞的胶囊在体内90天后含有活细胞，几乎没有宿主组织损伤/胶质增生的迹象。在损伤纹状体中仍有酪氨酸羟化酶（TH）阳性纤维的大鼠中，有TH阳性纤维长入BHK-GDNF胶囊的膜内。含PC12的胶囊在体内90天后多巴胺和左旋多巴的基础释放量比植入前更高，而含PC12A的胶囊中多巴胺和左旋多巴的基础释放量均下降。封装的PC12和PC12A细胞均可减少阿扑吗啡诱导的旋转，但封装的BHK-GDNF细胞则无此作用。即使在多巴胺仅耗竭25%的大鼠中，与多巴胺耗竭程度相关的帕金森症状（运动不能、冻结/支撑、感觉运动忽视）也很明显。未检测到封装细胞可能减轻这些帕金森症状的证据，但大多数大鼠的多巴胺耗竭程度比帕金森病患者更严重（整个纹状体中剩余多巴胺不足2%），并且这些测试对剩余多巴胺不足10%的大鼠之间的差异不敏感。这些结果表明，细胞封装技术可以在不抑制免疫系统且不使用胎儿组织的情况下，安全地在中枢神经系统内提供多巴胺能激动剂或生长因子的位点特异性递送。在本研究中检测的三种封装细胞类型中，PC12细胞似乎在多巴胺严重耗竭的大鼠中具有最大的治疗潜力。
