Breysse Nathalie, Carlsson Thomas, Winkler Christian, Björklund Anders, Kirik Deniz
Central Nervous System Disease Modeling Unit, Section for Neuroscience, Department of Experimental Medical Science, Lund University, 221 84 Lund, Sweden.
J Neurosci. 2007 May 30;27(22):5849-56. doi: 10.1523/JNEUROSCI.0626-07.2007.
Clinical trials involving intrastriatal transplants of human embryonic mesencephalic tissue have provided proof-of-principle that nigral dopamine (DA) neurons can survive and functionally integrate into the host neural circuitry. However, the degree of graft-induced symptomatic relief differs significantly between the patients. This variability has led to investigations aimed at identifying factors that could affect the clinical outcome. The extent and pattern of dopaminergic denervation in the brain may be one of the major determinants of the functional outcome after intrastriatal DA cell grafts. Here, we report that in animals subjected to an intrastriatal 6-hydroxydopamine lesion of the striatal dopaminergic afferent, the integrity of the host dopaminergic innervation outside the areas innervated by the graft is critical for optimal function of DA neurons placed in the striatum. Established graft-induced functional recovery, as assessed in the stepping and cylinder tests, was compromised in animals in which the dopaminergic lesion was extended to include also the medial and ventral striatum as well as the cortical and limbic DA projections. Poor clinical outcome after transplantation may, thus, at least in part, be caused by dopaminergic denervation in areas outside the graft-innervated territories, and similarly beneficial effects initially observed in patients may regress if the degeneration of the host extrastriatal DA projection systems proceeds with advancing disease. This would have two implications: first, patients with advanced disease involving the ventral striatum and/or nonstriatal DA projections would be unlikely to respond well to intrastriatal DA grafts and, second, to retain the full benefit of the grafts, progression of the disease should be avoided by, for example, combining cell therapy with a neuroprotective approach.
涉及人胚胎中脑组织纹状体内移植的临床试验已提供原理证明，即黑质多巴胺（DA）神经元能够存活并在功能上整合到宿主神经回路中。然而，患者之间移植诱导的症状缓解程度差异显著。这种变异性促使人们进行调查，旨在确定可能影响临床结果的因素。脑内多巴胺能去神经支配的范围和模式可能是纹状体内DA细胞移植后功能结果的主要决定因素之一。在此，我们报告，在接受纹状体多巴胺能传入纤维的纹状体内6-羟基多巴胺损伤的动物中，移植所支配区域之外的宿主多巴胺能神经支配的完整性对于置于纹状体内的DA神经元的最佳功能至关重要。在步进和圆筒试验中评估的既定移植诱导的功能恢复，在多巴胺能损伤扩展至包括内侧和腹侧纹状体以及皮质和边缘DA投射的动物中受到损害。因此，移植后不良的临床结果可能至少部分是由移植支配区域之外的区域的多巴胺能去神经支配引起的，并且如果宿主纹状体以外的DA投射系统随着疾病进展而退化，最初在患者中观察到的类似有益效果可能会消退。这将有两个影响：第一，患有涉及腹侧纹状体和/或非纹状体DA投射的晚期疾病的患者对纹状体内DA移植的反应可能不佳；第二，为了保留移植的全部益处，应通过例如将细胞疗法与神经保护方法相结合来避免疾病进展。
