Communication via gap junctions underlies early functional and beneficial interactions between grafted neural stem cells and the host
Communication via gap junctions underlies early functional and beneficial interactions between grafted neural stem cells and the host
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DOI：
10.1073/pnas.0915134107
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发表时间：
2010-03-16
影响因子：
11.1
通讯作者：
Herlenius, Eric
中科院分区：
文献类型：
--
作者：
Jaderstad, Johan;Jaderstad, Linda M.;Herlenius, Eric
移植物神经干细胞（NSCs）及其后代如何融入受体脑组织并与宿主细胞功能相互作用尚不清楚。我们报告说，通过比例延时钙成像、电流钳记录和染料偶联方法分析的器官型切片培养中，移植的小鼠或人类NSCs通过间隙连接偶联功能整合到宿主神经回路并影响宿主细胞的早期和基本方式，甚至在电生理成熟的神经元分化之前。快速建立的间隙连接允许外源性NSCs直接影响宿主网络活动，包括在波动网络中与宿主细胞同步的钙瞬态。外源性NSCs还可以保护宿主神经元免于死亡，并减少诸如反应性星形胶质增生等继发性损伤的迹象。为了确定NSCs和宿主细胞之间的间隙连接是否也可能在体内介导神经保护，我们在两种不同病因的小鼠模型中检测了NSC移植，其特征是相同细胞类型（浦肯野神经元）的变性，即神经和SCA1突变体。在这两种情况下，缝隙连接（包含连接蛋白43）在NSCs和处于危险中的宿主细胞之间形成，并且与神经元和行为的拯救有关（当植入在明显的神经元丢失之前进行时）。当间隙连接的形成或功能被药理学和/或rna抑制策略抑制时，体外和体内有益的NSC效应都被取消，支持间隙连接偶联对宿主系统的一些调节、稳态和保护作用的关键介导，并为随后发展的电化学突触细胞间通讯建立模板。
How grafted neural stem cells (NSCs) and their progeny integrate into recipient brain tissue and functionally interact with host cells is as yet unanswered. We report that, in organotypic slice cultures analyzed by ratiometric time-lapse calcium imaging, current-clamp recordings, and dye-coupling methods, an early and essential way in which grafted murine or human NSCs integrate functionally into host neural circuitry and affect host cells is via gap-junctional coupling, even before electrophysiologically mature neuronal differentiation. The gap junctions, which are established rapidly, permit exogenous NSCs to influence directly host network activity, including synchronized calcium transients with host cells in fluctuating networks. The exogenous NSCs also protect host neurons from death and reduce such signs of secondary injury as reactive astrogliosis. To determine whether gap junctions between NSCs and host cells may also mediate neuroprotection in vivo, we examined NSC transplantation in two murine models characterized by degeneration of the same cell type (Purkinje neurons) from different etiologies, namely, the nervous and SCA1 mutants. In both, gap junctions (containing connexin 43) formed between NSCs and host cells at risk, and were associated with rescue of neurons and behavior (when implantation was performed before overt neuron loss). Both in vitro and in vivo beneficial NSC effects were abrogated when gap junction formation or function was suppressed by pharmacologic and/or RNA-inhibition strategies, supporting the pivotal mediation by gap-junctional coupling of some modulatory, homeostatic, and protective actions on host systems as well as establishing a template for the subsequent development of electrochemical synaptic intercellular communication.