Department of Cell Therapy and Regenerative Medicine, Andalusian Center for Molecular Biology and Regenerative Medicine, Seville, Spain.
Cell Transplant. 2010;19(5):549-64. doi: 10.3727/096368910X491383. Epub 2010 Feb 8.
Defects in GABAergic function can cause epilepsy. In the last years, cell-based therapies have attempted to correct these defects with disparate success on animal models of epilepsy. Recently, we demonstrated that medial ganglionic eminence (MGE)-derived cells grafted into the neonatal normal brain migrate and differentiate into functional mature GABAergic interneurons. These cells are able to modulate the local level of GABA-mediated synaptic inhibition, which suggests their suitability for cell-based therapies. However, it is unclear whether they can integrate in the host circuitry and rescue the loss of inhibition in pathological conditions. Thus, as proof of principle, we grafted MGE-derived cells into a mouse model of seizure susceptibility caused by specific elimination of GABAergic interneuron subpopulations in the mouse hippocampus after injection of the neurotoxic saporin conjugated to substance P (SSP-Sap). This ablation was associated with significant decrease in inhibitory postsynaptic currents (IPSC) on CA1 pyramidal cells and increased seizure susceptibility induced by pentylenetetrazol (PTZ). Grafting of GFP(+) MGE-derived cells in SSP-Sap-treated mice repopulates the hippocampal ablated zone with cells expressing molecular markers of mature interneurons. Interestingly, IPSC kinetics on CA1 pyramidal cells of ablated hippocampus significantly increased after transplantation, reaching levels similar to the normal mice. More importantly, this was associated with reduction in seizure severity and decrease in postseizure mortality induced by PTZ. Our data show that MGE-derived cells fulfill most of the requirements for an appropriate cell-based therapy, and indicate their suitability for neurological conditions where a modulation of synaptic inhibition is needed, such as epilepsy.
GABA 能性功能障碍可导致癫痫。近年来，基于细胞的疗法试图通过在癫痫动物模型上取得不同程度的成功来纠正这些缺陷。最近，我们证明了内侧神经节隆起（MGE）衍生的细胞移植到正常新生儿大脑中，可以迁移并分化为功能性成熟的 GABA 能中间神经元。这些细胞能够调节 GABA 介导的突触抑制的局部水平，这表明它们适合细胞治疗。然而，尚不清楚它们是否能够整合到宿主回路中并挽救病理性条件下抑制的丧失。因此，作为原理验证，我们将 MGE 衍生的细胞移植到由注射神经毒性 SAP 与 P 物质缀合（SSP-Sap）引起的 GABA 能中间神经元亚群在小鼠海马体中特异性消除后引起的易发性癫痫模型小鼠中。这种消融与 CA1 锥体神经元上抑制性突触后电流（IPSC）的显著减少以及戊四氮（PTZ）诱导的易发性癫痫相关。在 SSP-Sap 处理的小鼠中移植 GFP(+) MGE 衍生的细胞会用表达成熟中间神经元分子标志物的细胞重新填充海马体消融区。有趣的是，消融海马体的 IPSC 动力学在移植后显著增加，达到类似于正常小鼠的水平。更重要的是，这与 PTZ 诱导的癫痫严重程度降低和癫痫后死亡率降低有关。我们的数据表明，MGE 衍生的细胞满足适当细胞治疗的大多数要求，并表明它们适合需要调节突触抑制的神经状况，例如癫痫。
