Pharmacological disruption of the outer limiting membrane leads to increased retinal integration of transplanted photoreceptor precursors.
Pharmacological disruption of the outer limiting membrane leads to increased retinal integration of transplanted photoreceptor precursors.
复制标题
外部极限膜的药理破坏会导致移植光感受器前体的视网膜整合增加。
DOI：
10.1016/j.exer.2008.01.004
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发表时间：
2008-04
影响因子：
3.4
通讯作者：
Ali, R. R.
中科院分区：
文献类型：
--
作者：
West, E. L.;Pearson, R. A.;Tschernutter, M.;Sowden, J. C.;MacLaren, R. E.;Ali, R. R.
关键词：
在发达国家，视网膜变性是导致无法治愈的失明的主要原因。细胞移植策略为修复视网膜和恢复视力提供了一种新的治疗方法。在此之前，我们已经证明，光感受器前体细胞在移植到成年小鼠的视网膜下空间后可以整合并形成功能性的光感受器。然而，在临床环境中，很可能需要更多的综合光感受器来恢复视觉功能。因此，我们试图评估外限制膜（OLM），视网膜下空间和外核层（ONL）之间的天然屏障，是否可以可逆地破坏，以及这种屏障的破坏是否会导致移植光感受器整合到ONL的数量增加。使用胶质毒素dl- α -氨基己二酸（AAA）诱导成年小鼠OLM的短暂化学破坏。在AAA给药后的不同时间点通过视网膜下注射移植分离的早期产后视网膜神经细胞。注射后3周，评估整合、分化的光感受器细胞数量，并与pbs治疗的对侧眼进行比较。我们首次证明，通过玻璃体内注射特定剂量的AAA，成年小鼠的OLM可以被可逆地破坏。在该模型中，OLM破坏在72 h时达到最大，并在2周后恢复。当与细胞移植相结合时，与pbs处理的对照组相比，OLM的破坏导致ONL内整合的光感受器数量显着增加。这种效果仅在移植前72小时给予AAA的动物中观察到，即当前细胞在最大OLM破坏的时间被递送到视网膜下间隙时。这些发现表明，在成年小鼠视网膜下空间移植后，OLM对光感受器整合存在物理障碍。OLM的可逆破坏可能在未来的治疗应用中为增加细胞整合提供了一种策略。
Retinal degeneration is the leading cause of untreatable blindness in the developed world. Cell transplantation strategies provide a novel therapeutic approach to repair the retina and restore sight. Previously, we have shown that photoreceptor precursor cells can integrate and form functional photoreceptors after transplantation into the subretinal space of the adult mouse. In a clinical setting, however, it is likely that far greater numbers of integrated photoreceptors would be required to restore visual function. We therefore sought to assess whether the outer limiting membrane (OLM), a natural barrier between the subretinal space and the outer nuclear layer (ONL), could be reversibly disrupted and if disruption of this barrier could lead to enhanced numbers of transplanted photoreceptors integrating into the ONL. Transient chemical disruption of the OLM was induced in adult mice using the glial toxin, dl-alpha-aminoadipic acid (AAA). Dissociated early post-natal neural retinal cells were transplanted via subretinal injection at various time-points after AAA administration. At 3 weeks post-injection, the number of integrated, differentiated photoreceptor cells was assessed and compared with those found in the PBS-treated contralateral eye. We demonstrate for the first time that the OLM can be reversibly disrupted in adult mice, using a specific dose of AAA administered by intravitreal injection. In this model, OLM disruption is maximal at 72 h, and recovers by 2 weeks. When combined with cell transplantation, disruption of the OLM leads to a significant increase in the number of photoreceptors integrated within the ONL compared with PBS-treated controls. This effect was only seen in animals in which AAA had been administered 72 h prior to transplantation, i.e. when precursor cells were delivered into the subretinal space at a time coincident with maximal OLM disruption. These findings suggest that the OLM presents a physical barrier to photoreceptor integration following transplantation into the subretinal space in the adult mouse. Reversible disruption of the OLM may provide a strategy for increasing cell integration in future therapeutic applications.
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DOI：
10.1006/bbrc.2000.2153
发表时间：
2000-02-24
影响因子：
3.1
作者：
Chacko, DM;Rogers, JA;Ahmad, I
通讯作者：
Ahmad, I
影响因子：
25
作者：
Kinouchi, R;Takeda, M;Chen, DF
通讯作者：
Chen, DF
影响因子：
4.4
作者：
Klassen, HJ;Ng, TF;Young, MJ
通讯作者：
Young, MJ
影响因子：
4.1
作者：
MacLaren, RE
通讯作者：
MacLaren, RE
DOI：
10.1073/pnas.0401596101
发表时间：
2004-11-02
影响因子：
11.1
作者：
Coles, BLK;Angénieux, B;van der Kooy, D
通讯作者：
van der Kooy, D