MacLaren R E, Pearson R A, MacNeil A, Douglas R H, Salt T E, Akimoto M, Swaroop A, Sowden J C, Ali R R
Division of Molecular Therapy, University College London Institute of Ophthalmology, 11-43 Bath Street, London EC1V 9EL, UK.
Nature. 2006 Nov 9;444(7116):203-7. doi: 10.1038/nature05161.
Photoreceptor loss causes irreversible blindness in many retinal diseases. Repair of such damage by cell transplantation is one of the most feasible types of central nervous system repair; photoreceptor degeneration initially leaves the inner retinal circuitry intact and new photoreceptors need only make single, short synaptic connections to contribute to the retinotopic map. So far, brain- and retina-derived stem cells transplanted into adult retina have shown little evidence of being able to integrate into the outer nuclear layer and differentiate into new photoreceptors. Furthermore, there has been no demonstration that transplanted cells form functional synaptic connections with other neurons in the recipient retina or restore visual function. This might be because the mature mammalian retina lacks the ability to accept and incorporate stem cells or to promote photoreceptor differentiation. We hypothesized that committed progenitor or precursor cells at later ontogenetic stages might have a higher probability of success upon transplantation. Here we show that donor cells can integrate into the adult or degenerating retina if they are taken from the developing retina at a time coincident with the peak of rod genesis. These transplanted cells integrate, differentiate into rod photoreceptors, form synaptic connections and improve visual function. Furthermore, we use genetically tagged post-mitotic rod precursors expressing the transcription factor Nrl (ref. 6) (neural retina leucine zipper) to show that successfully integrated rod photoreceptors are derived only from immature post-mitotic rod precursors and not from proliferating progenitor or stem cells. These findings define the ontogenetic stage of donor cells for successful rod photoreceptor transplantation.
在许多视网膜疾病中，光感受器的丧失会导致不可逆的失明。通过细胞移植修复此类损伤是中枢神经系统修复中最可行的方法之一；光感受器变性最初会使视网膜内层电路保持完整，新的光感受器只需建立单一的短突触连接就能对视网膜拓扑图做出贡献。到目前为止，移植到成年视网膜中的脑源性和视网膜源性干细胞几乎没有证据表明能够整合到外核层并分化为新的光感受器。此外，也没有证据表明移植的细胞能与受体视网膜中的其他神经元形成功能性突触连接或恢复视觉功能。这可能是因为成熟的哺乳动物视网膜缺乏接受和整合干细胞或促进光感受器分化的能力。我们推测，个体发育后期的定向祖细胞或前体细胞在移植后可能有更高的成功几率。在此我们表明，如果从发育中的视网膜中在视杆细胞生成高峰期获取供体细胞，它们就能整合到成年或退化的视网膜中。这些移植的细胞能够整合、分化为视杆光感受器、形成突触连接并改善视觉功能。此外，我们使用表达转录因子Nrl（参考文献6）（神经视网膜亮氨酸拉链）的基因标记的有丝分裂后视杆前体细胞来表明，成功整合的视杆光感受器仅来源于未成熟的有丝分裂后视杆前体细胞，而非增殖的祖细胞或干细胞。这些发现确定了成功进行视杆光感受器移植的供体细胞的个体发育阶段。
