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Transfer of cell material by photoreceptor transplantation: mechanisms and implications on therapy development

通过光感受器移植转移细胞材料：机制及其对治疗开发的影响

基本信息

批准号：
386777266
负责人：
Professor Dr. Marius Ader
金额：
--
依托单位：
Zentrum für Regenerative Therapien Dresden - CRTD
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2017
资助国家：
德国
起止时间：
2016-12-31 至 2021-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/386777266?language=en
关键词：
Transfer cell material photoreceptor transplantation

项目摘要

Pre-clinical studies provided evidence for successful photoreceptor cell replacement therapy. Migration and integration of donor photoreceptors into the host retinal tissue has been proposed as the underlying mechanism for restored visual function. However, recent results reveal that donor photoreceptors do not structurally integrate into the retinal tissue but instead reside at the injection site between the photoreceptor layer and the retinal pigment epithelium, the so called subretinal space, and exchange cytoplasmic material with host photoreceptors. By combining single cell analysis, Cre/LoxP technology, and independent labelling of cytoplasm and nucleus we reliably tracked allogeneic transplants demonstrating for the first time transfer of cytoplasmic content between graft and host photoreceptors without nuclear translocation. This unexpected interaction of donor with host photoreceptors represents a paradigm shift in the photoreceptor transplantation field and has vital implications on photoreceptor replacement approaches, as the majority of studies published on this topic within the last decade will have to be re-interpreted. Although the mechanism of vision improvement by photoreceptor transplantation may be different than originally conceptualized, capitalizing on the exchange of intracellular material may represent a productive novel route for future therapeutic strategies. Therefore, we will decipher components and mechanisms involved in the material transfer between donor and host cells by assessing (i) the potential of different cell types for exchange of cellular material in the retina, (ii) the cellular components that are transferred between donor and host cells, (iii) potential mechanisms of cytoplasmic exchange, (iv) the influence of outer segment affecting retinopathies on material transfer, and (v) whether pluripotent stem cell-derived photoreceptors show a similar potential for transfer of intercellular components. The expected results will be of utmost importance for the development of novel therapy approaches aiming to repair dysfunctional photoreceptors and thus visual function.

临床前研究为成功的感光细胞替代疗法提供了证据。供体光感受器迁移和整合到宿主视网膜组织中已被认为是恢复视觉功能的潜在机制。然而，最近的结果表明，供体光感受器在结构上不整合到视网膜组织中，而是驻留在光感受器层和视网膜色素上皮之间的注射部位，即所谓的视网膜下空间，并与宿主光感受器交换细胞质物质。通过结合单细胞分析，Cre/LoxP技术，和细胞质和细胞核的独立标记，我们可靠地追踪了同种异体移植物，首次证明了移植物和宿主感光细胞之间的细胞质内容物转移，而没有核转位。供体与宿主光感受器的这种意想不到的相互作用代表了光感受器移植领域的范式转变，并对光感受器替代方法具有重要意义，因为在过去十年中发表的关于这一主题的大多数研究将不得不重新解释。虽然通过感光细胞移植改善视力的机制可能与最初的概念不同，但利用细胞内物质的交换可能是未来治疗策略的一种有效的新途径。因此，我们将通过评估（i）不同细胞类型在视网膜中交换细胞物质的潜力，（ii）在供体和宿主细胞之间转移的细胞组分，（iii）细胞质交换的潜在机制，（iv）影响视网膜病变的外节对物质转移的影响，和（v）多能干细胞衍生的光感受器是否显示出类似的细胞间成分转移潜力。预期的结果对于开发旨在修复功能失调的光感受器从而修复视觉功能的新治疗方法至关重要。