Rescue of retinal degeneration by intravitreally injected adult bone marrow-derived lineage-negative hematopoietic stem cells.
Rescue of retinal degeneration by intravitreally injected adult bone marrow-derived lineage-negative hematopoietic stem cells.
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DOI：
10.1172/jci21686
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发表时间：
2004-09
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影响因子：
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通讯作者：
A. Otani;Michael I. Dorrell;Karen Kinder;Stacey K. Moreno;S. Nusinowitz;E. Banin;J. Heckenlively;M. Friedlander
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作者：
A. Otani;Michael I. Dorrell;Karen Kinder;Stacey K. Moreno;S. Nusinowitz;E. Banin;J. Heckenlively;M. Friedlander
遗传性视网膜变性每3,500人中就有1人患有遗传性视网膜变性，是一组异质性疾病，会导致严重的视力丧失，通常是视网膜神经细胞凋亡的结果。视网膜血管系统的萎缩性改变也可在许多此类变性中观察到。虽然人们认为这种萎缩是继发性的，因为面对视网膜退行性变的代谢需求减少，但视网膜神经元和血管退行性变之间的确切关系尚不清楚。在这项研究中，我们证明了每当含有内皮前体的一小部分小鼠或人类成人骨髓来源的干细胞(谱系阴性的造血干细胞[LIN-HSCs])稳定并挽救通常会完全退化的视网膜血管时，也观察到了戏剧性的神经营养拯救效应。在两种视网膜变性的小鼠模型RD1和RD10中，视网膜核层被保存下来，并在被拯救的小鼠中观察到可检测到的、尽管严重异常的视网膜电信号记录，而在对照治疗或未治疗的眼睛中从未观察到这些记录。正常小鼠的视网膜主要由视杆细胞组成，但经LIN-HSCs治疗后被挽救的细胞几乎都是视锥细胞。对挽救的视网膜进行的微阵列分析表明，许多抗凋亡基因显著上调，包括小的热休克蛋白和转录因子。这些结果提出了一种新的范式来思考血管系统和相关的视网膜神经元组织之间的关系，以及一种潜在的治疗方法，无论潜在的遗传缺陷如何，都可以延缓与视网膜退化相关的视力丧失的进展。
Inherited retinal degenerations afflict 1 in 3,500 individuals and are a heterogeneous group of diseases that result in profound vision loss, usually the result of retinal neuronal apoptosis. Atrophic changes in the retinal vasculature are also observed in many of these degenerations. While it is thought that this atrophy is secondary to diminished metabolic demand in the face of retinal degeneration, the precise relationship between the retinal neuronal and vascular degeneration is not clear. In this study we demonstrate that whenever a fraction of mouse or human adult bone marrow-derived stem cells (lineage-negative hematopoietic stem cells [Lin- HSCs]) containing endothelial precursors stabilizes and rescues retinal blood vessels that would ordinarily completely degenerate, a dramatic neurotrophic rescue effect is also observed. Retinal nuclear layers are preserved in 2 mouse models of retinal degeneration, rd1 and rd10, and detectable, albeit severely abnormal, electroretinogram recordings are observed in rescued mice at times when they are never observed in control-treated or untreated eyes. The normal mouse retina consists predominantly of rods, but the rescued cells after treatment with Lin- HSCs are nearly all cones. Microarray analysis of rescued retinas demonstrates significant upregulation of many antiapoptotic genes, including small heat shock proteins and transcription factors. These results suggest a new paradigm for thinking about the relationship between vasculature and associated retinal neuronal tissue as well as a potential treatment for delaying the progression of vision loss associated with retinal degeneration regardless of the underlying genetic defect.