Hematopoietic Stem Cells Regenerate RPE

造血干细胞再生 RPE

• 批准号: 7245351
• 负责人: Edward W Scott
• 金额: $ 32.96万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7245351
• 关键词: Acute; Adopted; Age; Age related macular degeneration; Animals; Area; Bone Marrow; Bone Marrow Transplantation; Brain; Catalytic RNA; Cell Adhesion Molecules; Cells; Cessation of life; Characteristics; Choroid; Chronic; Clinical; Data; Depth; Disease; Electrons; Eye; Female; Free Radicals; Functional disorder; Genes; Head; Hematopoietic; Hematopoietic stem cells; Hereditary Disease; Home environment; Homing; Human; Injury; Integrin alpha4beta1; Knockout Mice; Leukocytes; Link; Melanins; Melanosomes; Metabolic; Modeling; Monocyte Chemoattractant Protein-1; Morphology; Mus; Natural regeneration; Organ; PTPRC gene; Pan Genus; Pathology; Patients; Phagocytosis; Phase; Physiology; Pigments; Production; Proteins; Recruitment Activity; Research Personnel; Retina; Retinal; Retinal Cone; Retinitis Pigmentosa; Selectins; Siblings; Stargardt' s disease; Stem cells; Stress; Stromal Cell-Derived Factor 1; Structure; Structure of retinal pigment epithelium; Superoxide Dismutase; Testing; Therapeutic; Tight Junctions; Tissues; Transplantation; Vascular blood supply; Vertebrate Photoreceptors; Viral Vector; Visual Acuity; Visual Cortex; Y Chromosome; aged; base; blocking factor; cohort; cytokine; improved; in vivo; injured; light microscopy; macrophage; male; programs; repaired; response; retina blood vessel structure; sex; stem; success; transcription factor

DESCRIPTION (provided by applicant): Dysfunction of the retinal pigmented epithelium (RPE) has been linked to a variety of ocular disorders including age-related macular degeneration (AMD) as well as hereditary disorders such as Stargardt's disease and Retinitis Pigmentosa. The RPE has a wide variety of crucial functions that serve to protect the other cells of the retina and maintain proper retinal physiology. For the Eye the RPE layer Functions as tissue macrophages do in other organs. In this capacity the RPE are constantly exposed to free radical release and other metabolic breakdown products. With age the accumulated damage serves to decrease overall RPE function, which appears to be a critical step in the establishment and progression of AMD. RPE are generally considered to be terminally differentiated cells with little or no evidence that the layer turns over or regenerates. Several therapeutic models attempt to replace RPE within the eye by direct transplant. These models have so far yielded very limited success. One hallmark of the RPE layer is the production of a variety of cytokines such as MCP-1 and SDF-1. SDF-1 is one of the primary recruitment Factors for the hematopoietic stem and progenitor cells (HSC/HPC). The ample blood supply of the choroid provides HSC/HPC access to the RPE layer. Based on these data we tested whether HSC/HPC can contribute to repair and regeneration of the RPE layer. We used three models of acute injury to the RPE layer followed by tagged HSC/HPC transplantation. In each model donor HSC/HPC were able to home to and integrate within the injured RPE layer. The donor-HSC/HPC derived cells adopted the characteristic cuboidal morphology of RPE, expressed melanin by electron and light microscopy in albino recipients, and the loss of expression of the pan leukocyte marker CD45. Collectively, the data suggests that HSC/HPC can be recruited to an injured RPE layer where they differentiate into RPE or RPE-like cells. In this proposal we seek to extend these initial findings and test the following specific hypotheses: Aim 1: HSC/HPC can repair RPE function following an acute injury. Aim 2: Recruitment of HSC/HPC to areas of acute RPE injury requires specific cytokine expression by the injured area. Enhancement of these cytokine responses should improve HSC/HPC repair. Aim 3: HSC/HPC can also regenerate the RPE in response to chronic injury.

描述（由申请人提供）：视网膜色素上皮（RPE）功能障碍与多种眼部疾病有关，包括年龄相关性黄斑变性（AMD）以及遗传性疾病，例如斯塔加特氏病和色素性视网膜炎。 RPE 具有多种重要功能，可保护视网膜的其他细胞并维持适当的视网膜生理机能。对于眼睛，RPE 层的功能与组织巨噬细胞在其他器官中的功能相同。在这种情况下，RPE 不断暴露于自由基释放和其他代谢分解产物。随着年龄的增长，累积的损伤会降低整体 RPE 功能，这似乎是 AMD 形成和发展的关键一步。 RPE 通常被认为是终末分化细胞，很少或没有证据表明该层翻转或再生。一些治疗模型试图通过直接移植来替代眼内的 RPE。迄今为止，这些模型取得的成功非常有限。 RPE 层的标志之一是产生多种细胞因子，例如 MCP-1 和 SDF-1。 SDF-1 是造血干细胞和祖细胞 (HSC/HPC) 的主要招募因子之一。脉络膜充足的血液供应为 HSC/HPC 提供了到达 RPE 层的通道。根据这些数据，我们测试了 HSC/HPC 是否有助于 RPE 层的修复和再生。我们使用了三种 RPE 层急性损伤模型，然后进行标记的 HSC/HPC 移植。在每个模型中，供体 HSC/HPC 都能够归巢并整合到受伤的 RPE 层中。供体 HSC/HPC 衍生的细胞采用了 RPE 的特征性立方体形态，通过电子和光学显微镜在白化受体中表达黑色素，并且全白细胞标记物 CD45 的表达缺失。总的来说，数据表明 HSC/HPC 可以被募集到受损的 RPE 层，在那里它们分化成 RPE 或 RPE 样细胞。在本提案中，我们寻求扩展这些初步发现并测试以下具体假设： 目标 1：HSC/HPC 可以修复急性损伤后的 RPE 功能。目标 2：将 HSC/HPC 募集到急性 RPE 损伤区域需要受伤区域表达特异性细胞因子。这些细胞因子反应的增强应该可以改善 HSC/HPC 的修复。目标 3：HSC/HPC 还可以再生 RPE 以应对慢性损伤。