Hematopoietic Stem Cells Regenerate RPE

造血干细胞再生 RPE

基本信息

批准号：
8053316
负责人：
Edward W Scott
金额：
$ 31.33万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-04-01 至 2013-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8053316
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 Disease Electron Microscopy Eye Female Free Radicals Functional disorder Genes Head Hematopoietic Hematopoietic stem cells Hereditary Disease Home environment Homing Human Injury Integrin alpha4beta1 Integrin alpha5beta1 Knockout Mice Leukocytes Link Melanins Melanosomes Metabolic Modeling Monocyte Chemoattractant Protein-1 Morphology Mus Natural regeneration Organ PTPRC gene Pathology Patients Phagocytosis Phase Physiology Pigments Production Proteins Recruitment Activity Research Personnel Retina Retinal Retinal Cone Retinitis Pigmentosa Selectins Siblings Stargardt&apos 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 Viral Vector Visual Acuity Visual Cortex Y Chromosome aged base blocking factor cohort cytokine improved in vivo injured light microscopy macrophage male oxidative damage programs repaired response retina blood vessel structure retinal rods sex stem success transcription factor

项目摘要

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）的功能障碍与多种眼部疾病有关，包括与年龄相关的黄斑变性（AMD）以及遗传性疾病以及诸如Stargardt病和视网膜炎的遗传性疾病。 RPE具有多种关键功能，可保护视网膜的其他细胞并保持适当的视网膜生理。对于眼睛，RPE层像组织巨噬细胞一样在其他器官中起作用。以这种身份，RPE不断暴露于自由基释放和其他代谢分解产品。随着年龄的增长，累积的损害可降低整体RPE功能，这似乎是AMD建立和发展的关键步骤。通常认为RPE是终端分化的细胞，几乎没有证据表明该层翻转或再生。几种治疗模型试图通过直接移植代替眼睛内的RPE。到目前为止，这些模型取得了非常有限的成功。 RPE层的一个标志是生产各种细胞因子，例如MCP-1和SDF-1。 SDF-1是造血茎和祖细胞（HSC/HPC）的主要募集因子之一。脉络膜的充足血液供应可提供HSC/HPC进入RPE层。基于这些数据，我们测试了HSC/HPC是否可以有助于RPE层的修复和再生。我们对RPE层使用了三种急性损伤模型，然后使用标记的HSC/HPC移植。在每个型号中，供体HSC/HPC都能在受伤的RPE层中归还并集成。供体HSC/HPC衍生细胞采用了RPE的特征立方体形态，通过电子和光学显微镜在白化病接受者中表达黑色素，以及PAN白细胞标记CD45表达的丧失。总体而言，数据表明HSC/HPC可以募集到受伤的RPE层，在那里它们分化为RPE或RPE样细胞。在此提案中，我们试图扩展这些初始发现并测试以下特定假设：AIM 1：HSC/HPC可以在急性损伤后修复RPE功能。目标2：募集HSC/HPC到急性RPE损伤区域需要受伤区域的特定细胞因子表达。这些细胞因子反应的增强应改善HSC/HPC修复。 AIM 3：HSC/HPC还可以响应慢性损伤而再生RPE。