Direct cell to cell transfer of microRNA for tissue repair

直接细胞间转移 microRNA 用于组织修复

• 批准号: 8915212
• 负责人: Jan A. Nolta
• 金额: $ 53.38万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-30 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8915212
• 关键词: Acute; Anti-Inflammatory Agents; Anti-inflammatory; Apoptosis; Applications Grants; Area; Biological Models; Biophotonics; Blood Circulation; Cell Communication; Cell Survival; Cells; Cellular biology; Cessation of life; Coculture Techniques; Collaborations; Complex; Data; Disease; Disease Outcome; Distant; Endothelial Cells; Engineering; Equipment; Extracellular Protein; Gap Junctions; Gene Expression; Growth; Healed; Hematopoietic stem cells; Hindlimb; Histology; Human; Human Biology; Hypoxia; Image; In Vitro; Injection of therapeutic agent; Injury; Interdisciplinary Study; Ischemia; Lasers; Mammalian Cell; Matrix Metalloproteinases; Mediating; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Methods; MicroRNAs; Modeling; Molecular; Mus; Myocardial Infarction; Nature; Nerve; Neurons; Outcome; PECAM1 gene; Pathway interactions; Production; Proteins; RNA; RNA Interference; Recovery; Research; Site; Small Interfering RNA; Small RNA; Specific qualifier value; Staining method; Stains; Stromal Cells; System; Techniques; Testing; Tissue Model; Tissues; Transfer RNA; Transgenes; Transgenic Mice; Transplantation; Tube; Ulcer; Video Microscopy; Waxes; Western Blotting; Work; Xenograft procedure; axonal pathfinding; cell injury; cell type; cellular engineering; cellular imaging; chemokine; cytokine; design; efficacy testing; healing; in vivo; interest; mouse model; nerve stem cell; novel; overexpression; receptor; repaired; restoration; tissue repair; translational medicine; uptake; wound

DESCRIPTION (provided by applicant): The transformative nature of our research lies in the detailed study of cell-to-cell communication through direct exchange of small RNA species, including regulatory microRNA. For the past twenty years we have studied the biology of human mesenchymal stem cells and have engineered them to become delivery vehicles to secrete transgene protein products for receptor-mediated uptake by surrounding cells in a damaged tissue or by distant cells through systemic protein production. However in the past two years we have developed new as-yet unpublished data showing that direct transfer of RNA species can occur from the MSC to target cells through direct cell-to- cell communication. Through the use of advanced videomicroscopy and molecular techniques we have determined that this cell-contact-dependent intercellular transfer does not occur through small gap junctions but rather through exosomal transport and direct shuttle of small RNA species through tunneling nanotubules. Mesenchymal stem cells are known to respond rapidly to a damaged, hypoxic or inflamed microenvironment and to support the growth, survival and differentiation of other cell types, including hematopoietic stem cells, cells of the vasculature, neurons and others. This phenomenon has been thought to be almost entirely due to the secretion of extracellular proteins. In contrast, we hypothesize that the control of the fate of target cells by MSC can be also mediated through direct transfer of RNA species. We hypothesize that direct transfer of microRNA from human MSC to target cells is a common mechanism for modulating tissue repair and increasing target cell survival at sites of injury. Our planned studies will use our established xenotransplantation wound model systems to explore this novel, unconventional, and potentially paradigm-shifting hypothesis.

描述（由申请人提供）：我们研究的变革性本质在于通过直接交换小 RNA 种类（包括调节性 microRNA）来详细研究细胞间通讯。在过去的二十年里，我们研究了人类间充质干细胞的生物学，并将它们改造为输送载体，分泌转基因蛋白产物，通过全身蛋白生产，由受损组织中的周围细胞或远处细胞通过受体介导的摄取。然而，在过去两年中，我们开发了尚未发表的新数据，表明 RNA 物质可以通过直接细胞间通讯从 MSC 直接转移到靶细胞。通过使用先进的视频显微镜和分子技术，我们确定这种依赖于细胞接触的细胞间转移不是通过小间隙连接发生的，而是通过外泌体运输和小RNA种类通过隧道纳米管的直接穿梭发生的。众所周知，间充质干细胞能够对受损、缺氧或发炎的微环境做出快速反应，并支持其他细胞类型的生长、存活和分化，包括造血干细胞、脉管系统细胞、神经元等。这种现象被认为几乎完全是由于细胞外蛋白质的分泌造成的。相反，我们假设 MSC 对靶细胞命运的控制也可以通过 RNA 种类的直接转移来介导。我们假设将 microRNA 从人类 MSC 直接转移到靶细胞是调节组织修复和增加损伤部位靶细胞存活的常见机制。我们计划的研究将使用我们已建立的异种移植伤口模型系统来探索这种新颖的、非常规的、潜在的范式转变的假设。

项目成果

Concise review: MicroRNA function in multipotent mesenchymal stromal cells.

• DOI: 10.1002/stem.1623
• 发表时间: 2014-05
• 期刊: STEM CELLS
• 影响因子: 5.2
• 作者: Clark, Elizabeth A.;Kalomoiris, Stefanos;Nolta, Jan A.;Fierro, Fernando A.
• 通讯作者: Fierro, Fernando A.