Stem Cell-Based Therapies for Radiation-Induced Gastrointestinal Sydrome (RIGS)

基于干细胞的放射诱发胃肠道综合症 (RIGS) 疗法

• 批准号: 8013164
• 负责人: Chandan Guha
• 金额: $ 38.87万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8013164
• 关键词: Abdomen; Acceleration; Acute; Agonist; Animals; Apoptosis; Biological Markers; Biological Models; Blood Transfusion; Bone Marrow; Bone Marrow Transplantation; Cell Culture Techniques; Cell Death; Cell Proliferation; Cell Therapy; Cells; DNA Damage; Defect; Dehydration; Dose; Endothelial Cells; Enterocytes; Exposure to; Financial compensation; Goals; Growth; Growth Factor; Hematopoietic; Hemorrhage; Histopathology; Homeostasis; Hour; In Situ; Infection; Infection prevention; Inflammation Mediators; Injury; Intestinal Mucosa; Intestines; Ionizing radiation; Ligands; Lymphocyte; Macrophage Activation; Mediating; Mesenchymal; Mesenchymal Stem Cells; Modeling; Molecular Target; Mus; Natural regeneration; Organ; Plasma; Proliferating; Proteomics; Radiation; Radiation Syndromes; Radiation Toxicity; Radiation therapy; Radio; Radioprotection; Receptor Activation; Receptor Signaling; Replacement Therapy; Sepsis Syndrome; Septic Shock; Signal Pathway; Signal Transduction; Solid; Stem cells; Stromal Cells; Supporting Cell; Supportive care; Syndrome; Therapeutic; Tissue Model; Tissues; Toll-like receptors; Transplantation; Validation; base; bone morphogenetic protein 4; cell growth; cell injury; cytokine; gastrointestinal; improved; intestinal crypt; irradiation; macrophage; metabolomics; microbial; pathogen; regenerative; regenerative therapy; repaired; research study; response; stem cell niche

Radiation-induced gastrointestinal syndrome (RIGS) results from a combination of direct cytocidal effects on intestinal crypt and endothelial cells and subsequent loss of the mucosal barrier, resulting in microbial infection, septic shock and systemic infiammatory response syndrome. Currentiy, there is no therapy for RIGS. Irradiation induces apoptosis of crypt endothelial cells, intestinal stem cells (ISC) and enterocytes within hours. We rationalized that the acute loss of cells in situ requires rapid compensation of their functions and this was best achieved with cell replacement therapies, e.g., blood transfusion for hemorrhage. The stroma of solid organs contains a variety of supporting cells, such as, mesenchymal and microvascular endothelial cells, macrophages and lymphocytes. These stromal cells provide the niche and could supply critical growth factor/signals for ISC regeneration. For example, upon intestinal mucosal disruption, resident macrophages in the intestinal submocosal layers are activated by pathogen-derived ligands for Toll-like receptors (TLR) and transmit regenerative signals to ISCs. We thereby propose intestinal regenerative therapy with a combination of systemic administration of growth factors and cell replacement therapy to salvage Gl function post-radiation exposure. In order to develop an stem cell-based therapeutic strategy for RIGS, we hypothesized that combinations of: a) intestinal stem cell growth factor, R-spondinl (R-spol), b) TLR ligands, and c) transplantation of bone marrow-derived endothelial progenitor cells (EPC) and mesenchymal stem cells (MSC) would restore the IR-damaged ISC niche, protect against IR-induced cell death and provide growth signals for host ISC regeneration, thus providing protection and mitigation from RIGS. Aim I Pathophysiologic Mechanisms, Discovery and Validation of Molecular Targets in RIGS Aim II will investigate whether acceleration of ISC regeneration could mitigate/protect RIGS by administration of a Wnt agonist, R-spondinl and a BMP antagonist. Aim III will examine whether repair of the ISC niche by TLR activation and/or bone marrow-derived adherent stromal cell-based therapies could mitigate RIGS in mice. The final goal is to identify radio-mitigating factors secreted by stromal cells

辐射诱发的胃肠道综合征 (RIGS) 是由对肠隐窝和内皮细胞的直接杀细胞作用以及随后的粘膜屏障丧失共同导致的，导致微生物感染、感染性休克和全身炎症反应综合征。目前，RIGS 尚无治疗方法。辐射在数小时内诱导隐窝内皮细胞、肠干细胞（ISC）和肠上皮细胞凋亡。我们认为，原位细胞的急性损失需要快速补偿其功能，而这最好通过细胞替代疗法来实现，例如针对出血进行输血。实体器官的基质含有多种支持细胞，例如间充质和微血管内皮细胞、巨噬细胞和淋巴细胞。这些基质细胞提供了生态位，并且可以为 ISC 再生提供关键的生长因子/信号。例如，在肠粘膜破坏时，肠粘膜下层中的常驻巨噬细胞被 Toll 样受体 (TLR) 的病原体衍生配体激活，并向 ISC 传递再生信号。因此，我们建议采用生长因子的全身施用和细胞替代疗法相结合的肠道再生疗法来挽救放射暴露后的胃肠道功能。为了开发基于干细胞的 RIGS 治疗策略，我们假设以下组合：a) 肠干细胞生长因子、R-spondinl (R-spol)、b) TLR 配体和 c) 骨髓移植衍生的内皮祖细胞（EPC）和间充质干细胞（MSC）将恢复IR损伤的ISC生态位，防止IR诱导的细胞死亡，并为宿主ISC再生提供生长信号，从而提供RIGS 的保护和缓解。目标 I RIGS 中分子靶点的病理生理机制、发现和验证 目标 II 将研究 ISC 再生的加速是否可以通过施用 Wnt 激动剂、R-spondinl 和 BMP 拮抗剂来减轻/保护 RIGS。目标 III 将检查通过 TLR 激活和/或基于骨髓的贴壁基质细胞疗法修复 ISC 生态位是否可以减轻 RIGS 老鼠。最终目标是识别基质细胞分泌的放射缓解因子