Hematopoietic stem and progenitor cell regulation of the niche through extracellular vesicles

造血干细胞和祖细胞通过细胞外囊泡调节生态位

• 批准号: 10634681
• 负责人: Peter Kurre
• 金额: $ 44万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10634681
• 关键词: Acute Myelocytic Leukemia; Adoptive Transfer; Allogenic; Autologous; Back; Biogenesis; Biological; Blood Tests; Blood Vessels; Bone Marrow; CD34 gene; CRISPR/Cas technology; Candidate Disease Gene; Cell Cycle; Cell physiology; Cells; Complex; Cues; Data; Defect; Development; Disabled Persons; Disease; Elements; Endothelial Cells; Engraftment; Event; FRAP1 gene; Generations; Genetic; Goals; Hematologic Neoplasms; Hematopoiesis; Hematopoietic; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Homeostasis; Homing; Homologous Transplantation; In Vitro; Inflammatory; Integrins; Knowledge; Measures; Mediating; Membrane; MicroRNAs; Modeling; Mus; Non-Malignant; Outcome; Output; Pathway interactions; Patients; Population; Process; Progenitor Cell Engraftment; Proliferating; Property; Proteins; RNA; Regenerative capacity; Regulation; Role; Shapes; Signal Pathway; Signal Transduction; Specificity; Stimulus; Stress; Stromal Cell-Derived Factor 1; Supporting Cell; System; Testing; Tissues; Toxic effect; Transplant Recipients; Transplantation; Transplantation Conditioning; Vascularization; Vesicle; Work; allogeneic disease; cell motility; cellular targeting; conditioning; effective therapy; extracellular vesicles; fitness; functional outcomes; gene therapy; improved; improved outcome; in vivo; insight; interest; leukemia; nanoscale; novel strategies; paracrine; permissiveness; pharmacologic; progenitor; programs; receptor; regenerative; self-renewal; side effect; single-cell RNA sequencing; stem cell function; stem cell gene therapy; stem cell niche; trafficking; trait; transplantation therapy; uptake; vesicular release

ABSTRACT Adoptive transfer of hematopoietic stem and progenitor cells (HSPC) can provide effective treatment for non- malignant disorders in the form of allogeneic hematopoietic stem cell transplantation (HSCT) or as a platform for autologous gene therapy. Bone marrow (BM) niches are the operationally-defined core units that sustain hematopoietic function, where signals from non-hematopoietic support cells adapt HSPC output to organismal demand. HSPC occupancy in the BM, however, is a competitive process, and HSCT patients typically require conditioning to eliminate endogenous hematopoiesis and “create space”, thereby promoting homing and engraftment in highly vascularized niches. Secretory activity is a fundamental HSPC property, but the impact of signals that emerge from HSPC, and their cellular targets in the niche are not well understood. The gap in knowledge regarding the crosstalk between HSPC and vascular niche endothelial cells specifically, may hold important biological insight and opportunities to improve competitive HSPC niche fitness, and a potentially novel strategy to offset the toxicity and long-term side effects from HSCT conditioning treatments. The secretion of nanometer sized extracellular vesicles (EVs) that traffic protein and RNA cargo is a constitutive cellular function. Intriguingly, mobilized CD34+ HSPC -which provide known advantages to engraftment after HSCT- have been shown to release EVs (EVCD34) that are highly abundant in microRNA-126, an “angiomiR” that regulates Akt/mTOR signaling, which in turn is central to EC hematopoiesis support. Others showed that adoptively transferred EVCD34, rich in miR-126, enhance EC proliferation and function. Our principal hypothesis is that EVHSPC trafficking of miR-126 actively shapes EC function in the vascular BM niche to enhance occupancy and improve repopulation. Three aims will test our hypothesis. In Aim 1 we will determine the cell-autonomous impact of EVHSPC secretion on self-renewal and repopulation potency under conditions of homeostasis and stress. Aim 2 will test the role of endothelial cells as predominant cellular targets for EV trafficking in the BM niche. Aim 3 will dissect the specific role of miR-126 and in regulating BM endothelial cell fates and the involved signaling pathways. As a proof of principle study, this proposal places an experimental and mechanistic focus on EVHSPC, but insight into the biologic role of the HSPC secretome in the BM niche will be broad. Translationally, our long-term goal is the development of new, non-toxic approaches to improve outcomes after allogeneic HSCT and autologous gene therapy.

抽象的 造血干和祖细胞（HSPC）的过继转移可以为非 - 以同种异体造血干细胞移植（HSCT）或平台形式的恶性疾病 用于自体基因疗法。骨髓（BM）壁ches是维持操作定义的核心单位 造血功能，其中来自非杂波支持细胞的信号使HSPC输出适应有机 要求。但是，BM中的HSPC占用率是一个竞争过程，HSCT患者通常需要 调节以消除内源性造血并“创造空间”，从而促进归宿和 在高度血管化的壁ni中植入。秘书活动是HSPC的基本财产，但影响 从HSPC出现的信号及其在利基市场中的细胞靶标的信号尚不清楚。差距 有关HSPC和血管壁细胞内皮细胞之间串扰的知识，可能会持有 重要的生物学洞察力和改善竞争性HSPC利基健身的机会，并可能 HSCT调节治疗的毒性和长期副作用的新型策略。这 分泌纳米大小的细胞外蔬菜（EV），交通蛋白和RNA货物是一致的 细胞功能。有趣的是，动员的CD34+ HSPC-可在 HSCT-已显示出在MicroRNA-126中释放高度丰富的EVS（EVCD34），一种“ Angiomir” 调节AKT/MTOR信号传导，这反过来属于EC造血的核心。其他人则表明了这一点 富含miR-126的EVCD34转移，增强了EC的增殖和功能。我们的校长 假设是miR-126的EVHSPC运输在血管BM生态位中积极塑造EC的功能 提高占用率并改善重生。三个目标将检验我们的假设。在目标1中，我们将 确定EVHSPC分泌对自治的细胞自主影响对自我更新和重新分配效力的影响 体内平衡和压力的条件。 AIM 2将测试内皮细胞作为主要细胞的作用 BM利基市场中电动汽车贩运的目标。 AIM 3将剖析miR-126和在调节BM中的特定作用 内皮细胞命运和所涉及的信号通路。作为主要研究的证明，该提议位置 对EVHSPC的实验和机械重点，但对HSPC分泌组生物学作用的见解 BM利基市场将很广泛。翻译上，我们的长期目标是发展新的无毒 同种异体HSCT和自体基因疗法后改善预后的方法。