Cord Blood Expansion and Homing to Improve Engraftment

脐带血扩张和归巢以改善植入

• 批准号: 9340308
• 负责人: Elizabeth J Shpall
• 金额: $ 24.82万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-22 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9340308
• 关键词: Address; Adhesives; Adult; Allogenic; Angioblast; Antigen-Presenting Cells; Binding; Biology; Bioluminescence; Blocking Antibodies; Blood; Blood Cells; Blood Platelets; Blood Vessels; Bone Marrow; CD14 gene; CD3 Antigens; CD34 gene; Cell Therapy; Cell surface; Cells; Child; Clinical Trials; Coculture Techniques; Coupled; Critiques; Data; Defect; Disadvantaged; Dose; E-Selectin; Engraftment; Erythrocytes; Excision; Failure; Flow Cytometry; Fucosyltransferase; Hematologic Neoplasms; Hematopoiesis; Hematopoietic; Hemorrhage; Homing; Immunodeficient Mouse; Infection; Infusion procedures; Integrins; Investigation; Lead; Leukocytes; Liquid substance; Marrow; Membrane Glycoproteins; Mesenchymal Stem Cells; Methods; Modeling; Modification; Mononuclear; Mus; Oxygen; Patients; Phase I Clinical Trials; Population; Procedures; Recombinants; Recovery; Recruitment Activity; Reporting; Research Personnel; Research Project Grants; Resources; Safety; Selectins; Series; Surface; Survival Rate; Suspension Culture; System; T-Lymphocyte; Techniques; Testing; Therapeutic; Time; Transplant Recipients; Transplantation; Umbilical Cord Blood; Umbilical Cord Blood Transplantation; base; chemokine; cost; experience; fighting; graft failure; improved; migration; molecular imaging; mouse model; pre-clinical; prevent; progenitor; reconstitution; research clinical testing; research study; success

Umbilical cord blood (CB) can serve as an alternative graft for patients lacking a matched related donor, yet intrinsically low cell doses leading to delayed engraftment and graft failure severely restrict wider use of this valuable resource. Hence, the central hypothesis of Project 1 is that CB progenitors expanded ex vivo on mesenchymal stem cells (MSCs) will provide more rapid hematopoietic reconstitution, as well as less engraftment failure, than unmanipulated CB cells. Indeed, the CB mononuclear cell/MSC co-culture system we have developed should avoid the significant CD34+ cell losses we experienced in earlier liquid suspension culture studies and, because it provides a surrogate niche for the propagation of CB progenitors, should yield improved CB cell expansion overall. This prediction will be tested in a phase 1 clinical trial in patients undergoing CB transplantation for hematologic malignancies (Aim 1.1), coupled with mechanistic studies to determine if optimal expansion is inhibited by specific CB "accessory" cells in the coculture system (Aim 1.2). Although a low cell dose is clearly the chief limitation of CB transplantation, a number of investigators have reported a defect in the homing of CB cells to the bone marrow. Thus, even with improved CB expansion. Inadequate homing may limit the rapidity of engraftment ~ the focus of this research project. The homing defect has been attributed to low levels of fucosylation of cell surface molecules responsible for binding to P- and/or E-selections, a key component of the mechanism by which circulating blood progenitors are recruited to the marrow microvasculature. We hypothesize that increasing the level of CB cell surface fucosylation will improve interactions with selectins, thereby improving homing and then engraftment. Thus, to assess the modification of unmanipulated and expanded CB progenitors with fucosyltransferase, as means to facilitate their recruitment to the marrow, we have planned both a clinical trial (Aim 2) and mechanistic studies in mice (Aim 3) that will model the CB transplant setting. Success in this project will help to circumvent two of the remaining barriers to effective CB transplantation, thereby broadening the use of this procedure in patients who otherwise lack practical therapeutic options.

脐带血（CB）可以作为缺乏匹配的相关供体的患者的替代移植物，但 本质上低细胞剂量导致延迟植入和移植失败严重限制了其更广泛的使用 宝贵的资源。因此，项目 1 的中心假设是 CB 祖细胞在体外扩增 间充质干细胞（MSC）将提供更快速的造血重建，并且更少 与未操作的 CB 细胞相比，植入失败。事实上，CB 单核细胞/MSC 共培养系统 我们已经开发出应该避免我们在早期液体中经历的显着 CD34+ 细胞损失 悬浮培养研究，因为它为 CB 的繁殖提供了替代生态位 祖细胞，应该会产生总体上改善的 CB 细胞扩增。该预测将在第一阶段进行测试 在接受 CB 移植治疗血液恶性肿瘤的患者中进行的临床试验（目标 1.1），并结合 机制研究以确定最佳扩增是否受到特定 CB“辅助”细胞的抑制 共培养系统（目标 1.2）。尽管低细胞剂量显然是 CB 移植的主要限制， 许多研究人员报告了 CB 细胞归巢到骨髓的缺陷。因此，即使 改进了 CB 扩展。归巢不足可能会限制植入的速度~本篇的重点 研究项目。归巢缺陷归因于细胞表面岩藻糖基化水平低 负责与 P-和/或 E-选择结合的分子，这是该机制的关键组成部分 循环血液祖细胞被募集至骨髓微脉管系统。我们假设增加 CB细胞表面岩藻糖基化水平将改善与选择素的相互作用，从而改善归巢 然后植入。因此，评估未操作和扩增的 CB 祖细胞的修饰 利用岩藻糖基转移酶，作为促进其招募到骨髓的手段，我们计划了 临床试验（目标 2）和小鼠机制研究（目标 3）将模拟 CB 移植环境。 该项目的成功将有助于克服有效CB移植的两个剩余障碍， 从而扩大了该手术在缺乏实用治疗选择的患者中的应用。