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， 固有低细胞剂量导致移植物植入延迟和移植物失败，严重限制了这种方法的广泛应用 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）将提供更快的造血重建，以及更少的 移植失败，比未经处理的CB细胞。事实上，CB单核细胞/MSC共培养系统 我们已经开发了应该避免显着的CD 34+细胞损失，我们经历了早期的液体 悬浮培养研究，因为它提供了一个替代生态位的繁殖CB 祖细胞，总体上应该产生改善的CB细胞扩增。这一预测将在第1阶段进行测试。 在接受CB移植治疗恶性血液病的患者中进行的临床试验（目的1.1）， 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， 共培养体系（Aim 1.2）。虽然低细胞剂量显然是CB移植的主要限制， 许多研究者报道了CB细胞归巢到骨髓的缺陷。因此即使 改善CB扩展。不充分的归巢可能会限制植入的速度-这一点的重点 研究项目。归巢缺陷归因于细胞表面低水平的岩藻糖基化 负责结合P-和/或E-选择的分子，这是 循环血液祖细胞被募集到骨髓微血管系统中。我们假设， CB细胞表面岩藻糖基化的水平将改善与选择素的相互作用，从而改善归巢 然后移植。因此，为了评估未操作和扩增的CB祖细胞的修饰， 与岩藻糖基转移酶，作为手段，以促进他们的招聘到骨髓，我们已经计划了两个， 临床试验（目标2）和小鼠中的机制研究（目标3），其将对CB移植设置进行建模。 该项目的成功将有助于绕过有效CB移植的两个剩余障碍， 从而在缺乏实际治疗选择的患者中扩大了该方法的使用。