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更广泛的使用 宝贵的资源。因此，项目1的核心假设是CB祖细胞在体内扩展 间充质干细胞（MSC）将提供更快的造血重建，较少 植入失败，而不是未经操纵的CB细胞。实际上，CB单核细胞/MSC共培养系统 我们已经开发的应该避免在早期液体中遇到的明显CD34+细胞损失 暂停文化研究，因为它为CB的传播提供了一个替代利基市场 祖细胞应总体上产生改善的CB细胞扩展。该预测将在阶段1中进行测试 接受CB移植的血液系统恶性肿瘤的患者的临床试验（AIM 1.1），并与 机械研究以确定特定的CB“辅助”细胞是否抑制最佳扩张 共培养系统（AIM 1.2）。尽管低细胞剂量显然是CB移植的主要局限性，但 研究人员的数量报告了CB细胞向骨髓寄养的缺陷。因此，甚至 随着CB扩展的改善。不足的归宿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的岩藻糖基化水平较低 负责与P-和/或电子选择结合的分子，该机制的关键组成部分是 循环血祖招募到骨髓微脉管系统。我们假设增加 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，从而改善归宿 然后植入。因此，评估未操纵和扩展的CB祖细胞的修改 借助岩藻糖基转移酶，作为促进骨髓招募的手段，我们已经计划了 将在小鼠中进行临床试验（AIM 2）和机械研究（AIM 3），将对CB移植设置进行建模。 该项目的成功将有助于规避有效CB移植的剩余两个障碍， 从而扩大了该程序在其他缺乏实际治疗选择的患者中的使用。