Hematopoietic Progenitor Cells - Cord Blood

造血祖细胞 - 脐带血

• 批准号: 8056503
• 负责人: Elizabeth J Shpall
• 金额: $ 31万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-09-17 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8056503
• 关键词: Binding; Blood Cells; Blood Platelets; Bone Marrow; CD34 gene; Cell physiology; Cell surface; Cells; Clinical; Coculture Techniques; Commit; Complement; Data; Defect; Disadvantaged; Dose; E-Selectin; Engraftment; Failure; Fucosyltransferase; Funding; Generations; Goals; Grant; Hematologic Neoplasms; Hematopoiesis; Hematopoietic; Hematopoietic stem cells; Hemorrhage; Hereditary Disease; Home environment; Homing; Immunodeficient Mouse; Infusion procedures; Laboratories; Lead; Liquid substance; Marrow; Megakaryocytes; Membrane Glycoproteins; Mesenchymal Stem Cells; Modification; Mononuclear; Morbidity - disease rate; Mus; Outcome; Patients; Population; Recombinants; Reporting; Research; Research Personnel; Resources; Safety; Selectins; Siblings; Staging; Stem cells; Surface; Suspension Culture; System; Testing; Time; Transplant Recipients; Transplantation; Umbilical Cord Blood; Umbilical Cord Blood Transplantation; base; cost; decision research; design; extracellular; high risk; improved; in vivo; innovation; neutrophil; progenitor; public health relevance; reconstitution; research clinical testing; research study; stem cell niche; sugar; trend

DESCRIPTION (provided by applicant): Umbilical cord blood (CB) is used increasingly to restore hematopoiesis in transplant patients lacking sibling, or unrelated donors. A major disadvantage of CB transplantation (CBT) is the low cell dose with resultant delays in neutrophil and platelet engraftment, as well as a high rate of engraftment failure. A major hypothesis of this grant is that ex vivo-expanded CB progenitors will provide more rapid hematopoietic reconstitution and less engraftment failure than unmanipulated CB. In the two clinical CB expansion trials conducted during the last RO1 funding period, CD133+ progenitors were isolated and cultured ex vivo in a liquid culture system targeting committed, or more primitive hematopoietic progenitors. In those sequential trials, trends in faster time to engraftment were seen, but significant losses of CD34+ progenitors occurred. To avoid the need for positive selection, which results in a substantial loss of CD34+ cells, we have developed an alternative approach that involves the ex vivo co-culture of CB mononuclear cells (MNC) with bone marrow-derived mesenchymal stem cells (MSC). We hypothesize that MSC, by functioning as a surrogate hematopoietic 'niche', will provide a more suitable microenvironment for the expansion of lineage-committed CB hematopoietic progenitors than afforded by current liquid suspension culture systems. As accrual to the current CB expansion trials nears completion, this competitive renewal application will focus on the clinical evaluation of CB expansion in MSC co-cultures, with the long-term goal of improving neutrophil and platelet engraftment in CBT patients. Although a low cell dose is clearly the chief limitation of CBT, a number of investigators have also reported a deficit in the homing of CB cells to the marrow. Thus, it is conceivable that even with optimal ex vivo expansion, inadequate homing may limit the rapidity of engraftment which is the goal of this proposal. The homing defect has been attributed to low levels of fucosylation of cell surface molecules responsible for binding to P- and/or E-selectins expressed by the marrow microvasculature. This interaction is a key component of the recruitment of hematopoietic progenitors to the marrow. We hypothesize that increasing the level of CB cell surface fucosylation will improve interactions with selectins, thereby improving homing and engraftment. Aim 3 will evaluate the modification of unmanipulated and expanded CB progenitor cells with a fucosyltransferase, as a means to facilitate their recruitment to the marrow. PUBLIC HEALTH RELEVANCE: Umbilical cord blood is being used increasingly for many patients with high-risk hematological malignancies and genetic disorders who do not have a bone marrow donor, but is associated with a longer time to engraftment compared to marrow. The expansion of cord blood in the laboratory prior to infusion appears to shorten time to engraftment; additionally the treatment of the cord blood with a sugar molecule prior to infusion appears to improve its ability to home to the bone marrow quickly. Both these strategies will be explored in the grant thereby making the transplant safer for patients in terms of infectious and bleeding complications and will thus improve survival.

描述（由申请人提供）：脐带血（CB）越来越多地用于恢复缺乏兄弟姐妹或无关供体的移植患者中的造血。 CB移植（CBT）的主要缺点是低细胞剂量，导致嗜中性粒细胞和血小板植入的延迟，以及高植入失败率。这项赠款的一个主要假设是，与无操纵的CB相比，过体扩展的CB祖细胞将提供更快的造血重建和植入失败。在最后一个RO1融资期间进行的两项临床CB扩张试验中，在靶向承诺或更原始的造血祖细胞的液体培养系统中分离了CD133+祖细胞，并在体内进行了培养。在那些顺序的试验中，看到了更快的植入时间的趋势，但CD34+祖细胞的显着损失发生了明显的损失。为了避免需要阳性选择，这会导致CD34+细胞的大量损失，我们开发了一种涉及CB单核细胞（MNC）与骨髓衍生的间充质干细胞（MSC）的离体共文化（MNC）。我们假设MSC通过充当替代造型造血的“利基”，将提供比当前液体悬浮培养系统所提供的谱系CB造血祖细胞的扩展更合适的微环境。由于当前的CB扩展试验即将完成，因此该竞争性更新应用将集中在MSC共培养中CB扩张的临床评估上，其长期目标是改善CBT患者中性粒细胞和血小板植入。尽管低细胞剂量显然是CBT的主要局限性，但许多研究者还报告了CB细胞向骨髓寄养的不足。因此，可以想象的是，即使有最佳的离体扩张，归巢不足也可能限制植入的速度，这是该提议的目标。归因缺陷归因于导致骨髓微脉管系统表达的P-和/或E-选择素的细胞表面分子的岩藻糖基化水平较低。这种相互作用是将造血祖细胞募集到骨髓中的关键组成部分。我们假设增加CB细胞表面构造水平将改善与选择素的相互作用，从而改善归巢和植入。 AIM 3将评估使用岩藻糖基转移酶的未操纵和扩展的CB祖细胞的修饰，以促进其募集到骨髓中。 公共卫生相关性：许多没有骨髓供体的高危血液恶性肿瘤和遗传疾病的患者越来越多地使用脐带血，与骨髓相比，植入术的时间更长。在输注之前，实验室中脐带血的扩张似乎缩短了植入的时间。另外，在输注之前，用糖分子对脐带血进行处理似乎可以提高其迅速回家的能力。这两种策略都将在赠款中探索，从而使患者在传染性和出血并发症方面更安全，从而提高生存率。