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捐赠者的移植患者的造血功能。 CB移植（CBT）的一个主要缺点是细胞剂量低，导致中性粒细胞和血小板植入延迟，以及植入失败率高。这项资助的一个主要假设是，离体扩增的 CB 祖细胞将比未操作的 CB 提供更快的造血重建和更少的植入失败。在最后一个 RO1 资助期间进行的两项临床 CB 扩展试验中，在针对定向或更原始造血祖细胞的液体培养系统中分离并离体培养 CD133+ 祖细胞。在这些连续试验中，发现了植入时间加快的趋势，但 CD34+ 祖细胞发生了显着损失。为了避免正选的需要，这会导致 CD34+ 细胞大量损失，我们开发了一种替代方法，涉及 CB 单核细胞 (MNC) 与骨髓源性间充质干细胞 (MSC) 的离体共培养。我们假设 MSC 作为替代造血“生态位”，将为谱系定型 CB 造血祖细胞的扩增提供比当前液体悬浮培养系统更合适的微环境。随着当前 CB 扩增试验的进展接近完成，这项竞争性更新申请将重点关注 MSC 共培养物中 CB 扩增的临床评估，长期目标是改善 CBT 患者的中性粒细胞和血小板植入。尽管低细胞剂量显然是 CBT 的主要限制，但许多研究人员也报告了 CB 细胞归巢到骨髓方面的缺陷。因此，可以想象，即使具有最佳的离体扩增，归巢不足也可能会限制植入的速度，而这正是本提案的目标。归巢缺陷归因于负责与骨髓微脉管系统表达的 P-和/或 E-选择素结合的细胞表面分子的岩藻糖基化水平低。这种相互作用是造血祖细胞募集到骨髓的关键组成部分。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，从而改善归巢和植入。目标 3 将评估用岩藻糖基转移酶修饰未操作和扩增的 CB 祖细胞，作为促进其招募到骨髓的一种手段。 公共卫生相关性：脐带血越来越多地用于许多患有高危血液恶性肿瘤和遗传性疾病的患者，这些患者没有骨髓捐赠者，但与骨髓相比，脐带血的植入时间更长。输注前在实验室中对脐带血进行扩增似乎可以缩短植入时间；此外，在输注前用糖分子处理脐带血似乎可以提高其快速归巢到骨髓的能力。这两种策略都将在拨款中进行探索，从而使移植对于患者来说在感染和出血并发症方面更安全，从而提高生存率。