Endothelial Progenitor Cell Transplant to Accelerate Hematopoietic Recovery

描述（由申请人提供）：本项目的广泛、长期目标是确定内皮祖细胞（EPCs）移植是否可以加速体内造血恢复。在恶性血液病治疗中应用的剂量高的放射和化学疗法通常导致作为骨髓（BM）抑制的函数的长期血细胞减少。在成人脐带血移植（CBT）的背景下，延迟的供体细胞植入可导致严重和持续的中性粒细胞减少症、血小板减少症和免疫抑制，导致死亡风险增加。由于大多数移植预处理方案涉及清髓性化疗联合或不联合放疗，我们假设CBT后造血恢复延迟的一个促成因素是骨髓小生境（内皮细胞，基质细胞）造成的损伤。由于造血干细胞和祖细胞依赖于BM小生境来提供再生和增殖信号，我们试图确定旨在替代BM小生境功能的疗法是否可以在CB移植的情况下转化为更快的血液学恢复。越来越多的证据表明，骨髓血管内皮细胞在体外和体内为造血干细胞和祖细胞提供增殖和分化信号。因此，我们假设靶向替换血管内皮细胞活性可以加速体内造血恢复。为了在高度临床相关的模型中检验这一假设，我们提出了以下具体目的：1）确定原代胎血EPCs的移植是否可以在胎血移植的小鼠模型中增强造血恢复，2）确定人CB EPCs的移植是否可以在免疫缺陷小鼠中增强人CB干细胞的归巢和植入。我们的初步结果表明，移植原代内皮祖细胞单独显着加速辐射小鼠在自体和异体设置的内源性造血恢复。该提议提供了一种新的和潜在的有效策略，以加速CB移植受者的血液学恢复，更广泛地说，提供了替代内皮细胞活性的疗法的基础，以增强骨髓毒性化疗或放疗后的血液学恢复。公共卫生相关性许多白血病和淋巴瘤患者在治疗过程中接受高剂量化疗和放疗，其血液和免疫系统将受到长期抑制，导致感染、出血和住院的风险增加。这种血液和免疫系统的长期抑制也通常发生在接受脐带血移植治疗其疾病的成年患者中。我们提出，旨在替代骨髓中血管内皮细胞活性的细胞疗法将加速这些患者的血液和免疫系统恢复，我们的初步结果表明这种策略非常有效。

DESCRIPTION (provided by applicant): The broad, long-term objective of this project is to determine whether transplantation of endothelial progenitor cells (EPCs) can accelerate hematopoietic recovery in vivo. Dose intense radiation and chemotherapy as applied in the treatment of hematologic malignancies commonly result in prolonged cytopenias as a function of bone marrow (BM) suppression. In the setting of cord blood transplantation (CBT) in adults, delayed donor cell engraftment can result in profound and persistent neutropenia, thrombocytopenia and immune suppression leading to increased mortality risk. Since most transplant conditioning regimens involve the administration of myeloablative chemotherapy with or without radiotherapy, we hypothesize that a contributing factor to the delay in hematopoietic recovery post-CBT is the damage incurred by the bone marrow niche (endothelial cells, stromal cells). Since hematopoietic stem and progenitor cells depend upon the BM niche to provide regenerative and proliferative signals, we sought to determine whether therapies aimed at replacing BM niche function could translate into more rapid hematologic recovery in the setting of CB transplantation. Increasing evidence suggests that BM vascular endothelial cells provide proliferative and differentiative signals to hematopoietic stem and progenitor cells in vitro and in vivo. Therefore, we hypothesize that targeted replacement of vascular endothelial cell activity can accelerate hematopoietic recovery in vivo. In order to test this hypothesis in a highly clinically relevant model, we propose the following Specific Aims: 1) Determine whether transplantation of primary fetal blood EPCs can enhance hematopoietic recovery in a murine model of fetal blood transplantation, 2) Determine whether transplantation of human CB EPCs can enhance the homing and engraftment of human CB stem cells in immune deficient mice. Our Preliminary Results indicate that transplantation of primary EPCs alone significantly accelerates endogenous hematopoietic recovery in irradiated mice in both the autologous and allogeneic setting. This proposal provides a novel and potentially potent strategy to accelerate hematologic recovery in recipients of CB transplantation and, more broadly, provides the basis for therapies to replace endothelial cell activity in order to augment hematologic recovery following myelotoxic chemo- or radiotherapy. PUBLIC HEALTH RELEVANCE Many patients with leukemia and lymphoma who undergo high dose chemotherapy and radiotherapy in the treatment of their disease will suffer prolonged suppression of their blood and immune systems, resulting in increased risk of infections, bleeding and hospitalization. Such prolonged depression of the blood and immune systems also commonly occurs in adult patients who undergo cord blood transplantation in the treatment of their disease. We propose that cellular therapy aimed at replacing the activity of vascular endothelial cells in the bone marrow will accelerate blood and immune system recovery in these patients and our preliminary results indicate this strategy is highly effective.