Endothelial Progenitor Cell Transplant to Accelerate Hematopoietic Recovery

描述(由申请人提供)：该项目广泛的、长期的目标是确定内皮祖细胞(EPC)移植是否可以加速体内的造血恢复。在恶性血液病的治疗中，剂量高强度的放射治疗和化疗通常会由于骨髓抑制而导致长期的细胞减少。在成人脐带血移植(CBT)中，供者细胞植入延迟会导致严重而持久的中性粒细胞减少、血小板减少和免疫抑制，从而增加死亡风险。由于大多数移植预适应方案包括在接受或不接受放射治疗的同时进行清髓化疗，我们推测CBT后造血恢复延迟的一个促成因素是骨髓微环境(内皮细胞、基质细胞)的损伤。由于造血干细胞和造血祖细胞依赖于骨髓壁龛提供再生和增殖信号，我们试图确定旨在取代骨髓壁龛功能的治疗是否可以在脐带血移植的背景下转化为更快的血液学恢复。越来越多的证据表明，在体外和体内，骨髓血管内皮细胞为造血干/祖细胞提供增殖和分化信号。因此，我们假设靶向替代血管内皮细胞活性可以加速体内的造血恢复。为了在高度临床相关的模型中验证这一假说，我们提出了以下具体目标：1)确定原代胎儿血内皮祖细胞移植是否可以促进胎血移植小鼠模型的造血恢复；2)确定人脐血内皮祖细胞移植是否可以增强免疫缺陷小鼠的人脐血干细胞的归巢和植入。我们的初步结果表明，无论是在自体还是在异体环境中，单独移植原代内皮祖细胞都能显著加速受照射小鼠的内源性造血恢复。这一建议提供了一种新的、潜在的有效策略来加速CB移植受者的血液学恢复，更广泛地说，为替代内皮细胞活性以促进髓毒性化疗或放射治疗后的血液学恢复提供了基础。公共卫生相关性许多白血病和淋巴瘤患者在接受大剂量化疗和放射治疗时，他们的血液和免疫系统将长期受到抑制，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常见于接受脐带血移植治疗其疾病的成年患者。我们认为，旨在取代骨髓中血管内皮细胞活性的细胞治疗将加速这些患者的血液和免疫系统的恢复，我们的初步结果表明这一策略是非常有效的。

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.