Endothelial Progenitor Cell Transplant to Accelerate Hematopoietic Recovery

描述（由申请人提供）：本项目广泛而长期的目标是确定内皮祖细胞（EPCs）移植是否可以加速体内造血功能的恢复。高剂量放疗和化疗应用于血液恶性肿瘤的治疗，通常导致延长的细胞减少，作为骨髓（BM）抑制的功能。在成人脐带血移植（CBT）中，延迟供体细胞植入可导致深度和持续性中性粒细胞减少、血小板减少和免疫抑制，从而增加死亡风险。由于大多数移植调理方案涉及骨髓清除化疗加放疗或不加放疗，我们假设导致cbt后造血恢复延迟的一个因素是骨髓生态位（内皮细胞、基质细胞）的损伤。由于造血干细胞和祖细胞依赖于骨髓生态位提供再生和增殖信号，我们试图确定旨在取代骨髓生态位功能的治疗是否可以在骨髓移植中转化为更快的血液学恢复。越来越多的证据表明，BM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，我们假设有针对性地替代血管内皮细胞活性可以加速体内造血功能的恢复。为了在一个与临床高度相关的模型中验证这一假设，我们提出以下具体目的：1)确定原代胎血EPCs移植是否能增强小鼠胎血移植模型中的造血功能恢复；2)确定人CB EPCs移植是否能增强免疫缺陷小鼠中人CB干细胞的归巢和植入。我们的初步结果表明，在自体和异体环境下，单独移植原代EPCs可显著加速辐照小鼠的内源性造血恢复。该建议提供了一种新的和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的治疗提供了基础，以增强髓毒性化疗或放疗后的血液学恢复。许多白血病和淋巴瘤患者在接受高剂量化疗和放疗治疗时，其血液和免疫系统会受到长期抑制，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常发生在接受脐带血移植治疗的成年患者身上。我们提出，细胞疗法旨在取代骨髓血管内皮细胞的活性，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，这种策略是非常有效的。

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.