Chemokine induced hematopoietic stem cell mobilization

造血细胞因子提高外周血中干祖细胞的水平，为接受外周血造血干细胞移植的血液和实体瘤恶性肿瘤患者定义了新的护理标准。 然而，外周血干细胞移植（PBSCT）并非没有问题，涉及功效、后勤、费用和细胞产量，特别是在一些患者群体中，以及在部分匹配的相关供体和亚致死条件处理方案设置中。造血干细胞（HSC）动员可以通过结合CXCR 2趋化因子受体的趋化因子更快速地完成并且具有改善的功效。此外，趋化因子诱导的HSC动员与造血生长因子诱导的HSC动员是协同的。 趋化因子诱导的HSC动员和与G-CSF的协同作用为自体和同种异体PBSCT提供了新的范例。 干细胞动员的机制，无论是与生长因子或趋化因子在很大程度上是未知的。 阐明导致HSC释放和迁移的直接分子和生化事件可能允许直接动员，绕过趋化因子和/或生长因子受体。 我们的假设有两个方面：首先，中性粒细胞介导CXCR 2配体诱导的HSC动员，其次，由CXCR 2配体单独或与G-CSF组合动员的HSC群体具有允许更快速血液重建的内在特性，并且可以表型地定义。 为了更全面地了解这些机制在细胞，生物化学和分子水平，我们提出了一个全面的计划，以调查的生物化学和分子事件在CXCR 2受体启动的配体Gro-β和一种新的亚型，我们已经确定，Gro-β-T，导致HSC动员，并进一步确定的性质，动员造血移植物是负责上级重建能力。 研究将集中在CXCR 2受体和细胞内信号通路，导致基质金属蛋白酶-9的产生和激活，我们已经暗示了CXCR 2趋化因子的作用的生物机制。 我们将着重于确定趋化因子诱导的HSC移植物的细胞周期状态、粘附分子表达和归巢特征，以了解其优越的上级重建潜力。 了解动员的分子机制将导致开发新的和更可预测的和有效的方案，更快和更安全的协议，可测量的改善患者的发病率和死亡率，特别是在同种异体环境中，并定义新的护理标准，为患者的自身免疫性疾病，非恶性血液病和患者接受器官移植耐受诱导。

Hematopoietic cytokines elevate levels of stem progenitor cells in peripheral blood defining a new standard of care for patients with hematological and solid tumor malignancies receiving peripheral blood hematopoietic stem cell grafts. However, peripheral blood stem cell transplantation (PBSCT) is not without issues, related to efficacy, logistics, expense and cell yield, particularly in some patient populations, and in the partially matched related donor and sublethal conditioning regimen settings. Hematopoietic stem cell (HSC) mobilization can be accomplished more rapidly and with improved efficacy by chemokines that bind the CXCR2 chemokine receptor. Moreover, chemokine-induced mobilization of HSC is synergistic with hematopoietic growth factor-induced HSC mobilization. Chemokine-induced HSC mobilization and synergy with G-CSF offer new paradigms for autologous and allogeneic PBSCT. Mechanisms responsible for stem cell mobilization either with growth factors or chemokines are largely unknown. Elucidation of the immediate molecular and biochemical events leading to release and migration of HSC may permit direct mobilization, bypassing the chemokine and/or growth factor receptors. Our hypothesis are 2-fold: First that neutrophils mediate CXCR2-ligand induced HSC mobilization, and second that the HSC population mobilized by CXCR2 ligands alone or in combination with G-CSF posses intrinsic properties that allow for more rapid hematological reconstitution and can be defined phenotypically. To more fully understand these mechanisms at the cellular, biochemical and molecular level we propose a comprehensive plan to investigate the biochemical and molecular events initiated at the CXCR2 receptor by the ligands Gro-beta and a novel isoforms that we have identified, Gro-beta-T, that lead to HSC mobilization and to further define the nature of the hematopoietic graft mobilized that is responsible for superior reconstituting capacity. Investigation will focus on the CXCR2 receptor and intracellular signaling pathways leading to production and activation of matrix metalloproteinase-9, which we have implicated in the biomechanism of action of CXCR2 chemokines. We will focus on defining the cell cycle status, adhesion molecule expression and homing characteristics of the chemokine- induced HSC graft in order to understand its superior reconstituting potential. Understanding the molecular mechanisms of mobilization will lead to the development of novel and more predictable and efficacious regimens, and faster and safer protocols, measurable in improvement in patient morbidity and mortality, particularly in the allogeneic setting, and define new standards of care for patients with autoimmune disease, non-malignant hematological diseases and patients undergoing tolerance induction for organ transplantation.