DIRECTED STEM CELL HEMATOPOIESIS AND DIFFERENTIATION

定向干细胞造血和分化

• 批准号: 8168497
• 负责人: GERALD ALEXANDER COLVIN
• 金额: $ 28.21万
• 依托单位: RHODE ISLAND HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8168497
• 关键词: Activities of Daily Living; Blood Cells; Bone Marrow Transplantation; Cell Cycle; Cell division; Cell physiology; Cells; Clinical; Computer Retrieval of Information on Scientific Projects Database; Data; Funding; Germ Cells; Grant; Hematopoiesis; Hematopoietic; Hematopoietic stem cells; Human; In Vitro; Institution; Lead; Marrow; Megakaryocytes; Modeling; Mus; Nature; Outcome; Pattern; Phenotype; Population; Positioning Attribute; Process; Research; Research Personnel; Resources; Rhodamine; Rhodamines; Signal Transduction; Source; Stem cells; Stimulus; Time; Translations; Transplantation; United States National Institutes of Health; Variant; Work; bioprocess; cytokine; granulocyte; interest; pre-clinical; prevent; progenitor; research study; response; stem; stem cell differentiation

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The process of blood cell formation (hematopoiesis) has been extensively studied yet many basic mechanisms continue to be unclear. Dogma states that hematopoietic differentiation is generally stochastic in nature. In vitro stem cell studies indicate that stem cells have some ability toward directed cellular differentiation with use of specific cytokine cocktails, but lack of formation of adequate numbers of lineage specific cells currently prevents translation into the clinical realm. Prior work on cell cycle related hematopoietic stem cell (HSC) function has indicated that HSC are in a continuum, with constant reversible phenotypic variation through cycle. We have found that cell cycle position is an independent variable of the stem cell on the outcome of response to an identical stimulus. Examples of stimuli are bone marrow transplantation, progenitor expansion, and differentiation. We have found reproducible changes in the context of cell cycle position of the stem cell at the time of applying a stimulus. We have primarily studied this though initial cell cycle transit from a quiescent G0-1 state but have more recently looked at these stem cells after initial cell division and have found that this phenomenon continues to be tied to cell cycle position in a reproducible pattern. These data suggest that the functional phenotype of early marrow stem cells shifts as it traverses cell cycle. We have explored the functional ability of HSC differentiation through cell cycle, which is a reflection of time in culture and have found that there are points where differentiation toward specific lineage(s) occurs. We have found that an initial cytokine inductive signal prior to initial cell division influences the content of the cell population two weeks later. We believe that HSC have changing sensitivity to specific microenvironmental influences through cycle and this directly impacts on the HSC's progeny. We have performed experiments using purified stem/progenitors [lineage negative, rhodamine low, Hoescht low cells] and showed highly directed lineage differentiation into megakaryocytes or granulocytes at specific positions in cell cycle. The objectives of this grant are to define cell cycle related directed lineage differentiation in preclinical murine transplant models and to study human stem/progenitor cells for directed differentiation opportunities. These studies promise to further define the basic nature of the hematopoietic marrow stem cells and could lead to interesting preclinical cellular bioprocessing models for selective lineage support of various myeloablative therapy approaches or progenitor deficient states.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 血细胞形成（造血）的过程已被广泛研究，但许多基本机制仍不清楚。Dogma认为造血分化本质上通常是随机的。体外干细胞研究表明，通过使用特定的细胞因子混合物，干细胞具有一定的定向细胞分化能力，但目前缺乏足够数量的谱系特异性细胞的形成，阻碍了其转化为临床领域。细胞周期相关的造血干细胞（HSC）功能的先前工作表明，HSC是在一个连续的，通过周期恒定可逆的表型变异。我们已经发现，细胞周期位置是干细胞对相同刺激的反应结果的独立变量。刺激的例子包括骨髓移植、祖细胞扩增和分化。我们已经发现在施加刺激时干细胞的细胞周期位置的背景下的可再现的变化。我们主要研究了从静止的G 0 -1状态的初始细胞周期转换，但最近在初始细胞分裂后观察了这些干细胞，并发现这种现象继续与细胞周期位置以可再现的模式联系在一起。这些数据表明，早期骨髓干细胞的功能表型转移，因为它穿越细胞周期。 我们已经探索了HSC通过细胞周期分化的功能能力，这是培养中时间的反映，并且已经发现存在发生向特定谱系分化的点。 我们已经发现，在初始细胞分裂之前的初始细胞因子诱导信号影响两周后细胞群的含量。我们认为，HSC通过循环对特定微环境影响的敏感性发生变化，这直接影响HSC的后代。 我们已经使用纯化的干/祖细胞[谱系阴性、罗丹明低、Hoescht低细胞]进行了实验，并显示在细胞周期的特定位置高度定向谱系分化为巨核细胞或粒细胞。这项资助的目的是在临床前小鼠移植模型中确定细胞周期相关的定向谱系分化，并研究人类干/祖细胞的定向分化机会。这些研究有望进一步确定造血骨髓干细胞的基本性质，并可能导致有趣的临床前细胞生物处理模型，用于各种清髓性治疗方法或祖细胞缺陷状态的选择性谱系支持。