Establishment of a novel in vivo model of human leukemia

新型人白血病体内模型的建立

基本信息

批准号：
17500290
负责人：
YAHATA Takashi
金额：
$ 2.3万
依托单位：
Tokai University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17500290/
关键词：
Human Hematopoietic Stem Cell Leukemia Humanized mouse Clonal Analysis Hematopoietic Microenvironment Self-renewal ability Mesenchymal Stem Cell モデル動物骨髄内移植法 LAM-PCR法

项目摘要

It has been demonstrated that leukemic stem cells have extensive self-renewal potential and their hierarchical organization of stem cell pool was notably similar to the normal hematopoietic stem cell (HSC) compartment. These findings propose the idea that some forms of leukemia imitate a system of the normal long-term HSC and retain or acquire the extensive self-renewal capacity. However, the precise characteristics regarding the multipotency of human HSC remains elusive. To elucidate the multipotency of human HSCs, CD34^+CD38^- cells were infected with lentivirus vector and transplanted into immunodeficient mice. We analyzed the multilineage differentiation and self-renewal abilities of individual thymus-repopulating clones in primary recipients, and their descending clones paired secondary recipients, by tracing lentivirus gene integration sites in each lymphomyeloid progeny using a linear amplification-mediated PCR strategy. Our clonal analysis revealed that a single human thymus-re … More populating cell had the ability to produce lymphoid and myeloid lineage cells in primary recipient and each secondary recipient, indicating that individual human HSCs expand clonally by self-renewal division. Furthermore, we found that the proportion of HSC clones present in the CD34^+ cell population decreased as HSCs replicated during extensive repopulation and also as the differentiation capacity of the HSC clones became limited. This indicates the restriction of the ability of individual HSCs despite the expansion of total HSC population. We also demonstrated that the extensive self-renewal potential was confined in the relatively small proportion of HSC clones. We conclude that our clonal tracking studies clearly demonstrated that heterogeneity in the self-renewal capacity of HSC clones underlies the differences in clonal longevity in the CD34^+ stem cell pool. The clonal analysis for properties of long-term HSCs in vivo would be a powerful tool to understand the mechanisms for tumor initiation, progression and relapses, and lead to efficient utilization of HSCs in clinical transplantation medicine. Less

已经证明，白血病干细胞具有广泛的自我更新潜力，与正常的造血干细胞（HSC）相似的LY结构组织。 f人类HSC的广泛更新能力仍然难以捉摸。他们的下降克隆使用线性扩增的PCR策略配对二级受体，我们的克隆分析是一个人的胸腺。次级接受者，表明单个HSC通过自我更新分裂在克隆中扩展，我们发现CD34^+细胞种群中HSC克隆的建议随着HSC在广泛的tion中的复制而降低，并且随着HSC克隆的扩散性也受到限制。 HSC总体的扩展。 - 体内的HSC会使肿瘤起步，进展和复发，并导致HSC在临床移植医学中的效率