| Project/Area Number |
17500290
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Laboratory animal science
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| Research Institution | Tokai University |
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Principal Investigator |
YAHATA Takashi Tokai University, School of Medicine, Assistant Researcher, 医学部, 教授 (10398753)
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| Co-Investigator(Kenkyū-buntansha) |
ANDO Kiyoshi Tokai University, School of Medicine, Professor, 医学部, 教授 (70176014)
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| Project Period (FY) |
2005 – 2006
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| Project Status |
Completed (Fiscal Year 2006)
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| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2006: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 2005: ¥2,600,000 (Direct Cost: ¥2,600,000)
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| Keywords | 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 |
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| Research Abstract |
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
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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
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