| Project/Area Number |
11470206
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (B)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
Hematology
|
|---|
| Research Institution | Tokyo Metropolitan Organization For Medical Research, The Tokyo Metropolitan Institute of Medical Science |
|---|
Principal Investigator |
HARA Takahiko Tokyo Metropolitan Organization For Medical Research, The Tokyo Metropolitan Institute of Medical Science, Department of Tumor Biochemistry, Head, 東京都臨床医学総合研究所, 副参事研究員 (80280949)
|
|---|
| Project Period (FY) |
1999 – 2001
|
| Project Status |
Completed (Fiscal Year 2001)
|
| Budget Amount *help |
¥13,500,000 (Direct Cost: ¥13,500,000)
Fiscal Year 2001: ¥4,000,000 (Direct Cost: ¥4,000,000)
Fiscal Year 2000: ¥4,000,000 (Direct Cost: ¥4,000,000)
Fiscal Year 1999: ¥5,500,000 (Direct Cost: ¥5,500,000)
|
|---|
| Keywords | AGM region / hemangioblast / PCLP1 / AML1 / c-myb / hematopoietic stem cells / endothelial cells / stem cell plasticity / Runix-1 |
|---|
| Research Abstract |
Hematopoietic stem cells are known to be derived from hemangioblasts, common precursor cells for blood and endothelial cells. We have identified podocalyxin-like protein 1 (PCLP1) as a novel hemangioblast marker. PCLP1+CD45-cells in the AGM region are differentiated to hematopoietic cells and endothelial cells in vitro. When these cells were transplanted into busulfan-treated neonatal mice, they gave rise to hematopoietic stem cells (HSCs) as well as endothelial cells, smooth muscle cells, and stromal cells in lung, small intestine, and uterus. By retrovirus marking of stem cells in the AGM region, we proved that blood cells and vascular cells in small intestine are derived from single stem cells. Similar in vivo differentiation capacity was detected in the bone marrow CD45-positive side population, which are highly enriched for HSCs. Therefore, it is likely that hemangioblasts in the AGM region generated HSCs that are in turn transdifferentiated to non-hematopoietic cells in vivo.
We have shown that two transcription factors, AMI-1 and c-myb, are essential for the generation of HSCs in the AGM region. To know functions of these proteins, we newly established immortalized cell lines from the AGM regions of knockout mice ofAMI-1 or c-myb genes. Then we reintroduced missing genes by taking advantage of inducible promoter. Gene expression studies revealed that mRNA for insulin-like growth factor binding protein-3 is suppressed by AML1.Further search of down stream effectors of AML-1 and c-myb would clarify the molecular mechanism of HSC development from hemangioblasts in the AGM region.
|
