| Project/Area Number |
16H06232
|
|---|
| Research Category |
Grant-in-Aid for Young Scientists (A)
|
| Allocation Type | Single-year Grants |
|---|
| Research Field |
Immunology
|
|---|
| Research Institution | Osaka University |
|---|
Principal Investigator |
|
|---|
| Project Period (FY) |
2016-04-01 – 2019-03-31
|
| Project Status |
Completed (Fiscal Year 2018)
|
| Budget Amount *help |
¥25,740,000 (Direct Cost: ¥19,800,000、Indirect Cost: ¥5,940,000)
Fiscal Year 2018: ¥6,110,000 (Direct Cost: ¥4,700,000、Indirect Cost: ¥1,410,000)
Fiscal Year 2017: ¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000)
Fiscal Year 2016: ¥13,260,000 (Direct Cost: ¥10,200,000、Indirect Cost: ¥3,060,000)
|
|---|
| Keywords | 造血幹細胞 / ニッチ / 間葉系幹細胞 / 骨髄 / CAR細胞 / Foxc1 / Ebf3 |
|---|
| Outline of Final Research Achievements |
The special microenvironments, termed niches, with which hematopoietic stem/progenitor cells (HSPCs) are in contact, have been thought to be required for the maintenance of HSPCs and the generation of blood cells in bone marrow. Recent findings demonstrate that CXCL12-abundant reticular (CAR) cells are the major cellular components of niches for HSPCs, which express specific transcription factor Foxc1 and cytokines, including CXCL12 and stem cell factor, essential for their niche functions.
In this study, we found that the transcription factor Ebf3 is also preferentially expressed in CAR cells and that Ebf3-expressing cells are self-renewing mesenchymal stem cells in adult marrow. When Ebf3 is deleted in CAR cells, HSC niche function is severely impaired, and bone marrow is osteosclerotic with increased bone in aged mice. Thus, HSPC cellular niches express Ebf3 that is required to create HSC niches, to inhibit their osteoblast differentiation, and to maintain spaces for HSPCs.
|
| Academic Significance and Societal Importance of the Research Achievements |
骨髄に存在するCXCL12高発現細網細胞（CAR細胞）は造血幹細胞および前駆細胞の維持に必須の微小環境（ニッチ）を構成する細胞であるが、本研究によりCAR細胞に転写因子Ebf3が特異的に高発現すること、Ebf3および近縁な遺伝子であるEbf1をCAR細胞で欠損させたマウスではCAR細胞が骨芽細胞へと分化し骨髄腔が骨で埋まってしまうことが明らかになった。
脊椎動物の造血組織はなぜ硬い骨に保護された空間（骨髄腔）に存在しているのか、またこの骨髄腔がどのようにして維持されているかという問題に対し、造血幹細胞ニッチに必須の分子機構が深く関与することが明らかとなったことは本研究成果の大きな意義である。
|
