| Project/Area Number |
16390273
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (B)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
Hematology
|
|---|
| Research Institution | Chiba University (2005)
The University of Tokyo (2004) |
|---|
Principal Investigator |
IWAMA Atsushi Chiba University, Graduate School Medicine, Professor, 大学院・医学研究院, 教授 (70244126)
|
|---|
| Project Period (FY) |
2004 – 2005
|
| Project Status |
Completed (Fiscal Year 2005)
|
| Budget Amount *help |
¥14,300,000 (Direct Cost: ¥14,300,000)
Fiscal Year 2005: ¥6,900,000 (Direct Cost: ¥6,900,000)
Fiscal Year 2004: ¥7,400,000 (Direct Cost: ¥7,400,000)
|
|---|
| Keywords | hematopoietic stem cell / self-renewal / polycomb group gene / Bmi1 / Bmi-1 / M33 / Mph-1 / Rae-28 / Mel-18 |
|---|
| Research Abstract |
The Polycomb group (PcG) gene Bmi-1 has recently been implicated in the maintenance of hematopoietic stem cells (HSC) from the loss-of-function analysis. We demonstrate that increased expression of Bmi-1 promotes HSC self-renewal. Forced expression of Bmi-1 enhanced symmetrical cell division of HSCs and mediated a higher probability of inheritance of stemness through cell division. Correspondingly, forced expression of Bmi-1 but not the other PcG genes led to a striking ex vivo expansion of multipotential progenitors and marked augmentation of HSC repopulating capacity in vivo. Loss-of-function analyses revealed that among PcG genes, absence of Bmi-1 is preferentially linked with a profound defect in HSC self-renewal. These findings define Bmi-1 as a central player in HSC self-renewal and demonstrate that Bmi-1 is a novel target for therapeutic manipulation of HSCs. On the other hand, derepression of the Ink4a/Arf locus has been largely attributed to Bmi-1-deficient phenotypes in the nervous system. However, its role in hematopoietic stem cell (HSC) self-renewal remained undetermined. We show that derepressed p16^<Ink4a> and p19^<Arf> in Bmi-1-deficient mice were tightly associated with the premature senescence of HSCs and a drastic reduction in the osteoblastic niche size. Deletion of both Ink4a and Arf genes substantially restored the self-renewal capacity of Bmi-1^<-/-> HSCs as well as the osteoblastic niche size, but not the ability of the Bmi-1^<-/-> niche to maintain HSCs, leading to a sustained post-natal HSC depletion in Bmi-1^<-/->Ink4a-Arf^<-/-> mice. Our findings define Bmi-1 as a critical failsafe against the p16^<Ink4a> and p19^<Arf>-dependent cellular senescence of HSCs, and unveil a novel role of Bmi-1 in the organization of a functional HSC niche. Taken together, Bmi-1 regulates self-renewing HSC in both cell-autonomous and non-autonomous manners.
|
