2005 Fiscal Year Final Research Report Summary
Regulation of hematopoietic stem cell self-renewal by a polycomb gene product Bmi1
| Project/Area Number |
16390273
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Hematology
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| Research Institution | Chiba University (2005)
The University of Tokyo (2004) |
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Principal Investigator |
IWAMA Atsushi Chiba University, Graduate School Medicine, Professor, 大学院・医学研究院, 教授 (70244126)
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| Project Period (FY) |
2004 – 2005
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| Keywords | hematopoietic stem cell / self-renewal / polycomb group gene / Bmi1 |
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| 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.
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Research Products
(34 results)
