2017 Fiscal Year Research-status Report
Fibrinolytic factors control MSC expansion thereby enhancing hematopoiesis
| Project/Area Number |
16K09821
|
|---|
| Research Institution | The University of Tokyo |
|---|
Principal Investigator |
Heissig Beate 東京大学, 医科学研究所, 准教授 (30372931)
|
|---|
| Project Period (FY) |
2016-04-01 – 2019-03-31
|
| Keywords | hematopoiesis |
|---|
| Outline of Annual Research Achievements |
Tissue plasminogen activator (tPA), aside from its vascular fibrinolytic action, exerts various effects within the body, ranging from synaptic plasticity to control of cell fate.
The purpose of this study was to investigate the mechansim of action of fibrinolytic factors on bone marrow(BM) mesenchymal(MSC) proliferation and their capactiy to support hematopoiesis. This year we were able to showed that by activating plasminogen and matrix metalloprotenase-9, tPA expands murine bone marrow-derived CD45(-)TER119(-)Sca-1(+)PDGFRα(+) mesenchymalstromal cells (PαS-MSCs) in vivo through a crosstalk between PαS-MSCs and endothelial cells. Mechanistically, tPA induces the release of Kit ligand from PαS-MSCs, which activates c-kit(+) endothelial cells to secrete MSC growth factors: platelet-derived growth factor-BB(PDGF-BB) and fibroblast growth factor 2(FGF2). In synergy, FGF2 and PDGF-BB upregulate PDGFRα expression in PαS-MSCs, which ultimately leads to PαS-MSCs expansion. These data show a novel mechanism by which the fibrinolytic system expands PαS-MSCs through a cytokine crosstalk between niche cells.
These results were published: Dahri et al. Blood Blood 2016 128:1063-1075.
The remaining year, we are studying in more detail how this mechanism might influence other cell type in the BM microenvironment.
|
| Current Status of Research Progress |
Current Status of Research Progress
2: Research has progressed on the whole more than it was originally planned.
Reason
We were able to already published some of the data in Blood 2016, and Eiamboonsert ed al. BBCR 2017.
Reagents are all available. Research models are in place.
Therefore we are smoothly proceeding our research to achieve our goal on understanding how fibrinolytic factors regulate the bone marrow microenvironment.
|
| Strategy for Future Research Activity |
We are contining to study the role of fibrinolytic factors now in another cell type of the bone marrow microenvironment : endothelial cells. this cell type is know to respond to tissue type plasminogen activator treatment in other organs. But until now, nobody addressed the question how tPA regulates the BM endothelial cell maintenance or cell proliferation.
We are studying this currently in the lab.
|
| Causes of Carryover |
（理由）
平成29年度の予算を翌年度の研究に使用するべく約17万円を残す結果となった。
（使用計画）
残った金額は引き続き平成30年度に使用する。
|
-
-
-
[Journal Article] Pharmacological targeting of plasmin prevents lethality and tissue damage in a murine model of macrophage activation syndrome.2017
Author(s)
Shimazu H, Munakata S, Tashiro Y, Salama Y, Eiamboonsert S, Ota Y, Onoda H, Tsuda Y, Okada Y, Nakauchi H, Heissig B, Hattori K.
-
Journal Title
Blood
Volume: 130
Pages: 59-72
DOI
Peer Reviewed / Open Access / Int'l Joint Research
-
[Journal Article] Plasminogen activator inhibitor-1 regulates macrophage-dependent postoperative adhesion by enhancing EGF-HER1 signaling in mice.2017
Author(s)
Honjo K, Shinya Munakata S, Tashiro Y, Salama Y, Shimazu H, Eiamboonsert S, Dhahri D, Ichimura A, Dan T, Miyata T, Takeda K, Sakamoto K, Hattori K, Heissig B.
-
Journal Title
FASEB J
Volume: 31
Pages: 2625-2637
DOI
Peer Reviewed / Open Access / Int'l Joint Research
-
-
