2016 Fiscal Year Research-status Report
Fibrinolytic factors control MSC expansion thereby enhancing hematopoiesis
| Project/Area Number |
16K09821
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| Research Institution | The University of Tokyo |
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Principal Investigator |
Heissig Beate 東京大学, 医科学研究所, 准教授 (30372931)
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| Project Period (FY) |
2016-04-01 – 2019-03-31
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| Keywords | hematopoiesis |
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| 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. Htis year we were able to showed that by activating plasminogen and matrix metalloproteinase-9, tPA expands murine bone marrow-derived CD45(-)TER119(-)Sca-1(+)PDGFRα(+) mesenchymal stromal 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-MSC 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 types in the BM microenvironment.
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| 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.
Reagents are all available. Research models are in place.
Therefore we are smoothly proceeding our reserach to achieve our goal on understanding how fibrinolytic factors regulate the bone marrow microenvironment.
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| Strategy for Future Research Activity |
We are planning to study the role of fibrinolytic factors now in another cell type of the bone marrow microenvironment: endothelial cels. 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.
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| Causes of Carryover |
平成28年度は計画通りに支出したところ、少額を残す結果になった。
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| Expenditure Plan for Carryover Budget |
残った金額は引き続き平成29年度に使用する。
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[Journal Article] Pharmacological targeting of plasmin prevents lethality and tissue damage in a murine model of macrophage activation syndrome2017
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
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Journal Title
DOI
Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
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[Journal Article] Plasminogen activator inhibitor-1 regulates macrophage-dependent postoperative adhesion by enhancing EGF-HER1 signaling in mice2017
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
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Journal Title
FASEB J
Volume: －
Pages: －
DOI
Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
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[Journal Article] Fibrinolytic crosstalk with endothelial cells expands murine mesenchymal stromal cells2016
Author(s)
Dhahri D, Sato-Kusubata K, Ohki-Koizumi M, Nishida C, Tashiro Y, Munakata S, Shimazu H, Salama Y, Eiamboonsert S, Nakauchi H, Hattori K and Heissig B
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Journal Title
Blood
Volume: 128
Pages: 1063-75
Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
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