2018 Fiscal Year Annual Research 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 | stem cells / mesenchymal stem cells / fibrinolytic factors |
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| Outline of Annual Research Achievements |
Our results were published in the journal Blood by Dhahri et al. in 2016*
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. Here, we observed 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.
Another study was published by Salama et al. FASEB 2019*
The multifunctional endocytic receptor low-density lipoprotein receptor-related protein (LRP)1 has recently been identified as a hub within a biomarker network for multicancer clinical outcome prediction. Gain-of-function experiments revealed that melanoma LRP1 is critical for tumor growth, recruitment of mesenchymal stem cells into the tumor bed, and metastasis. Our results identify the tPA-LRP1 pathway as a key switch that drives melanoma progression, in part by modulating the cellular composition and proteolytic makeup of the tumor niche.
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